Multiple Sclerosis Resource Centre
  • Home
  • MSRC Grand Opening 30/05/12
  • About MS
  • MSRC Services
  • Get Involved
  • MS Research News
  • MSRC Groups
  • Useful Resources
  • Welcome To Josephs Court, MS Centre Of Excellence
  • Advertising
  • Best Bet Diet Group
  • E-Newsletter
  • Contact Us
  • Investor in People
    You are here : Home » MS Research News » New Discoveries » Antibodies, B Cells,T-Cell Activation and Immune R

    Antibodies, B Cells,T-Cell Activation, Immune Response

    A A A
    [Print this page]

    Share |

    Scientists pinpoint antibody that may be specific to MS patients‬

    AntibodiesResearchers have identified an antibody found in the blood of about half of patients with multiple sclerosis that is not found in people without the autoimmune disease.

    The implications of the antibody's presence aren't fully understood. But in rodents, the antibody binds to and damages brain cells that are known to be important to neurological function, according to the study.

    Although the research is preliminary, experts say the findings may open the door for a blood test that could more easily diagnosis multiple sclerosis (MS) patients. The results also suggest a new target for MS treatments that would prevent the antibody from binding to brain cells.

    "We have known for a long time that antibodies were involved in the destruction of nervous system tissue in MS, but we have not had a good handle on what the target was for these antibodies," said Timothy Coetzee, chief research officer for the National Multiple Sclerosis Society, who was not involved in the study. "What this research has identified is what might be a potential trigger or target in MS."

    The study is published in the July 12 issue of the New England Journal of Medicine.

    In multiple sclerosis, the body's own immune system attacks myelin, the substance that insulates nerve fibers of the central nervous system. The damage disrupts nerve signals traveling to and from the brain, which can lead to symptoms such as numbness, movement difficulties, blurred vision, fatigue and eventually cognitive problems.

    What isn't known, however, is precisely which components of the immune system go awry, which cell proteins the immune system specifically targets and to what extent this varies from patient to patient.

    In this study, researchers screened the blood serum of two sets of patients with MS and compared it to the serum of people without MS. About 47 percent of the nearly 400 people with MS had high levels of KIR4.1 antibodies, while none of the non-MS control participants did.

    In addition, only three of the nearly 330 people with other neurological diseases had high levels of KIR4.1, indicating that the antibody researchers are homing in on is specific to MS and not more general neurological problems.

    Researchers then injected KIR4.1 antibodies into the brains of rodents and found the antibody damaged the brain tissue and altered immune response in the region. It should be noted, however, that results found in animals often do not translate to humans.

    "If this is truly the target of the immune response, this could pave the way to other therapies for MS," said senior study author Dr. Bernhard Hemmer, professor of neurology at Technische Universitat in Munich.

    Dr. Emmanuelle Waubant, professor of neurology at the University of California, San Francisco, and director of the UCSF Multiple Sclerosis Center, called the results exciting yet preliminary.

    Prior research has found "lots of changes in the immune response that we think relates to the disease," she said. But pinpointing specific antibodies has been difficult, with some studies showing relevance but others failing to repeat the finding.

    "In this case, researchers had a large number of participants," she said. "Nearly half of them had the antibody, and the protein in the brain identified as a target for this antibody is known to be important for nerve functioning."

    "The antibodies are like Velcro. They bind to proteins or antigens in different tissues," she added. "Many antibodies don't bind in the brain, so they are unlikely to have relevance in MS. But this antibody did."

    Still, Hemmer said, not everyone with MS had high levels of KIR4.1 antibodies, meaning there are almost certainly other aspects of the immune system involved.

    And MS can vary significantly from person to person. Future research should seek to determine if MS patients with the antibodies fare better or more poorly than others, Coetzee said, as well as what other antibodies and elements of the immune system might be involved.

    Source: HealthDay Copyright © 2012 HealthDay.(12/07/12)

    Breakthrough in understanding human immune response has potential for the development of new drug therapies

    T CellsA team of researchers at Trinity College Dublin’s School of Medicine has gained new insights into a protein in the human immune system that plays a key role in the protective response to infection and inflammation. The research findings have just been published in the internationally renowned peer-reviewed Journal of Biological Chemistry.

    The TCD researchers investigated whether signalling via a protein known as the ‘LFA-1 integrin’ influences gene expression in immune cells called ‘T-cells’. In doing so, they discovered what is called “ a genetic signature”, that is a group of genes responding to the signal that make T-cells fail to respond to a controlling molecule called transforming growth factor-β (TGF-β).

    “This is a bit like removing the handbrake and setting the immune system into action,” says Professor of Medicine, Dermot Kelleher who led the research.

    The research may also have implications for treating inflammatory diseases where drugs targeting LFA-1 have had unacceptable and serious side effects such as progressive multi-focal leukoencephalopathy (PML) in the brain. “If we more fully understand the signalling mechanism leading to downstream gene regulation by LFA-1, we may be able to devise selective therapies to better treat various autoimmune diseases without major side effects such as PML,” according to Professor Kelleher.

    Scientists have known for decades that LFA-1 is responsible for the majority of T-cell migratory behaviours associated with the immune response. Central to the success of immune responses that restrain inflammation are regulatory molecules, including a multifunctional cytokine TGF-β, which is essential for the development and function of an immune cell type, called the regulatory T-cells.

    In the current study, Trinity College Dublin scientists conducted a genome wide analysis and detected that the expression of several genes were altered when T-cells were triggered to migrate to a site of inflammation through the interaction of LFA-1 with another protein called ICAM-1. This research was performed in collaboration with the Immunology Research Group at the National Children’s Research Centre at Our Lady’s Children’s Hospital, Crumlin led by SFI Stokes Professor of Translational Immunology, Padraic Fallon.

    “There is still much to learn about the genetic changes induced by the LFA-1 signal, but our studies are the first to show that a regulatory T-cells associated signal is influenced,” says TCD research fellow in clinical medicine, Dr. Navin Kumar Verma, a lead author on the study. “The findings are novel and significantly contribute to the understanding of how the organism mounts an immune response. Several other genes identified here offer a general framework for future research in order to identify excellent targets for novel therapies for immune-mediated human diseases such as rheumatoid arthritis or inflammatory bowel disease.”

    More information: The full citation of the paper is: Verma NK, Dempsey E, Long A, Davies A, Barry SP, Fallon PG, Volkov Y, and Kelleher D (2012) Leukocyte function-associated antigen-1/intercellular adhesion molecule-1 interaction induces a novel genetic signature resulting in T-cells refractory to transforming growth factor-β signalling. Journal of Biological Chemistry.

    Source: Medical Xpress © Medical Xpress 2011-2012 (09/07/12)

    Study could lead to new treatments for reversing symptoms of MS

    T CellsA novel study at Queen's University Belfast which could eventually lead to new treatments for Multiple Sclerosis (MS) has been awarded £425K by the Biotechnology and Biological Sciences Research Council (BBSRC).

    Currently some 100,000 people in the United Kingdom have MS which affects the ability of nerve cells in the brain, spinal cord and eye, to communicate with each other effectively.

    The new study, based in Queen's Centre for Infection and Immunity, will investigate how parts of the immune system can help repair the damage caused by MS attacks.

    The project is being led by Dr Denise Fitzgerald, who herself experienced a condition similar to MS, called Transverse Myelitis when she was 21. As a result of inflammation in her spinal cord, she was paralysed in less than two hours.

    Dr Fitzgerald had to learn to walk again as the damage in her spinal cord repaired itself over the following months and years. It is this natural repair process that often becomes inefficient in MS, a chronic life-long condition, and this failure of repair can lead to permanent disability. Boosting this natural repair process in the brain and spinal cord is the next frontier in treating MS, as currently there are no drugs that are proven to do so.

    Speaking about the importance of the new study, Dr Fitzgerald said: "The central goal of our research is to identify new strategies to treat MS and other inflammatory and demyelinating disorders.

    "Nerve cells communicate by sending signals along nerve fibres which are contained within a fatty, insulating, protective substance, known as Myelin. In MS, Myelin is attacked and damaged (demyelination) which can lead to either faulty signalling by nerves, or death of the nerve cells. As a result, patients experience loss of nerve function in the area of the brain/spinal cord that has been damaged. This research project centres around understanding Myelination, a process of insulating the nerve fibres with Myelin, and Remyelination, a natural regenerative process that replaces damaged Myelin.

    "We already know that the immune system is implicated as a potential culprit in MS, as the damage is thought to be caused by inflammation in the central nervous system (CNS; brain, spinal cord and optic nerve). But in recent years we have learned a great deal about how the immune system also supports tissue repair in the CNS.

    "In particular, there is a group of immune cells called T cells which have recently been shown to support remyelination. There are different subsets of T cells, however, and little is still known about which subsets are beneficial in this process. In our study we aim to discover if these different T cell subsets influence remyelination of the CNS, and if ageing of the T cells impairs remyelination in older individuals.

    "The outcomes of this study will include new knowledge of how the immune system, and T cells in particular, influence remyelination in the Central Nervous System. We will also learn a great deal about how ageing affects the ability of T cells to help tissue repair.

    "Given the profound neurological impairments that can accompany ageing, and our growing aged population, is it imperative that we understand how normal CNS repair can become impaired with age.

    "By understanding this process of CNS repair in detail. we will also gain an insight into other inflammatory and demyelinating disorders."

    Source: Phys Org © Phys.Org™ 2003-2012 (31/05/12)

    The balancing act between protection and inflammation in MS

    T CellsScientists have discovered a molecular mechanism that could help explain how multiple sclerosis (MS) and other autoimmune diseases can be exacerbated by the onset of an infection.

    MS is an autoimmune disease of the central nervous system which affects approximately 100,000 people in the UK.

    The research, directed by Dr Bruno Gran at The University of Nottingham, focused on a population of cells of the immune system known as regulatory T cells, which control and regulate the behaviour of other immune cells. The results of this study have been published in the Journal of Immunology.

    Dr Bruno Gran, from the School of Clinical Sciences, said: "The connection between infections and MS is complex. We have known for many years that in some cases, infections can promote disease exacerbations (also known as "MS relapses"). Our study sheds light on a new mechanism that could explain how infections can trigger such relapses. This might have relevance to other autoimmune diseases as well"

    When the immune system is functioning properly Regulatory T cells — also known as Tregs — keep in check the tendency of other cells of the immune system to over react and cause inflammation when the body is under attack from infectious agents such as bacteria or viruses.

    The battle of the immune cells

    In the battle that follows the research group discovered that bacteria and viruses activate certain receptors of the innate immune system — known as Toll-like receptors (TLRs), making the Tregs less inhibitory. The positive consequence is that inflammatory immune cells are more able to react against infectious agents and eliminate them. The problem is that such increased activity of inflammatory immune cells could also increase the occurrence of autoimmune reactions against organs such as the central nervous system.

    Research led by award winning PhD student

    Most of the experimental work was conducted in the laboratory by award winning PhD student Mukanthu Nyirenda under the supervision of Dr Gran in the Division of Clinical Neurology. The research was funded by the Multiple Sclerosis Society of Great Britain and Northern Ireland.

    Last year Mukanthu received the University Endowed Postgraduate Prize in recognition of the progress he has made with his research. He is also a previous recipient of a Jacqueline Du Pre' Award of the Multiple Sclerosis International Federation.

    Mukanthu said: "This publication is a very important part of the work leading to my doctoral dissertation, planned for 2012. I am grateful for the recognition and support given to me by the University with the Endowed Postgraduate Prize."

    The study was carried out in collaboration with Professor Cris Constantinescu and other researchers at The University of Nottingham and experts at McGill University in Montreal.

    Flirting with the enemy

    The research team also found that when stimulated by molecules that activate TLRs, regulatory T cells become themselves functionally more similar to inflammatory T cells, another reason why autoimmune reactions could occur in relation to infections.

    Although this part of the study focussed on healthy subjects, ongoing studies in Dr Gran's laboratory are comparing the properties of regulatory T cells in these people with those obtained from patients with MS. Other researchers have previously found that Tregs may in fact be defective in MS patients, and this study contributes to our understanding of how episodes of infections, known to influence the clinical course of MS, could in certain circumstances promote the occurrence of autoimmunity.

    Source: Science Codex (20/02/12)

    Intestine crucial to function of immune cells, research shows

    B CellsResearchers at the University of Toronto have found an explanation for how the intestinal tract influences a key component of the immune system to prevent infection, offering a potential clue to the cause of autoimmune disorders like rheumatoid arthritis and multiple sclerosis.

    "The findings shed light on the complex balance between beneficial and harmful bacteria in the gut," said Prof. Jennifer Gommerman, an Associate Professor in the Department of Immunology at U of T, whose findings were published online by the scientific journal, Nature. "There has been a long-standing mystery of how certain cells can differentiate between and attack harmful bacteria in the intestine without damaging beneficial bacteria and other necessary cells. Our research is working to solve it."

    The researchers found that some B cells - a type of white blood cell that produces antibodies - acquire functions that allow them to neutralize pathogens only while spending time in the gut. Moreover, this subset of B cells is critical to health.

    "When we got rid of that B-cell function, the host was unable to clear a gut pathogen and there were other negative outcomes, so it appears to be very important for the cells to adopt this function in the gut," said Prof. Gommerman, whose lab conducted the research in mice.

    Textbook immunology - based mostly on research done in the spleen, lymph nodes or other sterile sites distant from gut microbes - has suggested that B cells develop a specific immune function and rigidly maintain that identity. Over the last few years, however, some labs have shown the microbe-rich environment of the gut can induce flexibility in immune cell identity.

    Prof. Gommerman and her colleagues, including trainees from her lab Drs. Jörg Fritz, Olga Rojas and Doug McCarthy, found that as B cells differentiate into plasma cells in the gut, they adopt characteristics of innate immune cells - despite their traditional association with the adaptive immune system. Specifically, they begin to look and act like inflammatory cells called monocytes, while maintaining their ability to produce a key antibody called Immunoglobulin A.

    "What intrigued us was that this theme - B cells behaving like monocytes - had been seen before in fish and in vitro. But now we have a living example in a mammalian system, where this kind of bipotentiality is realised," said Prof. Gommerman.

    This B-cell plasticity provides a potential explanation how cells dedicated to controlling pathogens can respond to a large burden of harmful bacteria without damaging beneficial bacteria and other cells essential for proper function of the intestine.

    It also may explain how scientists had failed to appreciate the multi-functionality of some B cells. "There are classical markers immunologists use to identify B cells - receptors that are displayed on their surface - and most of them are absent from plasma cells," said Prof. Gommerman. "So in some cases, what people thought was a monocyte could have been a plasma cell because it had changed its surface identity, although monocytes play an important role in innate immunity as well."

    This transformational ability, the researchers also found, is dependent on bacteria called commensal microflora that digests food and provides nutrients. That relationship highlights the importance of the gut in fighting infection, and begs the question of whether plasma cells trained in the gut to secrete specific anti-microbial molecules can play a role in other infectious disease scenarios, such as food-borne listeria infection.

    It also opens a line of investigation into whether a systemic relationship exists between those anti-microbial molecules and healthy cells in sites remote from the intestine. Understanding the nature of that relationship could improve understanding of inflammatory mechanisms in autoimmune disorders such as lupus, rheumatoid arthritis and multiple sclerosis, in which immune cells attack and eventually destroy healthy tissue.

    But the next step, said Prof. Gommerman, is to look at human samples for the same type of multi-potentiality they saw in rodent plasma cells that acquired their anti-microbial properties in the gut.

    "We're really at the early stages of understanding what we call the microbiome in the gut," said Prof. Gommerman. "There is a role for plasma cells in many autoimmune diseases, and B cells can do a lot more than just make antibodies. We need to understand the full spectrum of their effects within the immune response."

    Source: Medical News Today © MediLexicon International Ltd 2004-2011 (15/12/11)

    Fooling immune system reverses MS-like symptoms in mice

    T CellsTo fight an autoimmune disease, you've got to outwit a rogue immune system that has turned on itself. By doing just that, symptoms of multiple sclerosis have been reversed in mice.

    MS occurs when the fatty myelin sheath that enwraps nerve fibres to improve their electrical conductivity comes under attack from the immune system. Impaired signal transmission can cause muscle weakness, vision problems and paralysis.

    To switch off the attack, Marco Prinz at the University of Freiburg, Germany, and colleagues, took mice genetically modified to present symptoms of MS and injected them with RNA that stimulates the production of a protein called interferon-b (IFNb).

    The mice showed "rapid improvement" with a decrease in tail weakness and paralysis over the following 48 hours. Increased IFNb appeared to slow the development of T-cells - immune cells that may play a key role in MS (Nature Neuroscience, DOI: 10.1038/nn.2964).

    Around 80 per cent of people with MS treated with injections of IFNb develop antibodies which reduce the efficacy of the protein. Getting the body to generate its own IFNb neatly dodges the antibody problem.

    Source: New Scientist © Copyright Reed Business Information Ltd. (12/12/11)

    MS research reveals possible new drug target

    Granzyme BMedical researchers at the University of Alberta have discovered a new drug target that could prevent the crippling physical effects of Multiple Sclerosis from setting in.

    It is the kind of news that MS patients across the country have been waiting years for.

    Doctors at the U of A in Edmonton are on the road to developing a new drug treatment that could completely change the lives of MS sufferers.

    During the first phase MS patients have lots of inflammation in their brain cells which results in a continuous cycle of inflammation attacks then recovery periods.

    During the second phase, the inflammation isn't as severe but physical disability begins to set in because of the effects of substantial brain cells being killed during the first phase.

    Immune cells that become active due to inflammation can pass the blood brain barrier and enter the central nervous system.

    These activated cells secrete a molecule, Granzyme B, that can get inside neurons and cause brain cell death.

    In lab experiments, researchers found that if they prevent this molecule from entering the neurons they can also prevent the killing of neurons in the early stages of the disease.

    The discovery could mean that MS patients would be free of the permanent physical effects of MS, which eventually set in as the disease progresses.

    The discovery is just a method right now and doctors at the U of A say a drug will need to be developed that would stop the enzyme's destructive journey.

    The drug treatment could be years away but for those afflicted with MS it offers new hope and relief from the debilitating effects of the disease.

    Source: © 2011 Bell Media (27/10/11)

    Discovery of T cells making brain chemicals may lead to autoimmune diseases treatments

    T CellsScientists have identified a surprising new role for a new type of T cell in the immune system: some of them can be activated by nerves to make a neurotransmitter (acetylcholine) that blocks inflammation. The discovery of these T cells is novel and suggests that it may be possible to treat inflammation and autoimmune diseases by targeting the nerves and the T cells. The study was published this week in Science.

    "The discovery that 2 percent of T cells can make acetylcholine under the control of nerves gives a new insight into how the nervous system regulates immunity," said Kevin J. Tracey, MD, president and chief executive officer of The Feinstein Institute for Medical Research, and principal investigator of the study. "The arrival of electrical signals from nerves activates these specialized T cells to produce the acetylcholine necessary to block inflammation, and protect against damage. It is possible to transfer these cells to cross-protect mice from inflammation, and to control these T cells by electrically stimulating the nerves directly."

    The present study followed years of work from Dr. Tracey's lab that identified the role of the vagus nerve, named for its wandering course from the base of the brain to the liver, spleen and other organs, in blocking inflammation. Applying electrodes to stimulate the vagus nerve blocked the release of tumor necrosis factor (TNF) and other cytokines that underlie the tissue damage in arthritis, inflammatory bowel disease and other syndromes. Stimulating this nerve pathway led to increased production of acetylcholine, a neurotransmitter that binds to the alpha 7 nicotinic acetylcholine receptor. Activating this receptor on macrophages blocked the release of immune molecules (the cytokines,) suggesting a novel strategy for developing anti-inflammatory agents.

    But these results raised an important question because the nerve fibers in spleen release norepinephrine, another neurotransmitter, but not acetylcholine. The search for the cells that produce acetylcholine led these investigators to use "nude" mice, devoid of T cells. Then they examined the spleen cells that make acetylcholine and that led them to a subset of T cells. Transferring these acetylcholine producing T-cells into nude mice restored the vagus nerve circuit that blocked inflammation.

    "Our results point to a population of acetylcholine-synthesizing memory T cells in spleen that is integral to the function of the inflammatory reflex, the nerve circuit that regulates inflammation and immunity," said Dr. Tracey. "It is as if these T cells occupy a nerve-like function in this important circuit."

    It should be possible to target these T cells and to modulate this neural circuitry to develop therapeutic modalities for inflammatory and autoimmune diseases. In the future, it may be possible to isolate these T cells and exploit their anti-inflammatory activity. In the meantime, there is a more direct route to use this discovery for therapy. Rheumatoid arthritis patients in Europe are being studied in clinical trials where vagus nerve stimulators are implanted and turned on to stimulate this circuit and suppress inflammation.

    Source: Medical News Today © MediLexicon International Ltd 2004-2011 (19/09/11)

    Starving inflammatory immune cells slows damage caused by MS

    Immune CellsIn a paper published today in the journal Scientific Reports, a pair of researchers at the University of California, San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences report that inhibiting the ability of immune cells to use fatty acids as fuel measurably slows disease progression in a mouse model of multiple sclerosis (MS).

    MS is an autoimmune disease resulting from damage to the myelin sheath, a protective layer surrounding nerve cells. When the sheath is damaged, nerve impulses are slowed or halted, resulting in progressive physical and neurological disabilities. The cause of the damage is inflammation occurring when the body’s immune cells attack the central nervous system (CNS).

    Marianne Manchester, PhD, professor of pharmacy and first author Leah P. Shriver, PhD, looked at how immune cells in the CNS oxidize fatty acids for energy when their preferred fuel source – glucose – is in short supply, which may occur in inflamed tissues. In a mouse model mimicking chronic MS, Manchester and Shriver discovered that by inhibiting a single enzyme that helps immune cells effectively exploit fatty acids, the cells eventually starved and died, preventing further inflammatory damage.

    Currently, no approved drug or therapy for MS targets fatty acid metabolism. And the specificity of the target – inhibiting a single enzyme – suggests that adverse side effects associated with existing treatments, such as increased infection risk, is unlikely.

    “We expect that because immune cells not in lesions in the CNS are able to use available glucose, they will function just fine during infection and that inhibition of this pathway would not produce general immune suppression,” Shriver said.

    The enzyme-inhibitor used by Manchester and Shriver in their study is a drug already tested in humans with congestive heart failure, and was generally well-tolerated. The scientists are now using mass spectrometry to determine whether their results in the mouse model are translatable to humans. “We are interested in determining how this pathway is utilized in human tissue samples from MS patients,” Manchester said.

    Funding for this study came from the National Institutes of Health and the National Institute of Neurological Disorders and Stroke.

    Source: UC San Diego © 2011 UCSD Medical Center. (02/09/11)

    Overactive immune response silenced by new anti-inflammatory agents

    Nucleic Acid Binding PolymersA new way to fight inflammation uses molecules called polymers to mop up the debris of damaged cells before the immune system becomes abnormally active, researchers at Duke University Medical Center report.

    The discovery, published in the journal Proceedings of the National Academy of Sciences, offers a promising new approach to treat inflammatory auto-immune disorders such as lupus and multiple sclerosis, which are marked by an overactive immune response.

    "Depending on the disease, cells that are damaged drive or perpetuate the immune response," said Bruce A. Sullenger, Ph.D., director of the Duke Translational Research Institute and senior author of the study. "We have shown that we can inhibit that process."

    Sullenger said the idea for the new approach stems from earlier findings by Duke scientists and others that dying and diseased cells spill nucleic acids - the building blocks of life that include DNA and RNA - that then circulate at high levels in the bloodstream.

    While DNA and RNA inside the cell regulate important functions such as growth and division, outside of cells in the blood, these nucleic acids serve as powerful signals to the immune system that something is amiss. Once activated, the immune system launches an attack to fight whatever caused the cell damage, whether an infection or toxic substance. Under normal circumstances, this inflammatory response eventually restores order.

    In some cases, however, the inflammatory response becomes persistent and out of control, leading to tissue damage and causing symptoms such as fever and pain. Chronic inflammation has been implicated in lupus, multiple sclerosis, obesity, psoriasis, irritable bowel syndrome, arthritis and numerous other maladies.

    The Duke scientists, working to interrupt this cycle, focused on a set of molecules called nucleic acid binding polymers that were designed to infiltrate the nucleic acid inside of cells and deactivate specific immune triggers.

    "Then we had a 'eureka moment,'" Sullenger said. "Because the inflammatory nucleic acids are outside of cells, whereas DNA and RNA normally function inside cells, we realized that the polymers could bind to the external nucleic acids without disrupting intracellular functions of DNA and RNA."

    It was a simple mop-up approach, and it worked as planned in experiments on mice: "We could use the polymers as molecular scavengers - sponges to go around and soak up and neutralize those inflammatory nucleic acids so the immune system doesn't recognize them and go into the overdrive of inflammation," Sullenger said.

    David S. Pisetsky, M.D., Ph.D., a rheumatologist at Duke and co-author of the study, said the anti-inflammatory approach has numerous potential applications, not only for auto-immune disorders, but also for the acute tissue damage of severe bacterial and viral infections, shock and injuries.

    "One setting to test the effects of the polymers involves acute events such as injuries, where it may be easier to measure the presence of the nucleic acids in the blood and the effects of polymer binding," Pisetsky said, adding that the long-term safety of the new anti-inflammatory approach in humans remains unknown.

    Sullenger said patents have been filed on the finding, and the team is pressing ahead to develop therapies. "At some level we've opened up this huge treasure chest of opportunities and now we have to figure out which way to go," he said.

    In addition to Sullenger and Pisetsky, study co-authors include: Jaewoo Lee; Jang Wook Sohn; Ying Zhang; and Kam W. Leong.

    The study was funded in part by the National Heart, Lung and Blood Institute. The researchers reported no conflicts of interest.

    Source: Medical News Today © MediLexicon International Ltd 2004-2011 (17/08/11)

    T cell deficiency may explain Multiple Sclerosis-virus link

    T CellsEvidence that MS patients are deficient in the T cells that normally control Epstein-Barr virus may help explain the pathogenesis of the disease, Australian researchers say.

    Professor Michael Pender and colleagues at the Royal Brisbane and Women’s Hospital found the average percentage of CD8 T cells was significantly decreased in the blood of MS patients compared with healthy subjects.

    They also made the “striking” discovery that the proportion of CD8 T cells declined markedly with age in MS patients compared with healthy controls,
    based on their study of 64 MS patients and 68 healthy age and sex-matched subjects.

    Reporting their findings in a letter in the Journal of Neurology, Neurosurgery and Psychiatry, they wrote: “What is remarkable about the CD8 T cell deficiency in MS is that normally when EBV load is increased, as it is in the blood and brain of MS patients, the CD8 T cell frequency should increase and not decrease.

    “This suggests that there is a fundamental defect in the ability of MS patients to make an appropriate CD8 T cell response to EBV.”

    Speaking with Neurology Update, Professor Pender said CD8 T cell deficiency in MS was first reported three decades ago, but had been “largely forgotten”.

    In the meantime, increasing evidence had suggested EBV had a role in MS.

    Bringing these two ideas together, he suggested CD8 T cell deficiency might contribute to the lack of control of EBV in MS patients, and to the development of the disease.

    “More work will be needed to confirm it and determine what’s causing the deficiency in the first place. We believe it’s genetically determined but that needs to be worked out,” he said.

    The researchers also tested the frequency of peripheral blood mononuclear cells producing IFN-ɣ in response to autologous EBV-infected B cell lymphoblastoid cell lines (LCL).

    They found that for a given percentage of CD8 T cells in the blood, the LCL-specific T cell frequency in MS patients was generally lower than in healthy subjects.

    This, they said, indicated that the decreased LCL-specific T cell frequency in MS was due to the CD8 T cell deficiency.

    Sources: J Neurol Neurosurg Psychiatry & Neurology Update (09/08/11)

    Gender difference in autoimmune disease explained by newly discovered B cells

    B CellsResearchers at National Jewish Health have discovered a type of cell that may contribute to autoimmune disease. The findings also suggest why diseases such as lupus, multiple sclerosis and rheumatoid arthritis strike women more frequently than men.

    The cells, a subset of immune-system B cells, make autoantibodies, which bind to and attack the body's own tissue. The researchers report in the journal Blood, that they found higher levels of these cells in elderly female mice, young and old mice prone to autoimmune disease, and humans with autoimmune diseases. National Jewish Health has applied for a patent for a method to treat autoimmune disease by depleting these cells.

    "We believe these cells could be useful in the diagnosis and treatment of autoimmune diseases, and may help us understand general mechanisms underlying autoimmunity," said senior author Philippa Marrack, PhD, Professor of Immunology at National Jewish Health and an investigator of the Howard Hughes Medical Institute.

    Autoimmune diseases occur when the immune system begins attacking its own tissues rather than external pathogens. Several autoimmune diseases, including lupus, rheumatoid arthritis and multiple sclerosis, afflict women anywhere from two to 10 times as often as they do males. Although sex hormones are known to play a role in autoimmune disease, other factors are involved in these gender differences.

    The research team came across the new cells when they were examining differential expression of X-chromosome genes in healthy male and female mice. They discovered a previously undescribed type of B cell, which expressed the cell-surface protein CD11c. The protein is an integrin, which helps cells attach to other cells or to an extracellular matrix. The researchers are not certain what role integrin might play in autoimmunity or if it is merely a marker for another mediator of autoimmunity.

    These cells increase as healthy female mice age, but remain at constant low levels in healthy male mice. As a result, the researchers named the cells Age-associated B Cells or ABCs. The researchers also found higher levels of ABCs in young and old mice that are prone to autoimmune disease. They could detect the elevated ABC levels before any disease developed and even before autoantibodies appeared, suggesting a role for these cells in early detection of disease.

    The researchers also found an almost identical type of cell in the blood of many human autoimmune patients. In women with rheumatoid arthritis the presence of these cells increased with age.

    ABCs in mice produce antibodies against chromatin, the combination of proteins and DNA that make up chromosomes in the cell nucleus. When they depleted the ABCs in mice, autoantibody levels fell, suggesting a potential treatment for autoimmune diseases. National Jewish Health has applied for a patent on the method of depleting the cells to treat autoimmune disease.

    The researchers also found that activation of these cells requires stimulation of TLR7, a cell-surface receptor involved in innate immune responses. The gene for TLR7 is located on the X chromosome. Women have two X chromosomes, men an X and a Y chromosome. Normally one copy of the X chromosome in women is silenced so that it does not produce excess protein. But the silencing is not always complete, and women commonly express elevated levels of some X-chromosome genes.

    "Not only do these cells appear more frequently in females, their activation depends on a gene of which women have two copies and men only one," said Anatoly V. Rubtsov, PhD, first author and postdoctoral fellow at National Jewish Health. "This could help us understand why women suffer many autoimmune diseases more often than men."

    Source: Medical News Today MediLexicon International Ltd © 2004-2011 (08/08/11)

    Myelin-phagocytosing macrophages modulate autoreactive T cell proliferation

    T CellsAbstract (provisional)
    Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) in which macrophages play a central role. Initially, macrophages where thought to be merely detrimental in MS, however, recent evidence suggests that their functional phenotype is altered following myelin phagocytosis.

    Macrophages that have phagocytosed myelin may be less inflammatory and may exert beneficial effects. The presence of myelin-containing macrophages in CNS-draining lymph nodes and perivascular spaces of MS patients suggests that these cells are ideally positioned to exert an immune regulatory role. Therefore we evaluated in this study the effect of myelin-phagocytosing macrophages on lymphocyte reactivity.

    Thioglycolate-elicited rat peritoneal macrophages were loaded with myelin and cocultured with myelin-basic protein (MBP) or ovalbumin (OVA) reactive lymphocytes. Lymphocyte proliferation was determined by CFSE-labeling. The role of nitric oxide in regulating lymphocyte proliferation was assessed by addition of an inhibitor of inducible nitric oxide synthase to the coculture. In vivo immune regulation was investigated by treating MBP- and OVA-immunized animals subcutaneously with myelin. Cognate antigen specific lymphocyte proliferation and nitric oxide production were determined 9d post-immunization.

    In this study we demonstrate that myelin-phagocytosing macrophages inhibit TCR-triggered lymphocyte proliferation in an antigen-independent manner. The observed immune suppression is mediated by an increase in NO production by myelin-phagocytosing macrophages upon contact with lymphocytes. Additionally, myelin delivery to primarily CD169+ macrophages in popliteal lymph nodes of OVA-immunized animals results in a reduced cognate antigen specific proliferation. In contrast to OVA-immunized animals, lymphocytes from MBP-immunized animals displayed an increased proliferation after stimulation with their cognate antigen, indicating that myelin-phagocytosing macrophages have dual effects depending on the specificity of surrounding lymphocytes.

    Collectively our data show that myelin phagocytosis leads to an altered macrophage function that inhibits lymphocyte proliferation. Additionally, results from this study indicate that myelin-phagocytosing macrophages fulfill a dual role in vivo. On one hand they aggravate autoimmunity by activating myelin-reactive lymphocytes and on the other hand they suppress lymphocyte reactivity by producing NO.

    Provisional Full Article

    Jeroen FJ Bogie, Piet Stinissen, Niels Hellings and Jerome JA Hendriks

    Source: Journal of Neuroinflammation 2011, 8:85 doi:10.1186/1742-2094-8-85 © 2011 BioMed Central Ltd (26/07/11)

    Why do women suffer autoimmune diseases more often?

    MS DiagnosisResearchers at National Jewish Health have discovered a type of cell that may contribute to autoimmune disease. The findings also suggest why diseases such as lupus, multiple sclerosis and rheumatoid arthritis strike women more frequently than men.

    The cells, a subset of immune-system B cells, make autoantibodies, which bind to and attack the body’s own tissue. The researchers report the journal Blood, that they found higher levels of these cells in elderly female mice, young and old mice prone to autoimmune disease, and humans with autoimmune diseases. National Jewish Health has applied for a patent for a method to treat autoimmune disease by depleting these cells.

    “We believe these cells could be useful in the diagnosis and treatment of autoimmune diseases, and may help us understand general mechanisms underlying autoimmunity,” said senior author Philippa Marrack, PhD, Professor of Immunology at National Jewish Health and an investigator of the Howard Hughes Medical Institute.

    Autoimmune diseases occur when the immune system begins attacking its own tissues rather than external pathogens. Several autoimmune diseases, including lupus, rheumatoid arthritis and multiple sclerosis, afflict women anywhere from two to 10 times as often as they do males. Although sex hormones are known to play a role in autoimmune disease, other factors are involved in these gender differences.

    The research team came across the new cells when they were examining differential expression of X-chromosome genes in healthy male and female mice. They discovered a previously undescribed type of B cell, which expressed the cell-surface protein CD11c. The protein is an integrin, which helps cells attach to other cells or to an extracellular matrix. The researchers are not certain what role integrin might play in autoimmunity or if it is merely a marker for another mediator of autoimmunity.

    These cells increase as healthy female mice age, but remain at constant low levels in healthy male mice. As a result, the researchers named the cells Age-associated B Cells or ABCs. The researchers also found higher levels of ABCs in young and old mice that are prone to autoimmune disease. They could detect the elevated ABC levels before any disease developed and even before autoantibodies appeared, suggesting a role for these cells in early detection of disease.

    The researchers also found an almost identical type of cell in the blood of many human autoimmune patients. In women with rheumatoid arthritis the presence of these cells increased with age.

    ABCs in mice produce antibodies against chromatin, the combination of proteins and DNA that make up chromosomes in the cell nucleus. When they depleted the ABCs in mice, autoantibody levels fell, suggesting a potential treatment for autoimmune diseases. National Jewish Health has applied for a patent on the method of depleting the cells to treat autoimmune disease.

    The researchers also found that activation of these cells requires stimulation of TLR7, a cell-surface receptor involved in innate immune responses. The gene for TLR7 is located on the X chromosome. Women have two X chromosomes, men an X and a Y chromosome. Normally one copy of the X chromosome in women is silenced so that it does not produce excess protein. But the silencing is not always complete, and women commonly express elevated levels of some X-chromosome genes.

    “Not only do these cells appear more frequently in females, their activation depends on a gene of which women have two copies and men only one,” said Anatoly V. Rubtsov, PhD, first author and postdoctoral fellow at National Jewish Health. “This could help us understand why women suffer many autoimmune diseases more often than men.”

    Source: Medical Xpress © Medical Xpress 2011 (05/07/11)

    Roles of Anti-MOG antibodies in demyelinating diseases

    Anti-MOG AntibodiesNew research shows that a substantial proportion of patients with acute disseminated encephalomyelitis have serum antibodies against myelin oligodendrocyte glycoprotein. The relationship between these antibodies and other demyelinating disorders such as multiple sclerosis, however, remains unclear.

    Two new articles1, 2 reassess the role of antibodies against myelin oligodendrocyte glycoprotein (MOG) in pediatric cases of neuroinflammatory demyelinating disease. The studies confirm that approximately 40% of children with acute disseminated encephalomyelitis (ADEM) display serum antibodies against MOG, whereas only a small percentage of cases of clinically isolated syndrome (CIS) or multiple sclerosis (MS) display these antibodies.1, 2, 3, 4, 5, 6 Various controls were essentially negative for this antibody specificity, suggesting that rather than being a secondary epiphenomenon of nervous system damage, the anti-MOG response may be mechanistically involved in the disease process.

    These studies provide solid evidence for an association between anti-MOG antibodies and a large fraction of ADEM cases. The implications of the findings are twofold: first, anti-MOG antibodies might provide a useful biomarker for ADEM, and second, the pathogenesis of demyelinating disease—in particular, ADEM, and perhaps to some extent MS—may involve an anti-MOG autoimmune response.

    The performance of anti-MOG assays as biomarkers is good in that they display a high specificity (up to 97%) for demyelinating disease, and sensitivity for ADEM is in the region of 40%. One can conclude from the new articles that the assays could sometimes be helpful where the differential diagnosis against other conditions is difficult.1, 2

    Interestingly, anti-MOG antibodies against conformational epitopes have been demonstrated in these new studies.1, 2 Such antibodies have been shown experimentally to be pathogenic and to mediate demyelination.7 A likely scenario, therefore, is that the antibodies produced during ADEM, perhaps along with MOG-specific T cells, are part of the disease mechanism. However, this finding would have little practical importance in ADEM, since this condition is by definition monophasic, and is nonspecifically treated with immune-modifying measures, such as steroids, intravenous immunoglobulin or plasma exchange. Any role for such antibodies that could be demonstrated in chronic conditions such as MS would be more important.

    The continued search for autoantibodies or autoantigen-specific T cells in organ-specific inflammatory diseases is vital. The exact definition of such entities in experimental models has enabled the development of highly selective therapies that do not disturb the immune system as a whole, thereby leaving the necessary defense against infections intact. Such an approach should also be possible in humans, where we have been witnessing the development of ever more effective immune-modifying agents that strike broadly at the immune system. In addition, even if the antibodies and T cells are not involved mechanistically in the disease, their detection may provide biomarkers for diagnosis, prognosis, disease subcategories and treatment responses. Over the years, progress has been made in this field with, for example, the anti-acetylcholine receptor antibodies in myasthenia gravis, anti-aquaporin-4 antibodies in neuromyelitis optica, and antibodies to citrullin in rheumatoid arthritis.

    In MS, developments have been slow and, so far, inconclusive. Given that the myelin sheath is primarily attacked by the immune system in MS, a series of autoantigens from this sheath has been explored in experimental autoimmune encephalomyelitis, an animal model of MS. The main antigens used to date are myelin basic protein, proteolipid protein and MOG. MOG is especially interesting since immunization of susceptible rat strains results in a chronic relapsing disease with scattered demyelinated plaques in the CNS, which strongly mimics human MS.8 Although immune T-cell responses have been detected to all of these proteins, including MOG,9 in MS, certain aspects of these responses can also be found in healthy individuals, and we currently have no way of knowing whether they actively promote disease or are innocuous secondary phenomena resulting from brain damage. We need new approaches to answer the important question of which autoantigens are relevant for MS.

    Interest in B cells and antibodies recently received a strong boost from the report of a dramatic therapeutic effect of B-cell depletion in people with MS.10 For many people, this finding was unexpected. One can consider several different, non-mutually-exclusive reasons for the effect. First, some as yet unknown antibody specificity could be driving the disease. Second, B cells could also produce cytokines that can act as effectors or potentially provide critical help for autoaggressive T cells. Third, by possessing surface immunoglobulin receptors for autoantigens, B cells might enrich for these antigens when present in very low concentrations, and provide efficient help for T cells by recognizing the same antigen and being autoaggressive. The last of these three options is theoretically an attractive option for how MOG, as well as other still-undefined proteins, could be relevant in MS. A small proportion of people with MS display anti-MOG antibodies, and one cannot exclude the possibility that many more possess B cells with surface immunoglobulin directed against MOG.

    A wealth of data now implicates MOG as an important myelin autoantigen in ADEM, which is of great theoretical importance but has little practical application in the clinic. The jury is still out with regard to the role of MOG autoimmunity in MS. Further attempts and new approaches will be needed to precisely define the specificities of the autoimmune attack in MS, with prospects for the development of immune-selective treatments.

    1.Lalive, P. et al. Highly reactive anti-myelin oligodendrocyte glycoprotein antibodies differentiate demyelinating diseases from viral encephalitis in children. Mult. Scler. 17, 297–302 (2011).
    2.Di Pauli, F. et al. Temporal dynamics of anti-MOG antibodies in CNS demyelinating diseases. Clin. Immunol. 138, 247–254 (2011).
    3.Selter, R. C. et al. Antibody responses to EBV and native MOG in pediatric inflammatory demyelinating CNS diseases. Neurology 74, 1711–1715 (2010).
    4.Brilot, F. et al. Antibodies to native myelin oligodendrocyte glycoprotein in children with inflammatory demyelinating central nervous system disease. Ann. Neurol. 66, 833–842 (2009).
    5.O'Connor, K. C. et al. Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein. Nat. Med. 13, 211–217 (2007).
    6.McLaughlin, K. A. et al. Age-dependent B cell autoimmunity to a myelin surface antigen in pediatric multiple sclerosis. J. Immunol. 183, 4067–4076 (2009).
    7.Brehm, U., Piddlesden, S. J., Gardinier, M. V. & Linington, C. Epitope specificity of demyelinating monoclonal autoantibodies directed against the human myelin oligodendrocyte glycoprotein (MOG). J. Neuroimmunol. 97, 9–15 (1999).
    8.Weissert, R. et al. MHC haplotype-dependent regulation of MOG-induced EAE in rats. J. Clin. Invest. 102, 1265–1273 (1998).
    9.Wallström, E. et al. Increased reactivity to myelin oligodendrocyte glycoprotein peptides and epitope mapping in HLA DR2(15)+ multiple sclerosis. Eur. J. Immunol. 28, 3329–3335 (1998).
    10.Hauser, S. L. et al. B-cell depletion with rituximab in relapsing–remitting multiple sclerosis. N. Engl. J. Med. 358, 676–688 (2008).

    Source: Nature Reviews Biology © 2011 Nature Publishing Group (18/05/11)

    Potential MS therapy could kill brain cells, study suggests

    T CellsResearchers with the Faculty of Medicine & Dentistry at the University of Alberta have discovered that some "protective" T-cells can kill neurons. This finding is significant because a specific type of T-cell therapy is being touted in the medical community as a potential treatment for MS and other autoimmune conditions.

    Dr. Fabrizio Giuliani and his post-doctoral fellow, Yohannes Haile, both from the Division of Neurology, collaborated on this research which was recently published in the Journal of Leukocyte Biology, a peer-reviewed medical journal.

    "Using T-cells has been seen as a potential treatment for autoimmune diseases," says Dr. Giuliani. "But these cells that are supposed to be regulatory, when activated, they can kill. In our hands, at least, they were able to kill neurons. So this is very important. In MS literature, they were starting to talk about using the infusion of these cells as treatment. This area needs to be studied more before these cells are used as a therapy for MS patients."

    The finding was serendipitous, says Giuliani.

    "We were using some of the cells that we have described here as a control in our project. And then the T-cells did something interesting, something we weren't expecting. In fact, we were expecting the exact opposite response with these cells.

    "We were looking at how a specific type of T-cell could prevent neuronal death and then we found out they were doing the killing…These are the best findings -- when you are expecting something different and then you observe an amazing phenomenon."

    T-cells are very important -- their primary role is to attack foreign viruses or bacteria and to regulate or maintain immune system tolerance. However, when T-cell tolerance is disrupted, they can cause autoimmune diseases.

    Researchers in the medical community have thought if they could carefully collect regulatory T-cells and inject them into patients with autoimmune diseases, these T-cells could keep autoimmune diseases under control. Work with lab models that had MS and were treated with T-cells was promising. However, recent studies of human cells have shown humans have different subpopulations of T-cells -- some of which do not have a regulatory function.

    Giuliani and Haile worked with different subpopulations of T-cells and discovered some were toxic to neurons. Giuliani and his colleague are the first medical researchers to demonstrate that activating a specific type of T-cell can kill brain cells.

    They want to continue their work in this area to determine what causes some T-cells to behave this way.

    "We want to take the research further. We want to continue this story in an attempt to try and solve the mystery."

    Their research was funded by: the MS Society of Canada, the University of Alberta Hospital Foundation and the Canadian Institutes of Health Research.

    Source: Science Daily Copyright © 1995-2010 ScienceDaily LLC (07/05/11)

    Research teams implicate GM-CSF in the pathogenesis of MS

    T CellsTwo research teams have separately implicated the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) as playing a central role in the IL-23-driven neuroinflammatory process that occurs in autoimmune diseases such as multiple sclerosis.

    The separate groups, led by scientists at Thomas Jefferson University in Philadelphia and the University of Zurich in Switzerland, have found that IL-23 induces IL-17-producing T helper cells (TH17) to express GM-CSF, and this cytokine plays a key role in their encephalitogenicity. The Thomas Jefferson team notes that although the role of GM-CSF in the pathology of multiple sclerosis is unknown, these latest studies in animal models suggest that blocking GM-CSF activity may represent a feasible therapeutic strategy for multiple sclerosis.

    Both research teams report their findings in Nature Immunology. The paper by Thomas Jefferson Medical College chairman and professor Abdolmohamad Rostami, M.D., and colleagues is titled “The encephalitogenicity of TH17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF.” The University of Zurich’s Laura Codarri, Ph.D., and team describe their findings in a paper titled “RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation.”

    TH17 cells are widely believed to play a key role in autoimmune diseases of the CNS, with stimulation by IL-23 driving their encephalitogenicity, the researchers explain. However, to date, the mechanism behind this pathogenicity has remained unknown.

    Dr. Rostami’s team differentiated naive CD4+ T cells into TH17 cells by stimulating the cells with TGF-β and IL-6 (first stimulation), and then reactivated the cells in the presence of various cytokines (second stimulation). During the first stimulation, a frac­tion of IL-17A+ T cells expressed GM-CSF, and small amounts of GM-CSF were present in culture supernatants. In the second stimulation, treatment with IL-23 resulted in a higher frequency of GM-CSF+ TH17 cells than in cultures treated with TGF-β and IL-6 without added cytokines. IL-23 also resulted in significant augmentation of GM-CSF secre­tion. When they then injected the resulting IL-23-treated TH17 cells into sublethally irradiated recip­ient mice, the animals all devel­oped severe experimental autoimmune encephalomyelitis (EAE) and died within seven days. In contrast, of the five mice injected with TH17 cells that had only been treated with TGF-β and IL-6, just two developed mild disease. They also found that adding IL-1β to IL-23 stimulation of the TH17 cells boosted production of both GM-CSF and IL-17A.

    Significantly, when mice treated with an anti-GM-CSF antibody were injected with the IL-23-stimulated TH17 cells, they developed significantly milder disease with delayed onset rela­tive to that of control mice, and all survived. Notably, the researchers add, IL-23-deficient mice developed EAE when exogenous IL-23 was delivered into the CNS, which indicates that IL-23 can act on already-developed TH17 cells.

    Experimental data has previously shown that GM-CSF induces IL-23 in APCs, which in turn induces GM-CSF expres­sion by TH17 cells, resulting in amplification of the inflammatory response, the authors note. TH1 cells also produced GM-CSF and responded to IL-1β by increasing GM-CSF production, which means they are another possible source of GM-CSF in EAE. However, the authors continue, it has also been shown that most CNS-infiltrating TH1 cells actually originate from TH17 cells.  “A plausible model can be proposed in which TH17 cells and their TH1 progeny (ex-TH17 cells) are essential in EAE, which includes the bulk of GM-CSF production, whereas classical TH1 cells have a marginal role,” Dr. Rostami’s team claims. “We propose a positive feedback loop whereby IL-23 produced by APCs induces GM-CSF production by TH17 cells, which in turn stimulates IL-23 production in APCs. Greater and/or prolonged production of IL-23 results in stronger and longer lasting TH17 responses, causing more profound inflammation.”

    Dr. Codarri’s team has similarly implicated IL-23, along with the transcription factor RORγt, as driving expression of GM-CSF in helper T cells. Their research in addition showed that IL-12, interferon-γ (IFN-γ), and IL-27 acted as negative regulators.

    They found that mice injected with T helper triggered to produce GM-CSF had a significantly earlier onset of EAE and greater disease severity than did recipients of cells polarized to secrete IFN-γ or IL-17. Also concurring with the Jefferson team’s findings, the Zurich team found that treating mice with an anti-GM-CSF antibody significantly reduced the severity of TH17 cell- or IFN-γ-secreting TH1 cell-mediated EAE. “This indicates that the secretion of GM-CSF is a critical feature for the encephalitogenicity of helper T cells in vivo regardless of whether they are polarized in vitro toward a TH17 or TH1 phenotype,” the team states.

    Significantly, T cells lacking GM-CSF completely failed to induce EAE, whereas the loss of IFN-γ or IL-17A only minimally impaired T cell pathogenicity. And in mice injected with T cells that only produced GM-CSF or IL-17A or IFN-γ, it was the animals receiving the GM-CSF-expressing cells that developed the most severe EAE. This importance of GM-CSF over IL-17A or IFN-γ was upheld in studies of T cells taken from mice which were doubly deficient in both IFN-γ and IL-17A. When these T cells were reactivated and transferred into wild-type recipient mice, the resulting disease profile in treated animals was the same as in mice administered with wild-type T cells.

    Further tests in mice showed that GM-CSF acts at least in part to stimulate the infiltration of myeloid cells into the CNS. “Conceptually, the finding that of all known T cell cytokines, GM-CSF seems to be the only one absolutely essential for endowing T cells with pathogenic properties links invasion of the CNS by T cells with the activation and maturation of cells belonging to the myeloid lineage,” the researchers concluded.

    Source: GEN © 2011 Genetic Engineering & Biotechnology News (25/04/11)

    Scientists develop new compound for multiple sclerosis treatment

    T CellScientists from the Florida campus of The Scripps Research Institute have developed the first of a new class of highly selective compounds that effectively suppresses the severity of multiple sclerosis in animal models. The new compound could provide new and potentially more effective therapeutic approaches to multiple sclerosis and other autoimmune diseases that affect patients worldwide.

    The study appeared April 17, 2011, in an advance online edition of the journal Nature.

    Current treatments for autoimmunity suppress the patient's entire immune system, leaving patients vulnerable to a range of adverse side effects. Because the new compound, known as SR1001, only blocks the actions of a specific cell type playing a significant role in autoimmunity, it appears to avoid many of the widespread side effects of current therapies.

    "This is a novel drug that works effectively in animal models with few side effects," said Tom Burris, Ph.D., a professor in the Department of Molecular Therapeutics at Scripps Florida who led the study, which was a multidisciplinary collaboration with scientists including Patrick Griffin, William Roush, and Ted Kamenecka of Scripps Research, and Paul Drew of the University of Arkansas for Medical Sciences. "We have been involved in several discussions with both pharmaceutical and biotechnology firms who are very interested in developing it further."

    A lengthy process of drug development and review is required to ensure a new drug's safety and efficacy before it can be brought to market.

    "This impressive multidisciplinary team has used a combined structural and functional approach to describe a class of molecules that could lead to new medicines for treating autoimmune diseases," said Charles Edmonds, Ph.D. who oversees structural biology grants at the National Institutes of Health. "Breakthroughs such as this highlight the value of scientists with diverse expertise joining forces to solve important biological problems that have the potential to benefit human health."

    Targeting Specific Receptors
    For the past several years, Burris and his colleagues have been investigating small-molecule compounds that affect particular disease-related receptors (structures that bind other molecules, triggering some effect on the cell). In particular, the scientists have been interested in a pair of "orphan nuclear receptors" (receptors with no known natural binding partner) called RORα and RORγ involved in both autoimmune and metabolic diseases.

    These particular receptors play a critical role in the development of TH17 cells, a form of T helper cells that make up part of the immune system. A relatively new discovery, TH17 cells have been implicated in the pathology of numerous autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and lupus. TH17 cells produce Interleukin-17, a natural molecule that can induce inflammation, a characteristic of autoimmunity.

    "If you eliminate TH17 cell signals, you basically eliminate the disease in animal models," Burris said. "Our compound is the first small-molecule orally active drug that targets this specific cell type and shuts it down. Once SR1001 is optimized, chances are it will be far more potent and effective."

    The compound works without affecting other types of T helper cells and without any significant metabolic impact, Burris added.

    Full Article

    Source: News Medical (18/04/11)

    Potential impact of B cells on T cell function in Multiple Sclerosis

    B CellsAbstract

    Multiple sclerosis is a chronic debilitating autoimmune disease of the central nervous system.

    The contribution of B cells in the pathoetiology of MS has recently been highlighted by the emergence of rituximab, an anti-CD20 monoclonal antibody that specifically depletes B cells, as a potent immunomodulatory therapy for the treatment of MS.

    However, a clearer understanding of the impact B cells have on the neuro-inflammatory component of MS pathogenesis is needed in order to develop novel therapeutics whose affects on B cells would be beneficial and not harmful.

    Since T cells are known mediators of the pathology of MS, the goal of this review is to summarize what is known about the interactions between B cells and T cells, and how current and emerging immunotherapies may impact B-T cell interactions in MS.

    Sara Ireland and Nancy Monson
    Departments of Neurology, Neurotherapeutics and Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA

    Full article -

    Source: Hindawi Publishing Corporation Copyright © 2011 Hindawi Publishing Corporation (25/03/11)

    Researchers publish results which may settle MS debate

    T CellsIn an effort to develop therapeutic remedies for multiple sclerosis, scientists debate two possible interventional approaches – but they’re on opposite sides of the spectrum. Researchers at Wayne State University’s School of Medicine, however, have reached a definitive conclusion as to which approach is correct, putting an end to a long-disputed issue.

    Harley Tse, Ph.D., associate professor of immunology and microbiology at WSU’s School of Medicine and resident of West Bloomfield, Mich., whose study was published in the January 2011 edition of the Journal of Neuroimmunology, found that targeting white blood cells of the immune system known as T cells is the effective approach to block the disease in an animal model of MS, experimental autoimmune encephalomyelitis.

    Normally, T cells are programmed to attack foreign substances in the body. However, sometimes these T cells attack an essential component of the central nervous system, the protective layer of nerve cells known as the myelin sheath. This causes the symptoms associated with MS, which include tremors, fatigue, memory loss and other problems.

    The debate was centered on treatment of the most common form of the disease, the relapsing-remitting form, in which attack episodes alternate with periods of remission. Roughly 85 percent of the 2.5 million sufferers of MS worldwide exhibit the relapsing-remitting pattern. “Scientists have been trying to understand how and why the relapse cycles occur and to design therapy to delay disease relapses and hence prolong the remission period,” said Tse.

    Scientists came up with two conflicting conjectures. Some found that the T cells involved in each relapse were different and were directed against different myelin proteins. As such, these T cells are not suitable targets for therapy. Others, however, could not find support for this in their studies. “It was important to resolve this issue because the two models suggested totally different therapeutic approaches,” Tse said.

    Studying the possibilities, Tse constructed a special mouse strain to tag the disease-causing T cells and observed that when these marked T cells were eliminated after a relapse, subsequent relapses did not occur.

    “Elimination of marked donor T cells could be done after development of the second or the third relapse episodes and each time, no further relapses occurred,” said Tse. “This work is significant because for the first time we are able to definitively establish a cause-and-effect relationship linking the marked T cells to the development of relapses and show unambiguously that it was the same T cells that mediated relapsing cycles. “

    “Targeting such disease-causing T cells in MS is definitely a valid therapeutic approach that should be pursued,” Tse added.

    Other WSU researchers involved in the study were Jinzhu Li, M.D., Ph.D., Xiaoqing Zhao, M.D., Ph.D, Hui-Wen Hao, M.D., Ph.D. and Michael K. Shaw, Ph.D. Tse’s study was supported in part by grants from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health and the National Multiple Sclerosis Society.

    Source: ScienceBlog © 2011 Science Blog. (24/02/11)

    Could monocytes play a part in the development of MS?

    MonocytesThere is currently no cure for Multiple Sclerosis (MS) – however scientists at the Malaghan Institute of Medical Research believe that specialised cells found in the blood might hold the key to improving the quality of life of the thousands of New Zealanders affected by this disease.

    In an "Outstanding Observation" published recently in the international scientific journal Immunology and Cell Biology, Drs Jacquie Harper, Thomas Bäckström and Clare Slaney describe how blood cells called monocytes may play a part in the development of MS.

    MS is thought to be an autoimmune disease of the central nervous system that affects one in every 1,500 New Zealanders and can render an individual unable to write, speak or walk.

    The Malaghan research, which was funded by the Health Research Council of New Zealand, showed that the ability of the blood monocytes to suppress inflammation is impaired in an experimental model of MS.

    “As such, these monocytes are no longer able to prevent inflammatory cells from destroying the central nervous system of MS sufferers,” said Dr Harper.

    “If we can find a way to reactivate suppressor function in the monocytes of MS sufferers, we might be able to provide a new treatment for MS that could delay or even prevent the progression of this disease.”

    Dr Thomas Bäckström was instrumental in laying the groundwork for the Malaghan study. He recently returned to Sweden to take up the position of Director of the T Cell Biology Department at Scandinavia‟s biggest pharmaceutical company Novo Nordisk. Dr Bäckström says that we all have these monocyte suppressor cells in our blood. The new challenge is to find tools to help them do a better job at controlling inflammation to treat dreadful diseases like MS.

    “Because MS hits adults in their prime, it dramatically reduces quality of life,” said coauthor and Malaghan MS Research Associate Dr Anne La Flamme. “Current treatments are not equally effective in all MS patients and often have side-effects associated with medium to long term use, so there is a desperate need for safer, more effective MS therapies.”

    Next week Dr La Flamme will participate in stage six of the Great New Zealand Trek, as it journeys the length of the country on horseback, mountain bike or by walking, to raise funds to help the Malaghan continue its groundbreaking research and find a cure for MS.

    Source: Scoop Health © Scoop Media 2011 (18/02/11)

    New Multiple Sclerosis target identified

    LymphocytesMultiple sclerosis (MS) is a disease caused by damage to myelin -- the protective covering wrapped around the nerves of the central nervous system (CNS).

    Previous studies have shown that certain white blood (immune) cells, called leukocytes, infiltrate the CNS and play a significant role in causing the damage that contributes to MS symptoms. It has also been shown that these leukocytes enter the CNS with help from a family of molecules called MMPs.

    Using a mouse model, researchers have discovered that a molecular switch called EMMPRIN plays an important role in MS. The researchers explored how in MS, EMMPRIN affects MMPs and the entry of leukocytes into the CNS to result in disease activity.

    "In our studies we inhibited EMMPRIN and noticed a reduced intensity of MS-like symptoms in mice," says Dr. V. Wee Yong, a professor of Clinical Neurosciences at the Hotchkiss Brain Institute at the University of Calgary's Faculty of Medicine and the study's principal investigator. "Our data suggests that if we target EMMPRIN in patients with MS, we may reduce the injury to the brain and spinal cord caused by immune cells."

    In addition to working with animal models, the authors also found that EMMPRIN is significantly elevated in the brain lesions of MS patients, indicating its potential significance in the disease.

    "This study has identified a new factor in MS, the blockade of which resolves disease activity in an animal model of MS. The results are exciting as they offer new insights into the MS disease process," says Dr. Smriti Agrawal, a postdoctoral fellow in Dr. Yong's lab and the study's lead author.

    "The authors have extended our knowledge of the molecules that regulate the trafficking of immune cells into the nervous system as occurs in multiple sclerosis. The current study identifies a new factor that can serve as a potential target of MS therapeutics," says Dr. Jack Antel, Professor of Neurology at McGill University.

    The research findings are published in the Jan 12th issue of the Journal of Neuroscience.

    The research was funded by the Canadian Institutes of Health Research and the MS Society of Canada.

    Source: Science Daily Copyright (c) 1995-2010 ScienceDaily LLC (12/01/11)

    Expression of chemokine receptors on peripheral blood lymphocytes in MS and neuromyelitis optica

    LymphocytesAbstract (provisional)

    The role of different chemokine receptors in the pathogenesis of multiple sclerosis (MS) has been extensively investigated; however, little is known about the difference in the role of chemokine receptors between the pathogenesis of neuromyelitis optica (NMO) and MS. Therefore, we examined the expression of chemokine receptors on peripheral blood lymphocytes (PBL) in MS and NMO.

    We used flow cytometry to analyse lymphocyte subsets in 12 patients with relapsing NMO, 24 with relapsing-remitting MS during relapse, 3 with NMO and 5 with MS during remission.

    Compared with healthy controls (HC), the percentage of lymphocytes in white blood cells was significantly lower in NMO and MS patients. The percentage of T cells expressing CD4+CD25+ and CD4+CD45RO+ was higher, while that of CD4+CC chemokine receptor (CCR)3+ (T helper 2, Th2) was significantly lower in MS patients than in HC. The ratios of CD4+CXC chemokine receptors (CXCR)3+/CD4+CCR3+ (Th1/Th2) and CD8+CXCR3+/CD8+CCR4+ (T cytotoxic 1, Tc1/Tc2) were higher in MS patients than in HC. The percentage of CD8+CXCR3+ T cell (Tc1) and CD4+CXCR3+ T cell (Th1) decreased significantly during remission in MS patients (P < 0.05). No significant differences were identified in the expression of the chemokine receptors on PBL in NMO patients compared with MS patients and HC.

    Th1 dominance of chemokine receptors on blood T cells and the correlation between CXCR3+ T cell (Th1 and Tc1) and disease activity in MS patients were confirmed by analysing chemokines receptors on PBL. In contrast, deviation in the Th1/Th2 balance was not observed in NMO patients.

    BMC Neurology © 1999-2010 BioMed Central Ltd (12/11/10)

    Atacicept: Targeting B Cells in Multiple Sclerosis

    B CellsAbstract
    Multiple sclerosis (MS) has traditionally been considered to be a T-cell-mediated disease. However, there is an increasing body of evidence for the involvement of B cells and autoantibodies in the pathology of this disease, providing a rationale for treatments directed against B cells.

    In this paper we summarize evidence for the key role of B cells in the immunopathology of MS and review data supporting the use of a novel B-cell targeted therapy, atacicept, in this condition.

    Atacicept is a human recombinant fusion protein that comprises the binding portion of a receptor for both BLyS (B-Lymphocyte Stimulator) and APRIL (A PRoliferation-Inducing Ligand), two cytokines that have been identified as important regulators of B-cell maturation, function and survival. Atacicept has shown selective effects on cells of the B-cell lineage, acting on mature B cells and blocking plasma cells and late stages of B-cell development while sparing B-cell progenitors and memory cells.

    The efficacy of atacicept in animal models of autoimmune disease and the biological activity of atacicept in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) has been demonstrated.

    Clinical studies were initiated to investigate the safety, tolerability and efficacy of atacicept in patients with MS. An unexpected increase in inflammatory activity in one of the trials, however, led to suspension of all atacicept trials in MS.

    Source: Medxscape Today Copyright © 1994-2010 by WebMD LLC (16/10/10)

    Immune system enzyme flaw may determine degree of MS severity

    B CellsA thesis from the Sahlgrenska Academy concluded that a flaw in one of the immune system's enzymes determines the degree of the severity of autoimmune diseases like multiple sclerosis (MS) and Guillain-Barré syndrome (GBS).

    These new findings can explain the way that this enzyme deficiency can be diagnosed and also why these diseases can vary so much.

    The immune system is based on white blood cells, that play a vital role in fighting against pathogens.

    The white blood cells contain an enzyme that transforms oxygen into reactive oxygen radicals – which break down microorganisms and stop infections, called NADPH oxidase.

    These new studies have used animal models to show that an inadequate production of oxygen radicals can favor the development of autoimmune diseases, as the patient's immune system would attack itself.

    The body has an ability of producing reactive oxygen radicals at an early stage in the immune defense against pathogens, and this has a serious impact on the way that these illnesses develop.

    Natalia Mossberg, doctoral student at the Institute of Neuroscience and Physiology at the Sahlgrenska Academy, said that “a strong but controlled production of oxygen radicals by the immune system is important for subduing illnesses such as MS and GBS.”

    These are the two autoimmune diseases that were covered by this thesis, as they can vary from insignificant to life-threatening, and their mechanism needed to be revealed.

    Mossberg says that they “wanted to look at this in humans, and examined the NADPH oxidase in the white blood cells of patients with MS, GBS and recurring GBS (RGBS).

    “The results show that patients with more severe forms of the illness have lower levels of oxygen radical production in their white blood cells as a result of deficient NADPH oxidase function.”

    Other autoimmune diseases can be investigated through this method, and this could help diagnose their severity.

    Also, early stages of MS treatment could benefit from a new approach, and use drugs that trigger the production of NADPH oxidase.

    Furthermore, researchers could develop a vaccination for people who are at risk of developing this kind of diseases.

    Source: Softpedia Copyright 2001-2010 Softpedia (11/10/10)

    New findings on multiple sclerosis, immune cells also attack neurons directly

    Immune CellsResearchers in Germany have gained new insight into how the immune system causes damage associated with multiple sclerosis (MS), an incurable neuroinflammatory disorder.

    Using imaging tools which enable investigation of processes in living organisms, they were able to show a direct interaction between immune cells and neurons which plays a significant role in neuronal injury. However, this direct interaction may respond to therapeutic intervention.

    The study by Dr. Volker Siffrin and Professor Dr. Frauke Zipp (formerly Max Delbrück Center for Molecular Medicine, MDC, Berlin-Buch, now University Medical Center Johannes Gutenberg University, Mainz) has now been published in the journal Immunity (DOI 10.1016/j.immuni.2010.08.018)*.

    Multiple sclerosis is an autoimmune disease in which a person's own immune system attacks the central nervous system. Symptoms of the disease are variable depending on which nerves are affected, but often include muscle weakness, walking difficulties, numbness and visual disturbances. Research has shown that MS is caused by damage to the protective myelin sheath, an insulating substance that surrounds nerve processes and is critical for transmission of nerve impulses.

    Research has also indicated that direct damage to neurons is prominent in early disease stages. "The contribution of direct neuronal damage to MS pathology has been debated since the first description of the disease," explained Professor Frauke Zipp, senior author of the study. "Although many different theories about possible underlying mechanisms have been proposed – such as neuron damage being a secondary effect of the disrupted myelin sheath – actual events leading to neural damage are not well understood."

    To investigate processes in the living organisms, Dr. Zipp and her colleagues used two-photon laser scanning microscopy (TPLSM), with which they studied the role immune cells play in neuronal damage in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. They observed direct synapse-like interactions between immune cells and neurons.

    T17 Cells

    Researchers in Germany have gained new insight into how the immune system causes damage associated with multiple sclerosis, an incurable neuroinflammatory disorder. Using imaging tools which enable investigation of processes in living organisms, they were able to show a direct interaction between immune cells and neurons which plays a significant role in neuronal injury. However, this direct interaction may respond to therapeutic intervention. The study by Dr. Volker Siffrin and Professor Dr. Frauke Zipp has now been published in the journal Immunity.
    (Photo Credit: Dr. Volker Siffrin/Copyright: MDC)

    Immune cells called Th17 cells, which have been linked to autoimmune inflammation, induced elevated calcium levels in the neurons, which in the long run are toxic to the cells. Normally, calcium within the neuron plays a crucial role in exciting nerve cells as well as muscle cells.

    This is significant because fluctuations in neuronal intracellular calcium levels that are linked to cell injury are partially reversible when the researchers expose the lesions of the animals to compounds used to treat excitotoxicity.
    These results highlight a specific interaction between the immune system and the nervous system, implicating direct neuronal damage in autoimmune-mediated inflammation. "Our use of in vivo imaging during disease has led to the characterization of neuronal dysfunction as early and potentially reversible, and suggests that immune-mediated disturbances of the neurons themselves contribute to multiple sclerosis, in addition to interruptions in nerve cell transmission as a result of changes to the myelin sheath," Professor Zipp concluded.

    "Furthermore, immune-mediated reversible calcium increases in neurons are a potential target for future therapeutics." However, it will take many years to find out if this is a strategy which will work for treating MS.

    Source: Science Codex (24/09/10)

    New pathway regulates immune balance, offers promising drug development target

    T CellsSt. Jude Children's Research Hospital scientists have identified a new pathway that helps control the immune balance through reciprocal regulation of specialized T lymphocytes, which play very different inflammatory roles.

    Investigators also determined that two drugs working in different ways to dampen the inflammatory response in patients with multiple sclerosis or following organ transplantation target this new mechanism. Further research into the pathway might lead to new medications to block other autoimmune disorders or to new anti-rejection drugs, researchers said. The work is published in the current online issue of Nature Immunology.

    T cells are the white blood cells responsible for both driving and modulating the immune response. This work focuses on a mechanism at work as T cells differentiate into the more specialized T-helper 1 (Th1) cells that drive inflammation or the regulatory T cells that work to shut it down and protect healthy tissue from a misguided immune attack.

    "The success or failure of the immune response requires T cells to make the right decision about their fate," said Hongbo Chi, Ph.D., assistant member of the St. Jude Department of Immunology and the paper's senior author.

    "In this paper we describe the receptor that controls the cell fate determination of different subsets of T cells; controlling the choice to become either an inflammatory or a regulatory T cell," Chi said. Earlier work from Chi and others linked the receptor, S1P1, to other aspects of T cell functioning.

    Researchers also found surprising evidence T cell response is regulated by a lipid the T cell secretes rather than a protein known as a cytokine. If confirmed, Chi said the finding would mark the first time a lipid, rather than a protein, served such a signaling function in T cells.

    For this study, investigators used both cultured cells and specially bred mice to link the S1P1 receptor to the fate of the two sub-groups of T cells. Stimulating S1P1 activates a pathway that drives the cell to become a pro-inflammatory Th1 cell. Th1 cells rally other immune components to act against infection and other threats. At the same time, S1P1 activation down regulates differentiation of regulatory T cells. The S1P1-dependent effect on both sub-groups of T cells relies on its ability to dampen signaling through another pathway in the T cell; this second pathway uses a different molecular route to influence the T cell's fate, working through cytokine TGF-beta activation of a signaling molecule called Smad3.

    "There is a reciprocal change between the two cell subsets. With this system, T cells that do not become regulatory T cells have a tendency to become T helper type 1 cells," Chi said.

    The S1P1 pathway is also targeted by the anti-rejection drug rapamycin, which is used to protect organ transplant patients, and FTY720, which has  become the first approved oral therapy for use against relapsing multiple sclerosis. This study is the first to show both work in part by modulating this molecular pathway.

    The work expands on earlier research from Chi's laboratory showing the S1P1 receptor played a central role in inhibiting the development and function of regulatory T cells. "In this paper, we show that the receptor controls differentiation of conventional T cells as well," he said, specifically Th-1 cells. S1P1 also plays a role in the movement of T cells throughout the body.

    Researchers are now focused on understanding the pathways in more detail. The questions include how S1P1 activates the mTOR pathway. Once activated, mTOR, a protein kinase complex, works to dampen signaling along the TGF-Beta Smad3 pathway, thereby promoting Th1 cell differentiation at the expense of regulatory T cells.

    The paper's co-first authors are Kai Yang of St. Jude and Guangwei Liu, formerly of St. Jude and currently of the Chinese Academy of Sciences. The other authors are Sharad Shrestha of St. Jude and Samir Burns, formerly of St. Jude.

    This work was supported in part by the National Institutes of Health, the Arthritis Foundation, the Lupus Research Institute and ALSAC.

    Source: Medical News Today © 2010 MediLexicon International Ltd (22/09/10)

    Class of immune cells involved in Multiple Sclerosis indentified

    T CellsScientists have identified a class of cells in mice, which determines the activity of their immune system against the pathogenic cells and the cells of their own tissues.

    The opening will lead to new methods of combating cancer and autoimmune diseases in humans, according to the journal Nature.

    According to the authors of this study, the discovery will deal with autoimmune diseases like lupus, type I diabetes, multiple sclerosis and others. Vaccines, used nowadays in order to intensify or strengthen the immune system to fight cancers, and thanks to this work they will have a longer duration of action. This, in turn, will significantly enhance the effectiveness of such methods in cancer therapy.

    “The traditional view of the immune system is of specialized groups of cells poised to attack foreign pathogens [disease-causing agents],” says senior author Harvey Cantor, MD, who is also the chair at the Department of Cancer Immunology and AIDS at Dana-Farber. “While that model is generally correct, we’ve come to appreciate that the immune system, like other complex biological information systems, includes a counterbalance mechanism – a set of cells programmed to suppress the immune response. Such cells are essential to preventing excessive reactions to pathogens and misguided attacks on the body’s own cells.”

    This work is not the first in this area – human immune system cells called T-cells CD4 +, are already known to the scientists. Their presence suppresses the inflammatory processes in tissues containing pathogenic cells, to which the immune response is directed.

    “Experience has shown that vaccines that simply activate or expand the number of T and B cells are not likely to result in a prolonged, robust anti-tumor response,” said Cantor. “The balancing mechanism within the immune system means that when more disease-fighting cells are generated, there’s a countervailing increase in the number of immune-suppressing cells that are generated. The key is to break that loop. This work brings that goal closer.”

    Source: Seer Press News © 2010 Seer Press (20/09/10)

    PTP-PEST discovery could impact treatment of Multiple Sclerosis

    T CellThe internationally-renowned scientific journal Immunity, from the Cell Press group, published online recently, and will publish in its August 27 print issue, the results of a study conducted by a team of researchers led by Dr. Andre Veillette, Director of the Molecular Oncology research unit at the Institut de recherches cliniques de Montreal (IRCM).

    Their scientific breakthrough could have an impact on the treatment of multiple sclerosis and other autoimmune diseases, which affect tens of thousands of Canadians.

    Dr. Veillette's team discovered the function of a protein located in T cells, which are immune cells known as lymphocytes that play a central role in the protection against viruses and other microbial agents. They also take part in the development of certain diseases, including diabetes and multiple sclerosis. The protein in question is the "phosphatase" PTP-PEST, an enzyme that removes phosphates from other proteins in the cell.

    "By removing PTP-PEST from mouse T cells, we determined that this protein was required for repeated immune responses such as those occurring during vaccination," explains Dr. Dominique Davidson, a researcher in Dr. Veillette's laboratory and first author of the study. "More particularly, we showed that PTP-PEST controls the activity of Pyk2, a molecule that stimulates the ability of cells to interact with one another and move within the body."

    The researchers showed that, through this mechanism, PTP-PEST stimulates the participation of T cells in an immune reaction. Once activated, T cells encourage other immune cells to join in an immune response, thereby explaining their pivotal role in this process. The team's results also show that the elimination of PTP-PEST in T cells can prevent certain autoimmune diseases, at least in mice. This suggests that suppressing the function of PTP-PEST through medication could be of value for the treatment of some human diseases.

    "The removal of PTP-PEST can unfortunately prevent immunization and weaken the response to a vaccine," concludes Dr. Veillette. "Fortunately, it can also prevent overactive immune responses and could eventually help treat autoimmune diseases. It's like a double-edged sword."

    According to the Multiple Sclerosis (MS) Society of Canada, MS is the most common neurological disease affecting young Canadians. Canada is known as having one of the highest prevalence rates of multiple sclerosis in the world, with an estimated 55,000 to 75,000 Canadians living with multiple sclerosis. The MS Society estimates that approximately 1,000 new cases of MS are diagnosed in the country each year, which means three Canadians are diagnosed with the disease every day.

    This research project was funded by the Canadian Institutes of Health Research (CIHR). "This new discovery regarding the immune regulatory properties of PTP-PEST may have profound implications for the treatment of MS and other autoimmune disorders," says Dr. Judith Bray, Assistant Director of the CIHR Institute of Infection and Immunity. "Current therapies for MS that target the immune system are general and can have significant adverse side effects, so clearly more specific, targeted therapies are needed. This is one of the reasons that CIHR has heavily invested in Clinical Autoimmunity research, in an effort to understand the mechanisms that cause autoimmune disorders and develop more effective treatments for them."

    Source: Medical News Today © 2010 MediLexicon International Ltd (22/08/10)

    Meningeal T cells associate with diffuse axonal loss in MS spinal cords

    T CellsAbstract

    OBJECTIVE: A link between diffuse axonal loss and diffuse inflammation has been established in the brain of patients with progressive multiple sclerosis (MS). In the present paper, we sought to determine whether such a link could be similarly demonstrated in the spinal cord of patients with progressive MS.

    METHODS: A neuropathological quantitative assessment of inflammation and axonal loss was performed in the cervical spinal cord of 18 patients with progressive MS and 5 control subjects.

    RESULTS: As previously reported, we found a mean 25% decrease of axonal density in the normal-appearing white matter (NAWM) of MS versus control spinal cords. T-cell perivascular infiltrates were rare, but a robust diffuse inflammation was observed in both the normal-appearing parenchyma and the meninges. The extent of diffuse axonal loss in the NAWM correlated with both the density of major histocompatibility complex (MHC) class II(+) microglia in the NAWM and, surprisingly, the density of CD3(+) T cells in the meninges. Interestingly, close interactions between T cells and MHC class II(+) macrophages were observed in the meninges of spinal cords from MS patients.

    INTERPRETATION: Recent studies assigned a major role to meningeal B-cell follicles in the pathophysiology of secondary progressive MS. The present work also emphasizes the link between meningeal inflammation and parenchymal lesions and points to a specific role exerted by both meningeal T cells and activated microglia in diffuse axonal loss in the spinal cord. ANN NEUROL 2010.

    Androdias G, Reynolds R, Chanal M, Ritleng C, Confavreux C, Nataf S.

    National Institute for Medical Research U842, Lyon, France.

    Source: Ann Neurol. 2010 Aug & Pubmed PMID: 20687208 (12/08/10)

    New study leads to hope of early MS diagnosis
    B CellsUCI immunological study finds earlier way to diagnose multiple sclerosis (MS).

    Assessing for the increasing presence of antibodies that blocks energy production in neurons, UCI immunologists discovered that it can be used also in diagnosing multiple sclerosis at an earlier stage of the disease than the usual diagnostic tools.

    The research demonstrated how these blockers initiate disintegration of both axons and neurons, leading to the removal of myelin, neurons’ protective coating.

    The research was headed Yufen Qin, assistant professor of neurology.

    The study reported that demyelination, or the removal of a neuron's protective covering, is the main determinant in detecting MS using spinal fluid tests at present.

    Quantifying the GAPDH inhibiting enzyme or antibodies, Qin says, could result in the fast and efficient treatment of MS, a commonly known debilitating disease that has the central nervous system as its usual target.

    The study appears online in The Journal of Immunology.

    Source: News-fire © 2010 / (02/08/10)

    Virus infection may trigger unusual immune cells to attack the brain and spinal cord in MS

    T CellsA virus infection can incite the body to attack its own nerve tissue by activating rare, disease-fighting cells with receptors for both viral and nerve proteins.

    The dual-receptor observation suggests a way nerve damage might be triggered in susceptible young adults afflicted with multiple sclerosis (MS).

    University of Washington Department of Immunology scientists Qingyong "John" Ji, Antoine Perchellet, and Joan M. Goverman conducted the study, which was published this week in Nature Immunology.

    This is thought to be the first study to reveal a mechanism for autoimmune disease that depends on destroyer immune cells expressing dual receptors for a normal protein made by the body and a pathogen.

    Multiple sclerosis is one of many autoimmune disorders in which the body's lines of defense become misguided and start damaging normal tissue. In the case of multiple sclerosis, the protective sheath around major nerves -- the myelin -- in the brain and spinal cord disintegrates. Like a frayed electrical cord, the nerves no longer transmit a clear signal.

    People with multiple sclerosis might lose their ability to see, walk, or use their arms, depending on which nerves are affected. The symptoms can appear, disappear, and re-appear. The disease is more common in women than in men.

    In healthy people, the immune system is kept in check to tolerate the usual proteins and cells in the body, much like an eager watch dog is put on a leash and trained to ignore friends and neighbours, yet still protect the family.

    "Autoimmunity is believed to arise from an accidental breakdown in this tolerance of the body's own proteins. This breakdown is triggered by something in the environment, most likely a pathogen," noted Goverman, professor and acting chair of immunology whose research concentrates on the origins of autoimmune disease. Her lab is studying mechanisms that maintain tolerance, as well as the "tripping" mechanisms that defeat it.

    In their most recently published study, her research team genetically engineered mice that over-produce a certain type of white blood cell from a group known as killer T cells. The normal function of killer cells is to attack tumor cells or cells infected with viruses or other pathogens. These T cells have receptors that recognize specific proteins that infected cells display to them, much like holding up a target in a window.

    The specific killer T cells examined in this study were CD8+ T cells. The Goverman lab engineered mice to over-produce CD8+cells that recognized myelin basic protein, a predominant protein in the myelin sheath that covers nerves. The major question investigated in the study was whether the genetically engineered mice would exhibit a disease that resembled multiple sclerosis.

    The researchers infected the mice with a virus that has itself been engineered to produce myelin basic protein. This infection should activate the CD8+T cells to first attack the virally infected cells making myelin basic protein to eliminate the virus, then kill other cells that make myelin basic protein to wrap around nerves. Killing those cells would destroy the myelin sheath.

    As expected, the mice developed a multiple sclerosis-like disease. But the researchers were surprised when viruses lacking the myelin basic protein also triggered the disease.

    Additional cross-breeding experiments revealed the existence of two receptors on a few of the CD8+T cells. These cells, engineered specifically to bind to myelin basic protein, also built their own receptors for viruses, and could recognize both. When exposed to cells infected with viruses, they would bind to and destroy them using one receptor. Geared up as if they were beserk, some of these double-agent cells then would head elsewhere to bind their other receptor to cells producing myelin basic protein and ruin the coats on nerve cells.

    "These results," the authors noted, "demonstrate a role for dual-receptor cells in autoimmunity." The study also points to why a ubiquitous viral infection could leave most people without any lasting effects, but trigger autoimmunity in genetically predisposed individuals.

    The findings open a new perspective on the proposal that multiple sclerosis is virally induced, despite the inability to detect infectious virus in the central nervous system of multiple sclerosis patients. Data from other studies show that CD8+T cells can cross the blood-brain barrier, and also that multiple sclerosis patients have more central nervous system protein-specific CD8+T cells, compared to healthy people.

    In the dual-receptor model, the autoimmune activity against nerve protein can continue after the virus is wiped out. Multiple sclerosis patients usually have high levels of antibodies indicating past infectious from several common viruses, but a live virus associated with multiple sclerosis has not been consistently observed. Therefore, to date, no specific virus has been confirmed as a causative agent for multiple sclerosis.

    The authors explained that it's possible that multiple viruses could influence susceptibility to multiple sclerosis. The ability of any particular virus to contribute to the disease could depend on an individual's own repertoire of other predisposing genes, exposure to other predisposing environmental factors, and the random chance that T cells had been generated that recognize a myelin protein and a pathogen.

    Receptors on T cells are randomly generated during their development. This observation helps explain why multiple sclerosis is partly a matter of chance. Some people with a genetic predisposition and environmental exposure develop the disease, while others with similar genetic predisposition and environmental exposure do not.

    It's uncertain how common these dual-receptor T cells are, according to the researchers, although there are reports that up to one-third of human T cells express dual receptors. Goverman and her group plan to test samples from multiple sclerosis patients and see how many have dual-receptor T-cells.

    A grant from the National Institutes of Health supported the study.

    Source: insciences organisation Copyright 2010 (11/06/10)

    Two noninvasive probes send snapshots of immune system in action, researchers say

    Immune CellsResearchers are reporting that they've used two different types of noninvasive probes to uncover the roles played by different types of cells in the immune system.

    One of the probes, known as an FDG, is commonly used in PET scans to track how cells break down glucose (sugar), while the so-called FAC probe -- developed recently at the University of California, Los Angeles -- measures the activity of specific biochemical pathways.
    The probes may help doctors evaluate treatments that target different cells in the immune system, senior study author Dr. Owen Witte, a professor of microbiology, immunology and molecular genetics at the University of California at Los Angeles, said in a news release from the school.

    "We demonstrated with this study that each probe targets different cells in the immune system with a high degree of specificity," said Witte, who added that the probes have special powers of detection, with the FDG probe recognizing immune system players like activated macrophages (immune scavenger cells) and the FAC probe recognizing activated lymphocytes (cells that lead the immune system charge on infected or cancerous cells).

    "When tested sequentially, the combined information from the scans using the two probes gives you a better status of immune response," Witte said.

    The probes were tested on mice and will be later tested on humans. Researchers think they could provide insight into how the immune system responds to diseases such as rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis.

    "This could give us another way to measure the efficacy of certain drugs," Witte said. "With some drugs, you could measure a change in the immune response within a week."

    Source: HealthDay © 2010 HealthDay. All rights reserved. (08/06/10)

    Out of the shadows: our unknown immune system

    Hook wormDeliberate infection with a blood-sucking worm seems an odd way to treat multiple sclerosis (MS).

    Yet more surprising is what this experiment may tell us about a "shadow" branch of our immune system. Completely unknown until recently, this is pointing to new ways of treating a host of complex diseases.

    A couple of recent studies suggest that parasitic infection dampens inflammation and reduces relapse rates in people with MS, in which the body's own cells are attacked by the immune system as if they were "foreign". So Cris Constantinescu at the University of Nottingham, UK, and his colleagues plan to place tiny hookworm larvae on the skin of 32 people with MS, allowing the worms to burrow down and infect the volunteers.

    The team won't just be looking for a reduction in volunteers' symptoms though. They will also be watching to see if the parasites boost numbers of a set of newly discovered immune cells, known as regulatory B cells (B regs).

    B regs are sending shockwaves through the immunology community. Until recently it was assumed that B cells' main role was to make antibodies at the behest of T-cells. These master regulators enhance or suppress an immune attack depending on the situation, as well as carrying out immune attacks in their own right. It was therefore thought that T-cells are at fault when the body attacks itself in autoimmune diseases, such as MS, asthma, diabetes and rheumatoid arthritis - and when it fails to route out disease agents, such as cancer cells.

    Now it seems that T-cells are not the immune system's only regulators. Experiments suggest that under some circumstances, B regs regulate T-cells, providing a shadow role for B cells.

    "Diseases we've traditionally thought to be mediated by T-cells might actually be regulated by B cells," says Kevan Herold of Columbia University in New York. Boosting B regs might therefore provide new opportunities for treating autoimmune diseases, while inhibiting B regs it could be a new way to treat cancer.

    Animal studies are already suggesting that the approach might work in one type of asthma. In a study published in May, Padraic Fallon of Trinity College, Dublin, and his colleagues isolated B regs from the spleens of mice infected with the parasite Schistosoma mansoni. When they transferred the B cells into mice primed to develop asthma, this either reduced their symptoms or stopped them developing asthma in the first place (The Journal of Allergy and Clinical Immunology, DOI: 10.1016/j.jaci.2010.01.018).

    "These are major regulators of the immune system in allergic disease," Fallon concludes. B regs seemed to work by releasing a chemical called IL-10 into the lungs, drawing in regulatory T- cells (T regs), which in turn inhibited immune attacks.

    IL-10 played a similar role in a subset of B regs, which Thomas Tedder at Duke University School of Medicine in Durham, North Carolina, calls B10 cells. His team found that transferring these cells into mice with a disease similar to multiple sclerosis reduced the severity of disease.

    Tedder has also identified similar cells in humans. "We can stimulate them and we can isolate them, but they're fairly rare," he says. He presented both findings in May at the annual American Association of Immunologists meeting in Baltimore, Maryland.

    The race is now on to identify drugs that might boost B regs in people with autoimmune diseases or suppress them in people who have cancer.

    One clue that such an approach might work comes from studies of rituximab, which kills B cells. First prescribed for the treatment of B cell lymphoma, a type of cancer, the drug has also reduced symptoms in people with diabetes, MS and rheumatoid arthritis. Rituximab most likely knocked out all the B cells to start with, and then, for some reason only the B regs grew back, which helped suppress autoimmunity, suggests Frances Lund of the University of Rochester Medical Center in New York (Nature Reviews Immunology, DOI: 10.1038/nri2729).

    In individuals with cancer, however, it might be desirable to suppress B regs. Preliminary evidence suggests that as well as keeping autoimmunity in check, B regs also help dampen the immune system's natural ability to recognise and destroy tumours.

    Tedder's team has already created antibodies that can deplete B10 cells - but not other B cells - in mice, and says he has similar antibodies that may selectively deplete human B10 cells - although he hasn't yet tested them in people.

    Arya Biragyn of the US National Institute of Aging, and his colleagues, also announced at the Baltimore meeting that they have identified a separate set of B regs that cancer seems to recruit in order to avoid detection by the immune system. Destroying these cells might make let's hope you have deep pockets cancer immunotherapies work better.

    "Even if you transiently wipe out B cells during immunotherapy, this should give you very potent anti-tumour responses against hidden tumour cells," Biragyn says.

    Working out how parasitic worms trigger B reg activity might suggest additional ways to do this - and to boost B regs. Indeed, Fallon has identified several molecules released by parasitic worms that seem to trigger B regs.

    Until such drugs are developed, parasites might be the best way to boost B regs. Severe hookworm infection can cause malnutrition, internal bleeding and anaemia, but in a mild and controlled infection, the dangers are minimal, says Constantinescu, though there may be some itchiness as the worms go through the skin.

    Source: New Scientist © Copyright 2010 Reed Business Information Ltd (04/06/10)

    When helper cells aren't helpful

    T CellsCurrent research suggests that T helper-type 1 (Th1) cells, previously thought to mediate autoimmunity, may actual inhibit the development of experimental immune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS), by suppressing Th17 cells.

    The related report by Wildbaum et al, "Antigen-specific CD25-Foxp3-IFN-γ high CD4+ T cells restrain the development of experimental allergic encephalomyelitis by suppressing Th17 cells," appears in the June 2010 issue of The American Journal of Pathology.

    MS is believed to be an autoimmune disorder, where damage to the nervous system is caused by the patient's own immune system. Th1 cells, which secrete high levels of the inflammatory mediator interferon-γ(IFN-γ), have been previously implicated as being pathogenic in autoimmune diseases such as MS. More recent data, however, suggests that antigen-specific T cells that produce the molecule IL-17 (Th17 cells) initiate the inflammatory process in EAE.

    As IFN-γ suppresses Th17 cell development, a group led by Dr. Nathan Karin at the Rappaport Family Institute for Research in the Medical Sciences hypothesized that IFN-γ-expressing T cells may serve as regulatory cells to block the development of autoimmunity. They discovered that EAE development depended on the death of these antigen-specific IFN-γ-expressing regulatory cells at early stages of disease and that inhibiting the killing of these cells at early stages of EAE suppressed disease development. In addition, overexpression of IFN-γ in EAE-mediating T cells caused them to act instead as antigen-specific regulatory cells. Thus, early suppression of Th17 cells may block the development of autoimmunity.

    Wildbaum et al conclude that "recent data from humans suggest that Th17 cells play an important role in the pathogenesis of a diverse group of immune-mediated diseases, including psoriasis, rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease, and that in these diseases Th17 cells are likely to be the driver cells even at advanced stages. This makes the challenge of understanding the regulatory mechanisms underlying Th17 function highly applicable, even at advanced stages of these diseases."

    Dr. Karin states that "the vast majority of multiple sclerosis patients develop a form of diseases know as relapsing-remitting disease, or relapsing-progressive disease, in which attacks are followed by remissions. It is believed that regulatory cells play a major role in restraining the progression of disease." In future studies, Dr. Karin's group will "explore the hypothesis that these new types of regulatory cells indeed participate in the regulation of multiple sclerosis, and if so, determine the mechanistic basis of their entry to program cell death just before the disease accelerates. In particular, [they will attempt to define] what makes these regulatory cells more susceptible to entering the process of programmed cell death compared with other cell types? This may lead to the development of novel ways to treat multiple sclerosis and other inflammatory autoimmune diseases."

    This study was supported by grants from the Israel Science Foundation (ISF), The Israel Ministry of Health Chief Scientist, and the by the L. Aronberg Research Fund in Neurology.

    Wildbaum G, Zohar Y, Karin N : Antigen-specific CD25-Foxp3-IFN-γ high CD4+ T cells restrain the development of experimental allergic encephalomyelitis by suppressing Th17 cells. Am J Pathol 2010, 176: 2764-2775

    Source: Eureka Alert! (24/05/10)

    Clearer picture of immune response to disease emerges

    Immune CellsCombination of 2 PET-scan probes provides clearer picture of immune response to disease.

    A commonly used PET-scanning probe and a new probe developed by UCLA researchers reveal different functions in diverse cells of the immune system and, when used in combination, provide a much clearer picture of an immune response in action, according to a new UCLA study.

    In addition to monitoring the extent and cellular composition of an immune response, the probes — FDG, which measures cellular glucose metabolism, and the UCLA-developed FAC, which measures the activity of a distinct biochemical pathway — may be useful in evaluating therapies that target different cellular components of the immune system, said the study's senior author, Dr. Owen Witte, a UCLA professor of microbiology, immunology and molecular genetics and a Howard Hughes Medical Institute investigator.
    "We demonstrated with this study that each probe targets different cells in the immune system with a high degree of specificity," said Witte, who is also director of the UCLA Broad Stem Cell Research Center and a researcher at UCLA's Jonsson Cancer Center.
    "When cells are activated to do their job as an immune cell, the FDG probe is good at recognizing the subset of activated macrophages, while the FAC probe is good at recognizing the activated lymphocytes, as well as the macrophages," he said. "When tested sequentially, the combined information from the scans using the two probes gives you a better status of immune response."
    The study, with lead author Evan Nair-Gill, a student in UCLA's Medical Scientist Training Program, was conducted on mice bearing virally induced sarcomas. The article is currently available in the early online edition of the Journal of Clinical Investigation. Testing the probes in humans is the next step, the researchers say.
    The scans provide clues to how the immune system works — for example, in response to cancer or autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis, Witte said. They also could be used to see how therapies, such as vaccines and monoclonal antibodies meant to stimulate an immune response, are functioning within the body of a patient.
    "This could give us another way to measure the efficacy of certain drugs," Witte said. "With some drugs, you could measure a change in the immune response within a week."
    If the drugs are working, Witte said, doctors could stay the course; if not, the therapy could be discontinued, sparing the patient months of exposure to an ineffective drug.
    The researchers say they plan to test the two probes in humans with a range of diseases, including cancer and autoimmune disorders, to confirm the work.
    The university licensed the FAC probe to Sofie Biosciences, a startup company owned in part by Witte and other UCLA faculty members. Researchers created the small molecule by slightly altering the molecular structure of one of the most commonly used chemotherapy drugs, gemcitabine. They then added a radiolabel so the cells that take in the probe can be seen during positron emission tomography (PET) scanning.
    The probe measures the activity of a fundamental cell biochemical pathway called the DNA salvage pathway, which acts as a recycling mechanism that helps with DNA replication and repair. All cells use this biochemical pathway to different degrees. But in lymphocytes and macrophages that are proliferating during an immune response, the pathway is activated to very high levels. Because of that, the probe accumulates at high levels in those cells, Witte said.

    Source: (21/05/10)

    Important control mechanism behind autoimmune diseases discovered

    B CellsResearchers at the Swedish medical university Karolinska Institutet have discovered a new control mechanism in our immune system. The discovery is of potential significance to the treatment of serious diseases such as MS (multiple sclerosis), rheumatoid arthritis, and SLE (Systemic lupus erythematosus).

    "Now that we've started to understand the regulatory mechanisms involved in these autoimmune diseases, we are hopeful that new treatments can be found," says Mikael Karlsson, associate professor at the Department of Medicine at Karolinska Institutet in Solna, and one of the team behind the study now published in the highly reputed periodical, The Journal of Experimental Medicine.

    An important component of our immune defence is a type of cell called a B cell. Normally, the job of these cells is to produce antibodies, which in turn bind to and neutralise invasive microorganisms, such as bacteria and viruses. In people with an autoimmune disease, explains Dr Karlsson, these B cells actually have an injurious effect and instead of serving the body, are activated against its own tissues, which they start to break down.

    Patients with SLE and other autoimmune diseases have lower levels of so-called NKT cells. Previously, it was not known what part these cells play in the origin and development of the disease; now, however, the research group at KI has shown that this deficiency is a contributory pathogenic factor.

    "We've demonstrated that NKT cells can regulate how B cells become activated against healthy tissue, and that a lack of NKT cells results in greater misguided B cell activation," says Dr Karlsson. "So now we can mechanically link the NKT cell defect in patients to the disease."

    The study also shows that the NKT cells directly impede faulty B cell activation, and that they do so early in the misdirected process. The team managed to inhibit the activity of pathogenic B cells by adding NKT cells - a result that may one day lead to new types of treatment.

    "This means that new treatments specifically targeting the protective NKT cells can help this patient group," concludes Dr Karlsson.

    Source: Medical News Today © 2010 MediLexicon International Ltd

    Muzzling killer T-cells may ease multiple sclerosis

    T CellsScientists identify potassium ion channel that T-cells use to kill target cells.

    Scientists at Hopkins' Department of Neurology have shed light on the way through which killer T cells induce apoptosis in their target cells around them, a discovery that could have ramifications for autoimmune diseases such as multiple sclerosis and stroke.

    Tongguang Wang, Avindra Nath and their colleagues at the School of Medicine have been trying to puzzle together the effect killer T cells have on neural progenitor cells (NPCs) - stem cells that have the potential to differentiate and become neurons.

    Though the immune system means well, sometimes, immune activation just isn't in the best interest overall of the organism - a situation widely acknowledged in patients who have suffered from stroke, or even those who endure multiple sclerosis (MS).

    In both of these disorders, the immune system, and killer T cells in particular, are inappropriately activated to protect the body when, in fact, the body is not in danger.

    Unfortunately, as killer T cells are killers, as their name implies, when they take action, sometimes the outcome is extreme - and often extremely detrimental to the organism.

    Figuring out how to modulate or even block this "killing" spree might prove in the end to be a beneficial treatment option for patients who suffer from MS or from stroke.

    The killer T cells secrete a signaling molecule called granzyme B (GrB). Granzyme B binds to a type of receptor molecule called a Gi-protein coupled receptor on the surface of neural progenitor cells.

    Once activated, the Gi-protein goes on to turn off the production of a small signaling molecule called cyclic AMP (cAMP). Cyclic AMP usually inhibits certain genes, and in its absence, transcription of these genes are turned on full blast.

    One of the genes that get transcribed as a result of this signaling sequence codes for a voltage-gated potassium (K+) ion channel called Kv1.3. In a healthy neural cell, the concentration of potassium is higher inside the cell than outside, and ions can only pass through to either side through the gated channels.

    Now, with so many extra Kv1.3s in the membrane of the cell, too much potassium floods out of the cell. For various reasons, this is an inhibitory signal to NPCs, which stop proliferating and stop differentiating.

    In other words, the cells that could become neurons instead die and don't make any more neurons, leaving the brain a few cells short of a full ride to Hopkins and the brain in a serious state of atrophy and deterioration.

    The recent work by Nath and Wang might shed some light on how scientists can approach the problems seen not in only MS, but also in stroke, as well as in other neurodegenerative disorders.

    The team has discovered a way to ameliorate the problems caused by having so many Kv1.3 proteins hanging out in the cell membrane, allowing the leakage of potassium from the intracellular environment.

    They have studied two ways the Kv1.3 pathway can be inhibited: blocking the channels' activity directly and decreasing expression of the gene for Kv1.3. In both methods, the negative effect usually seen when GrB signals to NPCs was lifted, allowing for normal proliferation and regeneration to occur.

    Thus, if scientists and physicians can better elucidate the mechanisms at work here, they may one day be able to apply these findings in a clinical setting to prevent the neural degeneration seen as a result of immune activation of killer T cells.

    Because Kv1.3 happens to be overexpressed in not only the NPCs to which killer T cells are signaling, but also in the killer T cells themselves, an even more promising line of research might be to attack the Kv1.3 proteins themselves.

    Any attack of Kv1.3 would have the advantage of being inherently two-fold, as it would work to decrease the signaling cascade not only in the receptive cell (the NPC), but also in the sending cell (the killer T cell).

    The increase of Kv1.3 in killer T cells is correlated with their activation, so by blocking this path, the T cells wouldn't be able to go around attacking any NPCs - leaving those NPCs safe, happy, and able to go on proliferating and helping the brain regenerate another day.

    Source: The John Hokins News-Letter © 2010 News-Letter (26/04/10)

    Italian researchers discover a possible onset mechanism for Multiple Sclerosis

    T CellsA non-pathogenic bacterium is capable to trigger an autoimmune disease similar to the multiple sclerosis in the mouse, the model animal which helps to explain how human diseases work.

    This is what a group of researchers from the Catholic University of Rome, led by Francesco Ria (Institute of General Pathology) and Giovanni Delogu (Institute of Microbiology), have explained for the first time in a recently published article on the Journal of Immunology.

    Multiple sclerosis is a disease due to an inflammatory reaction provoked by the immune system. It causes the disruption of the coating of the nerve fibres in the Central Nervous System.

    "We do not know what causes multiple sclerosis", explains Francesco Ria, immunologist of the Catholic University. "We know that there exist a genetic factor and an environmental factor, but we do not yet posses a satisfactory theory which can explain how exactly this environmental factor works".

    Currently, there are two competing theories on the field: according to a first hypothesis, a virus hides within the brain and what causes the disease is the immunologic antiviral reaction. On the other hand, the second hypothesis states that a viral or bacterial pathogen similar to specific molecules of the Central Nervous System causes an inflammation which provokes a reaction of the immune system. This reaction ends up destroying the brain cells. The latter is called the autoimmune hypothesis.

    This is the hypothesis that the researchers coming from the Institutes of General Pathology, Microbiology and Anatomy of the Catholic University of Rome have been testing with their two-year long work.

    To demonstrate the viability of this idea, scientists have fooled the mouse immune system, modifying subtly a bacterium of the common family of mycobacteria (the same family to which also the bacterium causing tuberculosis belongs) to make it look like to myelin, the protein coating nerve cells. This modified mycobacterium is completely innocuous. As all external agents, though, it is capable to trigger the reaction of the T-cells of the immune systems. They intervene to destroy it. Since they are innocuous bacteria, although very common in the environment, and since they induce an immune reaction, they are the ideal bacteria scientists can use to study the environmental factor contributing, together with the genetic factor, to cause multiple sclerosis.

    "Normally, T-cells cannot penetrate into the Central Nervous System", adds Rea, "because the hematoencephalic barrier prevents them from doing so. But the bacterium modifies the characteristics of the T-cells and allows them to overcome the barrier. In 15 days the bacterium disappears completely from the body".

    Yet these T-cells can now enter into the brain. This way, they begin to attack the myelin of the nerve cells, and here is how the immune disease breaks out.

    "We basically demonstrate – explains Rea – that in an animal model it is possible to be infected with something not carrying any disease, and later on develop a purely autoimmune disease".

    Yet there is another element in this complex research, sponsored by the Italian Association of Multiple Sclerosis (AISM). "Normally – clarifies Rea – to understand which diseases we have encountered, we measure the antibodies produced by that specific pathogen. But there is a whole world of infectious agents which do not induce the production of antibodies, as is the case in our research: mycobacteria and many other bacteria produce a very low and variable number of antibodies. It is thus very hard to establish whether a population has encountered that specific infectious agent. So, we demonstrate that those infectious agents which are more likely to produce an autoimmune reaction are just those which do not induce antibody production".

    Obviously, this is only the first step to better understand the way this very complex and devastating disease works. Ria and Delogu are not stopping here: "We want to try to understand the exact characteristics which this infectious agent should have", they explain. "Might it truly be a good experimental model for multiple sclerosis? If we had prolonged the action of the bacteria, would we have favoured or hampered the development of the disease? And what about the myelin-like bacterium protein: where should it lie? On the surface, or inside? These are all questions – conclude the two researchers – which we will be trying to answer in the next years, in the hope to defeat this terrible illness. We could even imagine to develop a vaccine by which we could prevent the immune response associated to multiple sclerosis".

    Source Eureka Alert! (26/02/10)

    Blocking cell movement for possible Multiple Sclerosis treatment

    Immune CellsUniversity of Adelaide researchers in Australia are finding new ways to block the movement of cells in the body which can cause autoimmune diseases and the spread of cancer.

    Led by Professor of Immunology Shaun McColl, the researchers have identified molecular "receptors" on the surface of cells which are involved in helping cells migrate to sites where they can cause disease.

    "A number of diseases like cancer and autoimmune diseases, such as multiple sclerosis and arthritis, involve the inappropriate migration of cells," says Professor McColl.

    "Our research shows that these receptors which help the cells migrate can be blocked pharmacologically, preventing the cell migration which causes the disease."

    The researchers have identified a number of such receptors in multiple sclerosis and have developed potential therapeutic drugs that could control this disease, and other autoimmune diseases.

    They are also in the process of identifying receptors on the surface of metastatic cancer cells.

    "These are exciting research outcomes and will offer new treatments for these diseases which affect millions of people," says Professor McColl.

    Professor McColl is Head of Chemokine Biology, Deputy Head of the School of Molecular and Biomedical Science and Deputy Executive Dean of the Faculty of Sciences at the University of Adelaide.

    Source: Science Daily © 1995-2009 ScienceDaily LLC (11/02/10)

    Australian study questions established concepts of early disease events in MS

    T CellsInvestigators at the University of Sydney have published a study suggesting that the earliest activity seen in the brain in MS is the destruction of cells that make myelin (oligodendrocytes), occurring before the onset of immune activity usually blamed for triggering the disease.

    This provocative study, co-funded by many sources including the National MS Society, opens up new possibilities for finding the cause of the disease and developing new treatments. The study is authored by Drs. John W. Prineas, Andrew P.D. Henderson and colleagues, and is published in the December issue of Annals of Neurology (2009;66:739–753).

    Background: Multiple sclerosis has long been thought to be triggered by immune attacks in the brain and spinal cord, causing a spectrum of neurological symptoms. Extensive research has been underway to better understand what triggers the immune attacks and which immune cells are involved, and to better understand the damage to the central nervous system that occurs during the course of MS. In addition to studies of immune activity underlying what has been considered an autoimmune process, another important approach has centered on pathology studies involving microscopic explorations of MS lesions (damaged areas, also called plaques) in the brains of people with MS.

    The lead author of the current study, John W. Prineas, MB, BS, FRCP, was the 2001 winner of the John Dystel Prize for MS Research, an award given jointly by the National MS Society and the American Academy of Neurology. He was recognized for being the investigator who first described how myelin, the substance that insulates nerve fibers, is broken down in MS, and he was the first to demonstrate that myelin repair occurs during the course of MS through the body’s natural repair processes.

    Current Study: For this study, the team used brain specimens from 11 people who had died early in the course of their MS, and the team also used comparison specimens from people with other disorders including stroke. Some of the tests focused on subsets of specimens from seven people who had lesions showing active myelin destruction. To get a sense of immune cell activity in the brain and at what stage it was occurring, the team examined newly active and resolved lesions, as well as nearby blood vessels, surrounding areas showing some disease activity and surrounding areas that appeared normal, and areas that were farther away from the lesions of interest.

    Results: In tissues surrounding newly forming lesions, the investigators found evidence of the loss of oligodendrocytes with an absence of immune T or B cells that would normally be held responsible for launching the immune attack against oligodendrocytes and the myelin they produce. These and other immune cells, including scavenger cells (macrophages and microglia), were more numerous in lesions and surrounding tissues at apparently later stages of destruction and sometimes in lesions that were in the process of repair. In specimens from two very early cases of clinical onset of disease, they found few immune cells within the lesions and no evidence of activation of scavenger cells.

    These and other unexpected findings from this study led the investigators to propose that the early immune activity seen in active lesions is that of macrophages and microglia, whose job it is to clean up and remove damaged myelin. They propose that lesion formation is caused by something other than destructive immune activity led by inflammatory cells against a component of myelin or oligodendrocytes.

    Comment: This study is a significant addition to a small but growing body of evidence that highlights the question of what triggers MS and whether there is something other than, or in addition to, the immune attacks that lead to tissue damage in the brain and spinal cord of people with MS. Further research, which is ongoing by investigators around the world, should shed further light on this question and may offer novel treatment approaches.

    Note: The availability of donor brain specimens was crucial to this and other studies focusing on disease pathology

    Source: US National Multiple Sclerosis Society (30/01/10)

    New tool in fight against autoimmune diseases, blood cancers

    T CellsA study led by a Scripps Research Institute scientist describes a new, highly pragmatic approach to the identification of molecules that prevent a specific type of immune cells from attacking their host. The findings add a powerful new tool to the ongoing search for potential treatments for autoimmune diseases, such as multiple sclerosis (MS), as well as blood cancers, such as myeloid leukemia.

    The study by Thomas Kodadek, a professor in the Chemistry and Cancer Biology Departments at Scripps Florida, and colleagues was published in the journal Chemistry & Biology.

    In the new study, Kodadek and his colleagues used samples from an animal model of multiple sclerosis to screen for T cells -- a type of white blood cell that plays a central role in the immune system -- with a heightened presence in the disease. The screen also identified molecules that interfere with these T cells' "autoreactivity," in other words, their attack on the body itself rather than a foreign invader such as virus or bacteria.

    "Our technique simultaneously uncovers and isolates autoreactive T cells as well as inhibitors to them," Kodadek said. "It's a double whammy. At the heart of this is a comparative screening process of normal T cells versus disease-causing T cells. While the process is technically complicated and difficult, the thinking behind it is not. We wanted to simplify the process of identifying compounds that could inhibit autoreactive T cells with exceptional specificity, and we succeeded."

    The scientists used a model of MS, an autoimmune inflammatory disease affecting the brain and spinal cord, for the study. In MS, the immune system attacks the myelin sheath covering and protecting nerve cells, leading to a variety of symptoms depending on which part of the nervous system is affected. Common symptoms of the condition include fatigue; numbness; walking, balance, and coordination problems; bladder and bowel dysfunction; vision problems; dizziness and vertigo; sexual dysfunction; pain; cognitive problems; emotional changes; and spasticity.

    Simplifying the Process

    In setting up the new method to shed light on such autoimmune diseases and other disorders, Kodadek and his colleagues created a large collection of peptoids -- molecules related to, but more stable than, the peptides that make up proteins. By arranging thousands of peptoids on a microscope slide, the pattern of binding antibodies (a type of immune molecule) and peptoids can be visualized. By looking at samples from animal models of a known disease like MS, peptoids that bind to antibodies closely associated with that disease can be easily recognized.

    Better still, peptoids that bind to autoreactive T cells can be identified without knowledge of the specific antigen (molecule triggering the immune attack), providing an unbiased method with which to search for potentially useful compounds.

    Most autoimmune research has focused on finding the disease-causing antigens first, Kodadek said, a Quixote-like quest that has lasted more than four decades with little success to show for it.

    "With our process, it doesn't really matter what the antigen is," said Kodadek, a 2006 recipient of the National Institutes of Health Director's Pioneer Award, which is designed to support individual scientists of exceptional creativity. "That was really the breakthrough. We're setting up a system that recognizes T cell receptors that are very abundant in a sick animal and at low levels in a healthy animal. Why the abundance? Because that's what making them sick."

    Potential for Therapeutic Discovery

    The new process creates new potential for therapeutic discovery. Molecules that target autoreactive T cells directly, while ignoring those T cells that recognize foreign antigens, could serve as the foundation for a novel drug development program aimed at eradicating autoreactive cells without affecting the normal function of the immune system.

    "Almost without exception, drugs currently used to treat autoimmune conditions either inhibit something downstream of the autoimmune response itself, like inflammation, or they moderate the immune system non-selectively and that results in significant side effects," Kodadek said.

    However, the new study isn't the final answer, according to Kodadek. He noted that the recent study used a model of MS triggered by a single antigen. In humans, there could be two -- or two dozen -- antigens triggering an autoimmune disease such as MS. This calls for further research. The method may be more easily applied to blood cancers, though, since the disease-causing T cells have been fully characterized and there are very few of them.

    Source: ScienceDaily © 1995-2009 ScienceDaily LLC (01/12/09)

    Herpes viruses and human endogenous retroviruses raised in active Multiple Sclerosis

    B CellsB cells and monocytes from patients with active multiple sclerosis exhibit increased surface expression of both HERV-H Env and HERV-W Env, accompanied by increased seroreactivity.

    The etiology of the neurogenerative disease multiple sclerosis (MS) is unknown. The leading hypotheses suggest that MS is the result of exposure of genetically susceptible individuals to certain environmental factor(s).

    Herpes  viruses and human endogenous retroviruses (HERVs) represent potentially important factors in MS development. Herpes viruses can activate HERVs, and HERVs are activated in MS patients.

    Results: Using flow cytometry, we have analyzed HERV-H Env and HERV-W Env epitope expression on the surface of PBMCs from MS patients with active and stable disease, and from control individuals.

    We have also analyzed serum antibody levels to the expressed HERV-H and HERV-W Env epitopes. We found a significantly higher expression of HERV-H and HERV-W Env epitopes on B cells and monocytes from patients with active MS compared with patients with stable MS or control individuals.

    Furthermore, patients with active disease had relatively higher numbers of B cells in the PBMC population, and higher antibody reactivities towards HERV-H Env and HERV-W Env epitopes. The higher antibody reactivities in sera from patients with active MS correlate with the higher levels of HERV-H Env and HERV-W Env expression on B cells and monocytes.

    We did not find such correlations for stable MS patients or for controls.

    Conclusions: These findings indicate that both HERV-H Env and HERV-W Env are expressed in higher quantities on the surface of B cells and monocytes in patients with active MS, and that the expression of these proteins may be associated with exacerbation of the disease.

    Author: Tomasz BrudekTove ChristensenLars AagaardThor PetersenHans HansenAnne Moller-Larsen

    Ref: Retrovirology 2009, 6:104

    Source: 7thSpace Interactive © 2009 7thSpace Interactive (17/11/09)

    Crossing the line: how aggressive cells invade the brain

    T Cells

    In diseases such as multiple sclerosis, cells of the immune system infiltrate the brain tissue, where they cause immense damage.

    For many years, it was an enigma as to how these cells can escape from the bloodstream.

    This is no trivial feat, given that specialised blood vessels act as a barrier between the nervous system and the bloodstream. Until now, tissue sections provided the sole evidence that the immune cells really do manage to reach the nerve cells.

    Now, a team of scientists from the Max Planck Institute of Neurobiology, the University Medical Center Göttingen, and other institutes, has witnessed the movements of these cells "live" under the microscope for the very first time. In the process, they discovered several new behavioural traits of the immune cells.

    The consolidated findings mark a significant step forward in our understanding of this complex disease ("Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions").

    The picture shows the movement of creeping T-cells (green) inside blood vessels (red) over a period of about 20 minutes. It clearly shows that some T-cells leave the blood vessels - the long exposure lets them leave a green trail as the cells make their way through the brain tissue. (Image: Max Planck Institute of Neurobiology / Bartholomäus)

    The brain and the spinal cord monitor and control the functions of all body parts and co-ordinate the whole organism's movements, senses and behaviour. Adequate protection of the brain and spinal cord are therefore of the utmost importance. Physical influences and injuries are warded off by the cranial bone and the vertebral column. Dangers lurking within the body, such as viruses circulating in the bloodstream, are kept at bay by highly specialized blood vessels. The vessels' walls form a barrier that cannot be penetrated by the cells or various other small particles, thus serving to protect the delicate nerve cells.

    There are, however, exceptions to the rule. In diseases such as multiple sclerosis (MS), aggressive cells in the immune system manage to break through the blood vessels' barrier. Having invaded the brain tissue, these cells wreak havoc by triggering off inflammatory reactions and attacking nerve cells. In Germany alone, the resulting adverse effects afflict over 120,000 MS-patients.

    Tracking down the culprits
    Since there is normally a clear division between the blood circulatory system and the central nervous system (i.e. brain plus spinal cord), scientists were baffled as to how immune cells manage to cross the blood-brain-barrier. This knowledge may aid in understanding the origins of multiple sclerosis. In the 1980s, scientists were able to prove conclusively that, under certain conditions, so called T-cells can recognize and attack components of the body's own brain cells. Thanks to tissue sections performed over the last few decades, scientists now have much better knowledge of the migration of these cells from their point of origin to their point of penetration into the brain and the damage that they cause. However, actual observations of such movements long remained impossible.

    Observing aggressive cells in action
    Scientists at the Max Planck Institute of Neurobiology, the University Medical Center Göttingen and their colleagues have now overcome this impossibility. Using a two-photon microscope, the researchers succeeded in tracing the movements of aggressive T-cells labelled with the green fluorescent protein (GFP) in the living tissue of rats. The systematic observation of these cells during the course of the disease provided amazing new insights into the cell's behaviour.

    The scientists discovered that the aggressive T-cells overcome the barrier between blood and nerve tissue in a number of steps. Outside the nervous system, the labelled cells moved just as we would expect them to; most cells were floating along with the flow of the bloodstream. Only now and again did a cell attach itself briefly onto the vascular wall. Here they rolled in the direction of the blood stream or were being carried off again by the current. Yet, once the cells reached the blood vessels of the nervous system, they began to act in a completely different manner.

    The scientists observed here far more cells clinging to the vascular walls. "Things got really exciting when we observed that the cells can actually creep, a behaviour so far unheard of for T-cells", Ingo Bartholomäus relates his observations. Here, "creeping" describes an active cell movement, usually against the flow of the bloodstream. The scientists watched T-cells as they took anything between a few minutes and several hours to creep along the vessels' walls. At the end of such a search movement, the cells were either swept away again by the bloodstream or they managed to squeeze through the vascular wall.

    Ominous encounters
    Having successfully penetrated the blood-brain-barrier, the cells continued their search in the vicinity of the blood vessels. It was thus only a question of time before the T-cells encountered one of the phagocytic cells abundant on the outer linings of blood vessels and on the surface of the nerve tissue. When a mobile T-cell came across such a phagocyte, the two cells formed a closely connected pair. Some of these pairs remained inseparable for several minutes.
    Although the scientists already knew that T-cells must make contact with phagocytes in order to become immune-activated, they were now able to observe these interactions right where they happened, i.e. at the blood-brain-barrier. And indeed, the T-cells did not launch their attack on the nervous system by releasing their inflammatory neurotransmitters until they had bonded with the phagocytes.

    As a result of the T-cells' activation, more and more T-cells passed through the vascular walls. "The activation of T-cells at the border to the nerve tissue appears to be a decisive signal for the invasion of the immune cells", concludes Alexander Flügel, supervisor of the study and director of the Department of Experimental and Clinical Neuroimmunology at the University Medical Center Göttingen and Head of the MS Hertie-Institute.

    Light bulb moments
    Thanks to their sophisticated observation methods, the scientists also established that some of the antibodies already being used in MS-therapy cause the creeping cells to disappear. As Ingo Bartholomäus explains "Up to now, it was only known that these antibodies prevented the T-cells' escaping from the blood vessels, but as our observations now show, they actually prevent them from creeping".

    Thanks to the scientists' observations, we now have a much clearer picture of how the immune cells move and obtain access to the nervous system. This knowledge is likely to also increase our knowledge of the immune system's security system functions in healthy tissue. However, as is often the case, new insights and information also give rise to many new questions.

    How do the immune cells manage to cling to the lining of the blood vessels and how do they recognize the weak spots, where they can slip through the barrier between the bloodstream and the nervous system? What governs the cells once they have surmounted the blood-brain-barrier?

    These are some of the questions the scientists will be addressing next. The long-term goal will be to develop new forms of therapy and medication for multiple sclerosis and other diseases.

    Source: Nanowerk ©2009, Nanowerk LLC. (06/11/09)

    Multiple sclerosis: T cells as serial killers

    T CellsIn multiple sclerosis, the immune system damages the nerve cells with its misguided activities. This is what regularly happens in the targeted immunological attack on the myelin sheaths of the nerve cells, as shown experimentally for the first time by researchers from Würzburg and Zürich.

    Inflammations in the central nervous system can be triggered by viruses or by the immune system. The latter is the case in multiple sclerosis. With drastic consequences: The cells responsible for building and maintaining an insulating sheath around the nerve fibers die off. The sheaths degenerate as well and often even the nerve cells are destroyed eventually.

    "In the example of multiple sclerosis, not only the loss of the myelin sheaths but particularly the death of the nerve cells is thought to be decisive for the permanent disabilities that many patients have to deal with," says Professor Heinz Wiendl at the Department of Neurology of the University of Würzburg. Such disabilities include paralysis or impaired vision.

    Now, for the first time, two study groups have simultaneously shown that certain T cells of the immune system not only directly affect the myelin-generating cells but also cause "collateral damage" to the nerve cells or their extensions. The research has been published in the journals Glia and American Journal of Pathology.

    T cells: Indirect effect causes nerve cells to die

    Wiendl's team at the Department of Neurology of the University of Würzburg was able to demonstrate this with brain tissue cultures: T cells exclusively targeting a specific structure on the surface of the myelin-generating cells also caused a significant loss of nerve cells within just a few hours. How this indirect effect might be accounted for is explained by Würzburg researcher Sven Meuth: "Possibly, the T cells release some soluble factors, such as perforin or granzyme B, which in turn migrate to and damage the nerve cells."

    Serial murder: Each T cell strikes many times

    The aggressive T cells act just like serial killers: "Every single one of them can kill off up to 30 myelin-generating cells and - at the same time - destroy up to ten nerve cells," says Heinz Wiendl.

    These T cells virtually cut through the extensions of the nerve cells. This has been established by the team headed by Professor Norbert Goebels of the University of Zürich (now Düsseldorf) in a similar experimental approach by means of video analysis.

    Possible target for new therapies

    "These results help us to better understand the development of acute and chronic damage in inflammations of the central nervous system," explains Professor Wiendl. In future, the patients might also benefit from the findings - after all, the aggressive T cells are an attractive target for new therapies. Therefore, the Würzburg scientists are eager to find out as much as possible about these serial killers.

    Multiple sclerosis: about the disease

    Globally, approximately 2.5 million people are affected by multiple sclerosis; in Germany, there are about 122,000 patients according to current estimates. Here, approximately 2,500 new cases of the disease are diagnosed per year. Women aquire the disease almost twice as often as men.

    In MS patients, the immune system mistakenly attacks the components of the nervous system, most prominently the nerve sheaths eventually destructing neural cells. Most often, the onset of the disease starts in early adulthood with relapsing remitting neurological symptoms. Initially people affected perceive tingling sensations in arms and legs, have walking disturbances or encounter visual problems. In the course of disease patients often acquire permanent disability. Some of them need a wheel-chair at later stages.

    At the moment, there is no cure for multiple sclerosis; however, medical treatment can alleviate the symptoms of the patients and improve their quality of life.

    Source: Department of Neurology of the University of Würzburg (14/10/09)

    Master gene that switches on disease-fighting cells identified by scientists

    Immune CellsThe master gene that causes blood stem cells to turn into disease-fighting ‘Natural Killer’ (NK) immune cells has been identified by scientists, in a study published in Nature Immunology Setember 13. The discovery could one day help scientists boost the body’s production of these frontline tumour-killing cells, creating new ways to treat cancer.

    The researchers have ‘knocked out’ the gene in question, known as E4bp4, in a mouse model, creating the world’s first animal model entirely lacking NK cells, but with all other blood cells and immune cells intact. This breakthrough model should help solve the mystery of the role that Natural Killer cells play in autoimmune diseases, such as diabetes and multiple sclerosis. Some scientists think that these diseases are caused by malfunctioning NK cells that turn on the body and attack healthy cells, causing disease instead of fighting it. Clarifying NK cells’ role could lead to new ways of treating these conditions.

    The study was carried out by researchers at Imperial College London, UCL and the Medical Research Council’s National Institute for Medical Research.

    Natural Killer cells – a type of white blood cell – are a major component of the human body’s innate, quick-response immune system. They provide a fast frontline defence against tumours, viruses and bacterial infections, by scanning the human body for cells that are cancerous or infected with a virus or a bacterial pathogen, and killing them.

    NK cells – along with all other types of blood cell, both white and red – are continuously generated from blood stem cells in the bone marrow over the course of a person’s lifetime. The gene E4bp4 identified in today’s study is the ‘master gene’ for NK cell production, which means it is the primary driver that causes blood stem cells to differentiate into NK cells.

    The researchers behind this new study, led by Dr Hugh Brady from the Department of Life Sciences at Imperial College London, are hoping to progress with a drug treatment for cancer patients which reacts with the protein expressed by their E4bp4 gene, causing their bodies to produce a higher number of NK cells than normal, to increase the chances of successfully destroying tumours.

    Currently, NK cells isolated from donated blood are sometimes used to treat cancer patients, but the effectiveness of donated cells is limited because NK cells can be slightly different from person to person. Dr Brady explains: “If increased numbers of the patient’s own blood stem cells could be coerced into differentiating into NK cells, via drug treatment, we would be able to bolster the body’s cancer-fighting force, without having to deal with the problems of donor incompatibility.”

    Dr Brady and his colleagues at the MRC National Institute for Medical Research proved the pivotal role E4bp4 plays in NK production when they knocked the gene out in a mouse model. Without E4bp4 the mouse produced no NK cells whatsoever but other types of blood cell were unaffected. As well as proving their hypothesis about the function of the E4bp4 gene, this animal model will allow medical researchers, for the first time, to discover if NK cell malfunction is behind a wide range of medical conditions, including autoimmune disorders, inflammatory conditions, persistent viral infections, female infertility and graft rejection.

    Dr Brady explains: “Since shortly after they were discovered in the 1970s some scientists have suspected that the vital disease-fighting NK cells could themselves be behind a number of serious medical conditions, when they malfunction. Now finally, with our discovery of the NK cell master gene and subsequent creation of our mouse model, we will be able to find out if the progression of these diseases is impeded or aided by the removal of NK cells from the equation. This will solve the often-debated question of whether NK cells are always the ‘good guys’, or if in certain circumstances they cause more harm than good.”

    The researchers were initially studying the effect of E4bp4 in a very rare but fatal form of childhood leukaemia when they discovered its importance for NK cells.

    The study was funded by the charities CHILDREN with LEUKAEMIA and Leukaemia Research.

    Source: Ethiopian Review (14/09/09)

    CD8+ T cells damage myelinated axons in a mouse model of multiple sclerosis

    AxonsA group led by Dr. Norbert Goebels of the University Hospital Zürich in Zürich, Switzerland reports that CD8+ T cells damage myelinated axons in a mouse model of multiple sclerosis (MS). This study can be found in the September 2009 issue of the American Journal of Pathology.

    Demylination and axonal damage cause the cognitive and motor symptoms of MS. Although the immune system, in particular CD8+ T cells, contributes to this axonal damage, it remains unclear whether this damage results from direct attack of the axons or as an indirect byproduct (collateral bystander damage).

    Sobottka et al used a live continuous confocal imaging approach to examine the role of CD8+ T cells in experimental autoimmune encephalitis (EAE), a mouse model of MS. They found that CD8+ T cells damaged myelinated axons, even when the stimulatory antigen was expressed inside but not on the surface of nearby oligodendrocytes, which produce the myelin that protects the axons from damage. Thus, axonal loss can be the result of "collateral bystander damage," and new treatments should be developed with a focus on the CD8+ T cell/oligodendrocyte interface.

    Dr. Goebels and colleagues "are confident that [these] findings critically contribute to the understanding of CD8-mediated neuropathology in CNS inflammation, strengthen a pathogenic role of CD8+ T cells in MS and advocate for the development of future immunotherapies aiming at the CD8-myelin/oligodendrocyte interface."

    Sobottka B, Harrer MD, Ziegler U, Fischer K, Hünig T, Becher B, Goebels N: Collateral bystander damage by myelin-directed CD8+ T cells causes axonal loss. Am J Pathol 2009, 175: 1160-1166

    Source: Medical News Today © 2009 MediLexicon International Ltd (28/08/09)

    Scientists’ discovery improves understanding of the development of autoimmune diseases such as Multiple Sclerosis

    MS Brain Scan

    Multiple sclerosis, rheumatoid arthritis and diabetes patients could benefit from a research discovery at Trinity College Dublin.

    Professor of Experimental Immunology, Kingston Mills and his research team at Trinity College Dublin have discovered new information on how autoimmune diseases such as those mentioned above, develop.

    The research found that the source of a particular messenger molecule (in technical terms this molecule is a cytokine called IL-17) which is the major cause of cellular inflammation was produced by a heretofore unsuspected group of cells. These cells called gamma delta T cells orchestrate the inflammatory process.

    Autoimmune and chronic inflammatory diseases, such as multiple sclerosis, rheumatoid arthritis, type 1 diabetes and inflammatory bowel disease affect 20% of the population worldwide. The findings of the research led by Professor Kingston Mills at TCD’s School of Biochemistry and Immunology and funded by Science Foundation Ireland and the Health Research Board have just been published in the Cell press journal, Immunity.

    They show that a population of white blood cells – called gamma T cells – infiltrate the brain and secrete a messenger molecule or cytokine – called IL-17 – which promotes the damage in the development of autoimmune diseases as shown in an experimental model for multiple sclerosis.

    In Ireland one in 100 or 40,000 people have rheumatoid arthritis and one in 800 or 4,500 have multiple sclerosis. There are no cures for these diseases and treatment options focus on relieving pain and inflammation and include steroids and non-steroidal anti-inflammatory drugs as well as ‘biologics’ that target mediators of inflammation. These drugs are only effective in a proportion of individuals and have mild to serious side effects. There is a pressing need for new drugs that are more effective in a high proportion of individuals and effective in a broader range of diseases.

    Commenting on the significance of the discovery, Professor Mills stated: “Our findings have considerably enhanced our understanding of the mechanisms which cause the cellular damage in autoimmune diseases, and should help in the design of more effective drug treatments.”

    In order to generate these new drugs, there is a need for a better understanding of the diseases processes and to identify new and more effective drug targets for disease therapy and intervention. The findings from the Trinity College Dublin research have shown that the white blood cells – gamma T cells – are a major source of the messenger molecule, cytokine IL-17, which is a primary agent in causing the damage in the development of autoimmune diseases. Furthermore, the research shows that production of IL-17 by the gamma T cells is stimulated in an unconventional manner by another pair of cytokines, called IL-1 and IL-23. This underlines the importance of targeting these messenger molecules or cytokines in the development of new drugs against autoimmune diseases.

    Professor Mills’ research team at TCD included postdoctoral fellow, Caroline Sutton and three PhD students, Stephen Lalor, Corinna Brereton and Cheryl Sweeney in collaboration with Dr Ed Lavelle, also in the School of Biochemistry and Immunology.

    Source: Irish Press Releases © Copyright 2009, (17/08/09)

    New immune-suppressing treatment forces multiple sclerosis into remission in mice

    Dr Jacques Galipeau

    A new experimental treatment for multiple sclerosis (MS) completely reverses the devastating autoimmune disorder in mice, and might work exactly the same way in humans, say researchers at the Jewish General Hospital Lady Davis Institute for Medical Research and McGill University in Montreal.

    MS is an autoimmune disease in which the body's own immune response attacks the central nervous system, almost as if the body had become allergic to itself, leading to progressive physical and cognitive disability.

    The new treatment, appropriately named GIFT15, puts MS into remission by suppressing the immune response. This means it might also be effective against other autoimmune disorders like Crohn's disease, lupus and arthritis, the researchers said, and could theoretically also control immune responses in organ transplant patients. Moreover, unlike earlier immune-supppressing therapies which rely on chemical pharamaceuticals, this approach is a personalized form of cellular therapy which utilizes the body's own cells to suppress immunity in a much more targeted way.

    GIFT15 was discovered by a team led by Dr. Jacques Galipeau of the JGH Lady Davis Institute and McGill's Faculty of Medicine. The results were published August 9 in the prestigious journal Nature Medicine.

    GIFT15 is composed of two proteins, GSM-CSF and interleukin-15, fused together artificially in the lab. Under normal circumstances, the individual proteins usually act to stimulate the immune system, but in their fused form, the equation reverses itself.

    "You know those mythical animals that have the head of an eagle and the body of a lion? They're called chimeras. In a lyrical sense, that's what we've created," said Galipeau, a world-renowned expert in cell regeneration affiliated with the Segal Cancer Centre at the Jewish General and McGill's Centre for Translational Research. "GIFT15 is a new protein hormone composed of two distinct proteins, and when they're stuck together they lead to a completely unexpected biological effect."

    This effect, explained Galipeau, converts B-cells -- a common form of white blood cell normally involved in immune response -- into powerful immune-suppressive cells. Unlike their better-known cousins, T-cells, naturally-occurring immune-suppressing B-cells are almost unknown in nature and the notion of using them to control immunity is very new.

    "GIFT15 can take your normal, run-of-the-mill B-cells and convert them -- in a Superman or Jekyll -Hyde sort of way -- into these super-powerful B-regulatory cells," Galipeau explained. "We can do that in a petri dish. We took normal B-cells from mice, and sprinkled GIFT15 on them, which led to this Jekyll and Hyde effect.

    "And when we gave them back intravenously to mice ill with multiple sclerosis, the disease went away."

    MS must be caught in its earliest stages, Galipeau cautioned, and clinical studies are needed to test the treatment's efficacy and safety in humans. No significant side-effects showed up in the mice, he said, and the treatment was fully effective with a single dose.

    "It's easy to collect B-cells from a patient," he added. "It's just like donating blood. We purify them in the lab, treat them with GIFT15 in a petri dish, and give them back to the patient. That's what we did in mice, and that's what we believe we could do in people. It would be very easy to take the next step, it's just a question of finding the financial resources and partnerships to make this a reality."

    Commenting on the study, Helen Yates, Multiple Sclerosis Resource Centre Chief Executive said, "This could be a very exciting development in the field of MS as well as a number of other conditions.

    As Dr. Galipeau rightly points out, this research needs much greater investigation and that requires funding. MSRC welcomes the findings of the Jewish General Hospital Lady Davis Institute for Medical Research and McGill University and hopes that further research is started soon."

    Source: McGill University and Jewish General Hospital (11/08/09)

    Increased numbers of IL-7 receptor molecules on CD4+CD25−CD107a+ T-cells in patients with autoimmune diseases affecting the central nervous system

    T Cells


    High content immune profiling in peripheral blood may reflect immune aberrations associated with inflammation in multiple sclerosis (MS) and other autoimmune diseases affecting the central nervous system.

    Methods and Findings

    Peripheral blood mononuclear cells from 46 patients with multiple sclerosis (MS), 9 patients diagnosed with relapsing remitting MS (RRMS), 13 with secondary progressive multiple sclerosis (SPMS), 9 with other neurological diseases (OND) and well as 15 healthy donors (HD) were analyzed by 12 color flow cytometry (TCRαβ, TCRγδ, CD4, CD8α, CD8β, CD45RA, CCR7, CD27, CD28, CD107a, CD127, CD14) in a cross-sectional study to identify variables significantly different between controls (HD) and patients (OND, RRMS, SPMS). We analyzed 187 individual immune cell subsets (percentages) and the density of the IL-7 receptor alpha chain (CD127) on 59 individual immune phenotypes using a monoclonal anti-IL-7R antibody (clone R34.34) coupled to a single APC molecule in combination with an APC-bead array.

    A non-parametric analysis of variance (Kruskal-Wallis test) was conducted in order to test for differences among the groups in each of the variables. To correct for the multiplicity problem, the FDR correction was applied on the p-values. We identified 19 variables for immune cell subsets (percentages) which allowed to segregate healthy individuals and individuals with CNS disorders. We did not observe differences in the relative percentage of IL-7R-positive immune cells in PBMCs. In contrast, we identified significant differences in IL-7 density, measured on a single cell level, in 2/59 variables: increased numbers of CD127 molecules on TCRαβ+CD4+CD25 (intermed) T-cells and on TCRαβ+CD4+CD25−CD107a+ T-cells (mean: 28376 Il-7R binding sites on cells from HD, 48515 in patients with RRMS, 38195 in patients with SPMS and 33692 IL-7 receptor binding sites on cells from patients with OND).


    These data show that immunophenotyping represents a powerful tool to differentiate healthy individuals from individuals suffering from neurological diseases and that the number of IL-7 receptor molecules on differentiated TCRαβ+CD4+CD25−CD107a+ T-cells, but not the percentage of IL-7R-positive cells, segregates healthy individuals from patients with neurological disorders.

    Source: Elites TV © 2009 KBC Media (06/08/09)

    Multiple Sclerosis: benefactors in the brain

    T Cells

    The inflammatory process in the brain of multiple sclerosis patients is triggered by their own immune system. However, there is one type of immune cells that seems to fight against the destructive progress - and might be used for therapeutic purposes in future.

    These "beneficial" immune cells display a propensity to migrate from the blood into inflamed nervous tissue. "Drawn in by specific chemoattractants, they obviously counteract the detrimental effects of other immune cells in the brain," explains Heinz Wiendl, Professor at the Department of Neurology of the University of Würzburg.

    Wiendl's research group presents this new research results in the journal Annals of Neurology. The findings are based on a variety of experiments using biomaterial from multiple sclerosis (MS) patients including blood, cerebrospinal fluid and tissue of the central nervous system (CNS).

    A concept for a new form of therapy?

    Thus, this work represents a demonstration of the existence of protective elements in the immune activities within the brain of MS patients. Conceptually this beneficial inflammatory factor should counterbalance inflammation in the CNS, but their impact obviously is not strong enough to dampen the disease. However, the notion of such activities might be enhanced in a therapeutic approach eventually benefiting the patients.

    How can this be achieved? "An answer to this question as well as a possible practical approach is the long-term objective of our work," says Wiendl. But the next step for the Würzburg researchers is to characterise this regulatory T-cell population more precisely and to find ways of using them for therapeutic purposes.

    Interesting molecules on the surface

    The beneficial immune cells have been identified as so-called naturally regulatory T-cells. Wiendl's team discovered and described them in a publication in the journal Blood in 2007.

    The characteristic of these cells: On their surface, they express a protein called HLA-G, which is attributed to have a strong immunosuppressive function. The signal for the migration of the cells into inflamed tissue is obviously influenced by another surface molecule, the so-called chemokine receptor CCR5. This is an additional new finding of the Würzburg scientists.

    Source: Specific Central Nervous System Recruitment of HLA-G+ Regulatory T Cells in Multiple Sclerosis, Huang YH, Zozulya A, Weidenfeller C, Metz I, Buck D, Toyka KV, Brück W, Wiendl H., Annals of Neurology 2009; DOI: 10.1002/ana.21705 (10/07/09)

    Important modulator of immune cell entry into the brain discovered

    T Cells

    Researchers in Berlin, Germany have ameliorated inflammation of the brain in mice caused by immune cells.

    A receptor they discovered on the surface of T cells in the central nervous system (CNS) plays the key role. The researchers showed that this bradykinin receptor 1 (B1) controls the infiltration of immune cells into the CNS. When they activated B1 in mice with encephalitis, they were able to slow down the crossing of the immune cells through the blood-brain-barrier into the CNS. As a result, the inflammation markedly decreased.

    Commenting on the findings, Helen Yates, Multiple Sclerosis Resource Centre Chief Executive said, "This is a very important piece of research.  We have long known that the crossing of immune cells into the CNS is a major problem in MS.  This work shows that inflammation can be decreased and hopefully will lead to further research into prevention of the inflammatory response completely."

    The work by Dr. Ulf Schulze-Topphoff, Prof. Orhan Aktas, and Professor Frauke Zipp (Cecilie Vogt-Clinic, Charité - Universitätsmedizin Berlin, Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch and NeuroCure Research Center) together with researchers in Canada and the USA may unveil a new target for the treatment of chronic inflammatory diseases such as multiple sclerosis (MS) (Nature Medicine, doi 10.1038/nm.1980)*.

    It has been known for a long time that T cells can attack the body's own structures and, if they infiltrate the CNS, cause diseases such as multiple sclerosis (MS). The T cells damage the myelin sheath, the material that surrounds and protects the fibers of nerve cells. This damage slows down or blocks messages between the brain and the body, leading to various symptoms of MS such as impaired movements.

    The molecular analysis of damaged tissue from patients with MS led the researchers to the B1-receptor. The data they evaluated showed that two different pathways known to play a crucial role in the cardiovascular area also seem to play an important role in the CNS: namely, the renin-angiotensin-system, and the kallikrein-kinin-system, the latter of which the researchers in Berlin put their focus on.

    The B1-receptor is part of the kallikrein-kinin-system. Together with Professor Alexandre Prat from the Université de Montréal, Montréal, Canada, and Professor Lawrence Steinman from Stanford University in Stanford, California, USA, the researchers in Berlin detected the B1-receptor on T cells of MS patients as well as on T cells of mice with encephalitis, an inflammation of the brain.

    The disease got worse in those mice that lacked B1 on their T cells. Therefore, using a certain substance (Sar-[D-Phe]desArg9-bradykinin), they activated the receptor in mice which had B1 on their T cells. As a result, the entry of T cells into the CNS slowed down and the clinical symptoms of the inflammation markedly decreased.

    "We have discovered a control mechanism, which reduces inflammation caused by the immune system" neurologist and MDC research group leader Professor Zipp explains. "It remains to be seen if we succeed in developing a new therapy for chronic inflammation in the CNS, such as MS, in the future."

    *Activation of kinin receptor B1 limits encephalitogenic T lymphocyte recruitment to the central nervous system

    Ulf Schulze-Topphoff1, Alexandre Prat2, Timour Prozorovski1, Volker Siffrin1, Magdalena Paterka1, Josephine Herz1, Ivo Bendix1, Igal Ifergan2, Ines Schadock3, Marcelo A. Mori3, Jack Van Horssen2, Friederike Schröter1, May Htwe Han4, Michael Bader3,Lawrence Steinman4, Orhan Aktas1* & Frauke Zipp1*

    (1) Cecilie Vogt Clinic, Charité - Universitätsmedizin Berlin, Max Delbrück Center for Molecular Medicine and NeuroCure Research Center, Charitéplatz 1, 10117 Berlin, Germany

    (2) Neuroimmunology Research Laboratory, CHUM - Université de Montréal, Montréal, Canada

    (3) Max Delbrück Center for Molecular Medicine, Berlin, Germany

    (4) Department of Neurology and Neurological Sciences, Stanford University, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California, USA

    * OA and FZ contributed equally to this work

    Source: Medical News Today © 2009 MediLexicon International Ltd (30/06/09)

    Tracking down the causes Of Multiple Sclerosis - new discoveries in immune response

    MS MRI

    Over 100,000 people suffer from multiple sclerosis in Germany alone. Despite intensive research, the factors that trigger the disease and influence its progress remain unclear. Scientists from the Max Planck Institute of Neurobiology in Martinsried and an international research team have succeeded in attaining three important new insights into the disease.

    It would appear that B cells play an unexpected role in the spontaneous development of multiple sclerosis and that particularly aggressive T cells are activated by different proteins. Furthermore, a new animal model is helping the scientists to understand the emergence of the most common form of the disease in Germany.

    Multiple Sclerosis (MS) poses enormous problems for both patients and doctors: it is the most common inflammatory disease of the central nervous system in our part of the world and often strikes patients at a relatively young age. In some patients it leads to severe disability. Moreover, despite decades of research on MS, the causes and course of the disease are still largely unclear.

    There is much evidence to support the fact that MS is triggered by an autoimmune reaction: immune cells that should actually protect the body against threats like viruses, bacteria and tumours, attack the body's own brain tissue. New treatments now available can attenuate the harmful immune reaction and thus delay the progress of the disease. However, the more effective the treatment, the more serious its side effects. Therefore, it is a matter of extreme urgency that new forms of treatment be developed which can differentiate in a targeted way between the immune cells that cause the disease and those that should be protected. A better understanding of the disease is required in order to achieve this.

    Entirely new possibilities

    The research of multiple sclerosis has proven particularly difficult. This is due, not least, to the fact that the focus of the disease is embedded in the sensitive brain tissue and is, therefore, inaccessible. More than other branches of medicine, MS research is dependent, therefore, on animal models in its study of the disease. Working in collaboration with an international team, scientists at the Max Planck Institute of Neurobiology have succeeded in developing a very effective animal model. The specially bred mice spontaneously develop a disease pattern that is practically identical to the course of the human form of MS most common in our part of the world. Because the disease also develops spontaneously in humans, the new model is superior to all of the previous models which only develop MS symptoms following injection with brain tissue. Moreover, the research using the new model has already prompted a rather sensational discovery: the emergence of the disease requires significantly more immune cells than previously assumed.

    Unrecognised significance

    Up to now, MS research has worked on the assumption that the disease mainly arises as a result of attacks on a group of white blood cells known as T cells. These immune-system cells provide a kind of 'immediate response' to pathogens - they recognise the pathogens, activate the immune response and thus trigger the destruction of the harmful cells. In addition to T cells, the immune system also has B cells. These also react to the presence of a pathogen, are activated and start to divide rapidly. Thousands of cells are created which produce a pathogen-specific antibody. An invasion of pathogens can be overcome quickly and effectively through the targeted interaction of T and B cells.

    Unlike the T cells, the B cells have hitherto only been assigned a subordinate role in the emergence of multiple sclerosis - erroneously, as the new model now shows. Previous experimentally-generated models of the disease had simply failed to reveal the true role of the B cells.

    In the new mouse model, T cells also attack the body's own brain tissue. However, this is not sufficient to trigger the disease, as when the scientists remove the B cells, the animals remain healthy. "This observation surprised us all because it contradicted the prevailing doctrine," notes Gurumoorthy Krishnamoorthy. The new model shows that there most be some kind of interaction between the T and B cells, that the resulting army of B cells triggers the full-blown form disease through its antibody attacks.

    More aggressive than others

    Even if B cells play a far more significant role than was previously believed, the fact remains that T cells can cause extensive damage to nerve cells in the context of multiple sclerosis. Basically, they can misinterpret any component of the nervous system as a foreign body and launch an attack. However, it is well known that some of the autoreactive T cells are significantly more aggressive than others. One group of these 'special' T cells recognises and attacks the protein MOG, which is found on the surface of brain cells. To the amazement of the neuroimmunologists, however, these cells also attack mice that lack MOG. "This finding was completely unexpected, since the T cells should not really attack anything in the absence of MOG", says Krishnamoorthy. The solution to this puzzle was provided by a broad-based biochemical study: T cells that identify MOG as a foreign body also react to a second, completely different protein in the brain.

    New understanding - possible treatments

    "Such doubly or even triply activated T cells could be the reason for the significantly greater aggressiveness of these cells", suggests Hartmut Wekerle, the head of the study. And, of course, he is already thinking one step ahead: "We must now find a way of identifying these special T cells in the patient." Based on this, treatments could be developed that specifically suppress the activity of these particularly aggressive T cells or remove them from the tissue. Such a treatment should have considerably fewer side effects than the previous, rather unspecific approaches.

    The new animal model, which provides a far better simulation of the human form of the disease, has prompted surprising insights into the role of the B cells in the spontaneous development of MS. This and the astonishing finding that particularly aggressive T cells are activated by different proteins both represent considerable advances in the research of multiple sclerosis. All of these insights could provide the basis for the development of new approaches to the treatment of the disease.

    Commenting on the findings, Helen Yates, Multiple Sclerosis Resource Centre Chief Executive said, "These findings from the Max Planck Institute of Neurobiology  provide yet more pieces of the MS ‘jigsaw’.  It has long been suggested in some areas that the current mouse model, EAE, is not a close enough match to the development of MS in humans, so to develop a new model in itself is a real step forward.  The research also suggests a different weighting of the activity of B cells and T cells.  We hope to see more research in this area."

    Journal references:

    1.Krishnamoorthy et al. Myelin-specific T cells also recognize neuronal autoantigen in a transgenic mouse model of multiple sclerosis. Nature Medicine, 2009; 15 (6): 626 DOI: 10.1038/nm.1975
    2.Bernadette Pöllinger, Gurumoorthy Krishnamoorthy, Kerstin Berer, Hans Lassmann, Michael R. Bösl, Robert Dunn, Helena S. Domingues, Andreas Holz, Florian C.Kurschus and Hartmut Wekerle. Spontaneous relapsing-remitting EAE in the SJL/J mouse: MOGreactive transgenic T cells recruit endogenous MOG-specific B cells. Journal of Experimental Medicine, June 1st, 2009

    Source: Science Daily  © 1995-2009 ScienceDaily LLC and MSRC(11/06/09)

    Stopping autoimmunity before it strikes


    Current research describes a new method to track the development of autoimmune diseases before the onset of symptoms. The related report by Zangani et al, "Tracking early autoimmune disease by bioluminescent imaging of NF-κB activation reveals pathology in multiple organ systems," appears in the April 2009 issue of The American Journal of Pathology.

    Autoimmune diseases such as lupus, multiple sclerosis, rheumatoid arthritis and diabetes are caused when the immune system attacks the body's own cells. Normally, immune cells are prevented from attacking normal cells; however, in patients with autoimmune disease, this "tolerance" is lost. The immediate causes of autoimmune diseases remain unknown, partially due to the inability to detect disease before the onset of symptoms. Early detection of autoimmune disease is critical for assessing new treatments.

    The molecule NF-κB is activated by inflammation, which plays a key role in autoimmune disease development, making NF-κB a prime candidate to track autoimmune activity. Researchers at the University of Oslo led by Drs. Ludvig Munthe and Bjarne Bogen in collaboration with Rune Blomhoff engineered NF-κB such that it would emit light when activated. Using a mouse model of systemic autoimmunity with features of lupus, they found that NF-κB activation signals were present in affected organs several weeks before the clinical manifestations of disease. The light signal intensity correlated with disease progression. NF-κB tracking may therefore provide a new tool in the evaluation of early autoimmune therapies.

    The article from Zangani et al "indicate[s] that NF-κB mediated bioluminescence is a very sensitive and early indicator of inflammation and disease", allowing precise identification of incipient disease sites for biomedical and pathogenetic studies. In future studies, Drs. Munthe, Bogen, and colleagues will utilize this new model "for studies on early intervention, e.g. drug treatment, to prevent or treat autoimmune disease", and for studies of the development of B cell lymphoma.

    Source: Bio-Medicine © 2003-2009 Bio-Medicine.(26/03/09)

    Protein helps immune cells to divide and conquer

    Researchers at the University of California, San Diego School of Medicine have identified a key protein that is required for immune cells called B lymphocytes to divide and replicate themselves. The rapid generation of large numbers of these immune cells is critical to the body's antibody defense mechanism. However, when B cells grow unchecked, it can lead to immune cell cancers such as multiple myeloma or, when they grow to attack the wrong targets, such as in the autoimmune disease, Multiple Sclerosis. By discovering the role of the CD98hc protein, scientists may find new therapy targets for such diseases.

    The study from the laboratory of Mark H. Ginsberg, MD., professor of medicine, has been published online in advance of print in Nature Immunology. It describes why CD98hc is essential in order for B lymphocytes to transition into antibody-secreting cells. It also describes how this relates to the protein's role in the signaling ability of integrins - a large family of adhesion molecules that transfer information between the inside and outside of a cell.

    According to first author Joseph Cantor, PhD, UC San Diego School of Medicine, scientists have known for nearly 25 years that CD98hc, common to all vertebrates, probably played a role in their adaptive immune system, but it wasn't known how this protein functioned.

    "This protein was used as a marker of activation because it was found in low levels on resting lymphocytes," said Cantor. "But when B or T lymphocytes were stimulated by antigens - for instance, to protect the body against bacteria - levels of CD98hc went up 20 fold."

    The scientists generated a mouse model lacking the CD98hc protein in B lymphocytes. When vaccinated, these mice were unable to mount a normal antibody response to the pathogen. Cantor says this was the first clue to the researchers of the protein's importance.

    "In purifying B lymphocytes without the CD98hc protein, we discovered that the lymphocytes couldn't divide rapidly," Cantor said, adding that this proved the protein was essential to expanding the number of immune cells, a necessary step in the immune response. While deletion of the protein didn't impair early B cell activation, it did inhibit later activation of elements along the signaling pathway that push the cell forward to divide.

    "Since B cells can't rapidly divide and replicate without CD98hc, perhaps by blocking this protein we could stop the unchecked growth of B lymphocyte cells that can result in cancer or block misdirected B cell attacks that can cause certain autoimmune diseases," said Ginsberg.

    The CD98hc protein functions in cells by helping to transmit integrin signals, as well as transporting amino acids - the building blocks of proteins - into the cell. But the scientists didn't know which, if either, of these functions was related to the protein's role in the rapid division of immune cells. By replacing normal CD98hc in B cells with a version that lacked one or the other of these two functions, they discovered that the integrin-binding domain of this protein is required, but the amino acid transport function is dispensable for B cell proliferation.

    "CD98hc interacts with certain integrin subunits to prompt signaling events that control cell migration, survival and proliferation. Our study shows that the rapid proliferation of B cells, necessary for the body to fight infection, is aided by the CD98hc protein's support of integrin signaling," Cantor said.


    Additional contributors to this paper include Cecille D. Brown and Robert C. Rickert of the Burnham Institute; Raphael Ruppert and Reinhard Fässler of the Max Planck Institutte, Germany; and Chloé C. Féral, Nice-Sophia Antipolis University, France.

    This work was supported by National Institutes of Health grants; Joseph Cantor is a post-doctoral fellow of the National Multiple Sclerosis Society.

    Source: Medical Terms (10/03/09)

    Babies know: A little dirt is good for you


    Ask mothers why babies are constantly picking things up from the floor or ground and putting them in their mouths, and chances are they’ll say that it’s instinctive — that that’s how babies explore the world. But why the mouth, when sight, hearing, touch and even scent are far better at identifying things?

    When my young sons were exploring the streets of Brooklyn, I couldn’t help but wonder how good crushed rock or dried dog droppings could taste when delicious mashed potatoes were routinely rejected.

    Since all instinctive behaviors have an evolutionary advantage or they would not have been retained for millions of years, chances are that this one too has helped us survive as a species. And, indeed, accumulating evidence strongly suggests that eating dirt is good for you.

    In studies of what is called the hygiene hypothesis, researchers are concluding that organisms like the millions of bacteria, viruses and especially worms that enter the body along with “dirt” spur the development of a healthy immune system. Several continuing studies suggest that worms may help to redirect an immune system that has gone awry and resulted in autoimmune disorders, allergies and asthma.

    These studies, along with epidemiological observations, seem to explain why immune system disorders like multiple sclerosis, Type 1 diabetes, inflammatory bowel disease, asthma and allergies have risen significantly in the United States and other developed countries.

    Training the Immune System

    “What a child is doing when he puts things in his mouth is allowing his immune response to explore his environment,” Mary Ruebush, a microbiology and immunology instructor, wrote in her new book, “Why Dirt Is Good” (Kaplan). “Not only does this allow for ‘practice’ of immune responses, which will be necessary for protection, but it also plays a critical role in teaching the immature immune response what is best ignored.”

    One leading researcher, Dr. Joel V. Weinstock, the director of gastroenterology and hepatology at Tufts Medical Center in Boston, said in an interview that the immune system at birth “is like an unprogrammed computer. It needs instruction.”

    He said that public health measures like cleaning up contaminated water and food have saved the lives of countless children, but they “also eliminated exposure to many organisms that are probably good for us.”

    “Children raised in an ultraclean environment,” he added, “are not being exposed to organisms that help them develop appropriate immune regulatory circuits.”

    Studies he has conducted with Dr. David Elliott, a gastroenterologist and immunologist at the University of Iowa, indicate that intestinal worms, which have been all but eliminated in developed countries, are “likely to be the biggest player” in regulating the immune system to respond appropriately, Dr. Elliott said in an interview. He added that bacterial and viral infections seem to influence the immune system in the same way, but not as forcefully.

    Most worms are harmless, especially in well-nourished people, Dr. Weinstock said.

    “There are very few diseases that people get from worms,” he said. “Humans have adapted to the presence of most of them.”

    Worms for Health

    In studies in mice, Dr. Weinstock and Dr. Elliott have used worms to both prevent and reverse autoimmune disease. Dr. Elliott said that in Argentina, researchers found that patients with multiple sclerosis who were infected with the human whipworm had milder cases and fewer flare-ups of their disease over a period of four and a half years. At the University of Wisconsin, Madison, Dr. John Fleming, a neurologist, is testing whether the pig whipworm can temper the effects of multiple sclerosis.

    In Gambia, the eradication of worms in some villages led to children’s having increased skin reactions to allergens, Dr. Elliott said. And pig whipworms, which reside only briefly in the human intestinal tract, have had “good effects” in treating the inflammatory bowel diseases, Crohn’s disease and ulcerative colitis, he said.

    How may worms affect the immune system? Dr. Elliott explained that immune regulation is now known to be more complex than scientists thought when the hygiene hypothesis was first introduced by a British epidemiologist, David P. Strachan, in 1989. Dr. Strachan noted an association between large family size and reduced rates of asthma and allergies. Immunologists now recognize a four-point response system of helper T cells: Th 1, Th 2, Th 17 and regulatory T cells. Th 1 inhibits Th 2 and Th 17; Th 2 inhibits Th 1 and Th 17; and regulatory T cells inhibit all three, Dr. Elliott said.

    “A lot of inflammatory diseases — multiple sclerosis, Crohn’s disease, ulcerative colitis and asthma — are due to the activity of Th 17,” he explained. “If you infect mice with worms, Th 17 drops dramatically, and the activity of regulatory T cells is augmented.”

    In answer to the question, “Are we too clean?” Dr. Elliott said: “Dirtiness comes with a price. But cleanliness comes with a price, too. We’re not proposing a return to the germ-filled environment of the 1850s. But if we properly understand how organisms in the environment protect us, maybe we can give a vaccine or mimic their effects with some innocuous stimulus.”

    Wash in Moderation

    Dr. Ruebush, the “Why Dirt Is Good” author, does not suggest a return to filth, either. But she correctly points out that bacteria are everywhere: on us, in us and all around us. Most of these micro-organisms cause no problem, and many, like the ones that normally live in the digestive tract and produce life-sustaining nutrients, are essential to good health.

    “The typical human probably harbors some 90 trillion microbes,” she wrote. “The very fact that you have so many microbes of so many different kinds is what keeps you healthy most of the time.”

    Dr. Ruebush deplores the current fetish for the hundreds of antibacterial products that convey a false sense of security and may actually foster the development of antibiotic-resistant, disease-causing bacteria. Plain soap and water are all that are needed to become clean, she noted.

    “I certainly recommend washing your hands after using the bathroom, before eating, after changing a diaper, before and after handling food,” and whenever they’re visibly soiled, she wrote. When no running water is available and cleaning hands is essential, she suggests an alcohol-based hand sanitizer.

    Dr. Weinstock goes even further. “Children should be allowed to go barefoot in the dirt, play in the dirt, and not have to wash their hands when they come in to eat,” he said. He and Dr. Elliott pointed out that children who grow up on farms and are frequently exposed to worms and other organisms from farm animals are much less likely to develop allergies and autoimmune diseases.

    Also helpful, he said, is to “let kids have two dogs and a cat,” which will expose them to intestinal worms that can promote a healthy immune system.

    Source: The New York Times Copyright 2009 The New York Times Company (27/01/09)

    Unexpected finding may help stop autoimmune diseases such as Multiple Sclerosis

    T Cells

    After several years of battling recurring infections, the last thing a patient and her doctors ever expected was that the cause of her problems might actually help millions live longer, more active lives.

    Now, researchers have high hopes because Edward Goetzl and his colleagues from the University of California and The Ohio State University discovered that the patient made a unique antibody to her own T cells, the cells that mediate much of autoimmunity. Acting on the surface of T cells via a novel mechanism, the antibody reduced the number of T cells in her blood stream: a result that usually requires a host of "immunosuppressive" and possibly toxic drugs.

    Their research discovery, published online in The FASEB Journal, may lead to entirely new therapies for a wide range of autoimmune disorders, such as colitis, lupus, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis, as well as new ways to prevent transplant rejection.

    "The possibility that these antibodies can be used to treat diverse autoimmune diseases with minimal risk of infections represents a new horizon for reversing these disabling and often fatal conditions," said Edward Goetzl, a senior researcher involved in the study.

    In the research report, Goetzl and colleagues explain how they discovered that the antibodies produced by this patient blocked the sphingosine 1-phosphate (S1P) receptor on T cells. The S1P receptor is a cell-surface antenna that receives signals telling T cells to leave the lymph nodes and patrol the body. When this antenna was disabled, the T cells failed to leave the lymph nodes (chemotaxis), reducing their numbers in the bloodstream. Taking this discovery one step further, the researchers created more of the patient's antibodies in the laboratory and gave them to mice with colitis (an autoimmune disorder). After receiving the antibodies, symptoms of colitis were reduced.

    "This discovery is very good news for people with autoimmune disorders." said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal "It also shows that when modern scientists work out exactly what is wrong with one patient they can come up with unexpected new ways to treat many thousands.

    Source: Lab Spaces © 2005-2008. (23/01/09)

    Potential autoimmunity-inducing cells found in healthy adults

    B Cells

    It's not just patients with autoimmune diseases like Lupus and Multiple Scelrosis (MS) that have self-attacking immune cells - healthy people have them too, according to a new report in the Journal of Experimental Medicine. In healthy adults, however, these cells are maintained in an 'off' state, perhaps explaining their innocuous nature. Whether these cells are the true predecessors of the self-attacking cells prevalent in Lupus and MS and, if so, what prevents them from causing disease in everyone is not yet known.

    As antibody-producing B cells develop in the bone marrow, the body tests them to determine whether their antigen receptors are apt to confuse self tissues for intruders. If so, their receptors are either rearranged to make new, non-autoreactive versions-a process called 'receptor editing'-or the cells are killed off while still in the bone marrow. Yet a minority manages to escape, slipping into the body as mature B cells with a propensity for self-attack.

    Using mice, researchers have shown that these self-reactive escapees are arrested in a state of anergy that prevents them from mounting an immune attack. But, until now, a similar population of cells had never been found in humans. In the new study, a team of researchers led by J. Andrew Duty at the Oklahoma Medical Research Foundation have pin-pointed a similar population of anergic B cells in the blood of healthy adults, where they accounted for 2.5% of B cells in the circulating blood.

    Although these anergic cells did not appear to cause problems in healthy people, the authors demonstrated their potential to produce self-reactive antibodies by providing the cells with a strong stimulus in cell culture. The potential to produce these trouble-making antibodies lead the authors to suspect that these cells may contain the precursors for the self-attacking B cells in patients with autoimmune diseases. Perhaps anergy somehow breaks down in these patients, allowing self-sabotaging cells to run free.

    Source: Rockefeller University Press (23/12/08)

    Popular hypothesis concerning emergence of Multiple Sclerosis contested by scientists

    T Cell

    During an autoimmune disease, the endogenous defence system (the immune system) loses the ability to distinguish between "self" and "foreign". As a consequence, the immune system directs its defence against itself, with fatal consequences. In the case of multiple sclerosis, a chronic, inflammatory autoimmune disease, the immune system attacks the protective layer encapsulating the nerve fibres: This protective layer formed by myelin works like insulation for electrical cables. If the insulation is damaged, the nerves can no longer transmit messages effectively.

    In the emergence of certain autoimmune diseases so-called T helper cells play a decisive role; like the small proteins called cytokines, which they produce. In particular, 'Th17' cells which were discovered only few years ago as a subclass of the T helper cells. Their presence at the emergence of autoimmune disease like multiple sclerosis has been the object of numerous publications within the last three years. The Th17 cells are named after the cytokine Interleukin 17 (IL-17), which they produce in large amounts. Therefore, it was easy to assume that the emergence of MS was linked to the function of this molecule. Particularly, the two main proteins of the Interleukin 17 family, namely IL-17A and IL-17F, moved into the spotlight of many researchers.

    In a collaborative study, researchers the laboratories of Prof. Ari Waisman (I. Medizinische Klinik) and the Zürich group under Prof. Burkhard Becher (Institute for experimental immunology, University Hospital Zürich) together with colleagues from Berlin and Geneva examined the direct effects of those two cytokines on the development of "EAE" in mice. This disease is comparable with the MS in man on many levels and therefore serves an animal model for MS.

    On the one hand the researchers could point on that mice not producing one of the two cytokines, are just as susceptible to the emergence for EAE as "normal" mice. On the other hand the specific overproduction of the two cytokines in the brain did not lead to a higher vulnerability for MS-related disease either. Interestingly, the increased production of the cytokine in the whole body of the mice led to inflammations in a variety of organs, primarily in the skin. This shows that IL-17 can be a harmful cytokine, but not necessarily in connection with autoimmune diseases of the brain.

    "The result that neither IL-17A nor IL-17F play a decisive role in the emergence of the EAE was a great surprise for us", stated Prof. Ari Waisman of the I. Medical Clinic. "This will supposably lead to change among experts because we could not confirm a popular hypothesis with that. The results of the current study are, however, very important for the development of future treatment strategies of autoimmune diseases of the brain. In connection with MS the focus should be taken away from the Interleukin 17 and placed on other cytokines."

    Source: Medical News Today © 2008 MediLexicon International Ltd (19/12/08)

    Sheffield Hallam University seeks early diagnosis for MS

    Brain Protein research

    Sheffield Hallam University has begun a new three-year study which it hopes will lead to a test for early diagnosis of multiple sclerosis (MS). Early diagnosis means treatment can be started sooner, helping people with MS to remain active for longer.

    Lead by Professor Nicola Woodroofe, head of The Biomedical Research Centre (BMRC) at the University, the project will seek to determine whether specific modifications to amino acids in specific brain proteins may ultimately be responsible for the body's own immune system attacking proteins found exclusively in the central nervous system. The grant of £105,000 will fund a full time PhD student over three years and associated research costs.

    "This study will further research the causes and crucial early stages of multiple sclerosis," said Professor Woodroofe. "Previous studies carried out have recently provided evidence changed proteins may be found in people with MS - a vital clue to understanding causes of the disease."

    Using post mortem tissue samples from the UK MS Society Tissue Bank, MS patients and healthy controls, the BMRC will measure: the levels of PAD enzymes (which produce the amino acid changes), the changed proteins themselves and the antibodies developed by patients. Analysing the results obtained and their relationship to symptoms, they hope to find an antibody specific to people with MS.

    The grant is one of a number of major awards to be given to Sheffield Hallam by the MS Society in recent weeks. Ed Holloway from the MS Society, said: "We hope this project will contribute not only to our understanding of MS, but to our ability to diagnose and combat the disease. MS is a challenging affliction and the research undertaken by Sheffield Hallam is a key step in our ongoing efforts to help sufferers.

    "We have chosen the University thanks to its superb research track record and the excellent working relationship which we have developed with them."

    Source: Sheffield Hallam University (12/12/08)

    Interferon could be a key to preventing or treating Multiple Sclerosis

    MS Brain

    Multiple sclerosis (MS) results when the body's own defense system attacks nerve fibers in the brain and spinal cord. Now scientists led by John Russell, Ph.D., at Washington University School of Medicine in St. Louis have shown that interferon-gamma plays a deciding role in whether immune cells attack and injure the central nervous system (brain and spinal cord) in mice.

    Interferon-gamma is an immune system protein that helps the body defend itself from invaders. In their latest research, which appeared in the October issue of the Journal of Experimental Medicine, the researchers show that interferon-gamma determined whether activated immune cells — previously primed to go after nerve cells — would actually cause nerve damage in experimental mice.

    The researchers found that in the cerebellums and brainstems of the mice, interferon-gamma was protective. However, in the spinal cord, interferon-gamma had the opposite effect, permitting nerve cell damage.

    "Some studies show that the most serious cases of MS in people occur when the immune system specifically targets the cerebellum, a part of the brain responsible for sensory perception, coordination and movement control," says Russell, professor of developmental biology. "Our study suggests that researchers need to look at the amount of interferon-gamma produced in the cerebellum and other brain regions in people with MS."

    The researchers studied mice genetically engineered to be physiologically "blind" to interferon-gamma — the mice had none of the usual receptors on their cells that recognize and respond to interferon-gamma. So in these mice it was as though interferon-gamma didn't exist.

    In the interferon-insensitive mice, immune cells primed to attack nerves and then injected into the mice's veins were able to get into the cerebellum and brain stem and initiate nerve cell damage leading to MS-like disease.

    In comparison, in mice with normal interferon-gamma recognition, immune cells were prevented from entering the brain and causing problems. The exact mechanism to account for this is still under study.

    "Down the road, we would like to investigate whether we can prevent disease in the cerebellum in mice if we promote interferon production in that brain region," Russell says. "One way to do that would be to use gene therapy to insert a gene that would increase interferon in the mice's brains. Then we would test the mice to see if they gained protection against MS-like disease."

    In contrast to its protective role in the brain, in the spinal cord interferon-gamma helped instigate nerve damage. In mice with intact interferon-gamma recognition, activated and injected immune cells were able to enter the spinal cord and cause injury. In mice without interferon recognition, the immune cells were unable to initiate spinal cord inflammation, and no damage occurred.

    "Our research shows that certain characteristics inherent in different regions of the brain and spinal cord can provoke immune attacks on nerve cells," Russell says. "An understanding of the mechanisms involved in immune system invasion of the nervous system may allow development of better models for determining prognosis and treating many neurological diseases such as multiple sclerosis."

    This latest research bolsters Russell's central hypothesis about MS and related disorders, which goes against some widely held assumptions. He holds that in physiological circumstances that ultimately lead to MS, the central nervous system itself allows or even aids immune system attacks.

    "A scientifically popular view of how MS occurs is that the immune system somehow gets armed against normal brain antigens and attacks neurons," Russell says. "In that view, brain cells have a passive role. But in this and previous research, we've shown that there's a 'conversation' between the immune system and the central nervous system and that molecular signals passed between them are involved in the development of MS-like disease in mice."

    Lees JR, Golumbek PT, Sim J, Dorsey D, Russell JH. Regional CNS responses to IFN-γ determine lesion localization patterns during EAE pathogenesis. Journal of Experimental Medicine. 2008 Oct 27;205(11):2633-2642. (03/11/08)

    Response to immune protein determines pathology of multiple sclerosis

    New research may help reveal why different parts of the brain can come under attack in patients with multiple sclerosis (MS). According to a new study in mice with an MS-like disease, the brain's response to a protein produced by invading T cells dictates whether it's the spinal cord or cerebellum that comes under fire.

    The study—from researchers at the University of Maryland School of Medicine in Baltimore and Washington University in St. Louis—was published online on October 13th in the Journal of Experimental Medicine.

    In most MS patients, the disease primarily affects the spinal cord and the white matter of the brain. But a small percentage of patients develop an atypical form of the disease, which primarily affects the cerebellum—the part of the brain that controls sensory perception and movement. For these patients, the disease tends to progress more rapidly and the prognosis is particularly bleak.

    MS ensues when the body's T cells invade the brain and trigger nerve-damaging inflammation, in part by secreting proteins called cytokines. According to the new study, lead by Washington University scientist John Russell, the brain's response to one particular immune protein, called interferon-g (IFNg), determines which part of the brain the T cells attack. In mice that are oblivious to IFNg (because they lack its receptor), mice suffer cerebellum and brain stem inflammation, but their spinal cords are spared. When IFNg receptors were left intact, the reverse occurred.

    Exactly how the brain's response to IFNg directs the T cell attack is not yet known, but the authors suspect that IFNg triggers a localized production of T cell-attracting proteins in the spinal cord. Translating the details of the "conversation" between T cells and brain cells, suggests Russell, might bring scientists closer to understanding the variable manifestations of human MS.

    Source: Rockefeller University Press (14/10/08)

    Multiple sclerosis patients have higher spinal fluid levels of suspicious immune molecule

    Immune Cells

    A protein that helps keep immune cells quiet is more abundant in the spinal fluid of patients with multiple sclerosis (MS), further boosting suspicion that the protein, TREM-2, may be an important contributor to the disease.

    More of an immune-control protein might seem like a boon to MS sufferers, whose symptoms are caused by misdirected immune attacks on the protective lining that coats nerve cell branches. But researchers at Washington University School of Medicine in St. Louis found the extra TREM-2 was not in the right place to reduce aggression in immune cells, a revelation that could eventually lead scientists to new pharmaceutical targets for MS prevention.

    "Previously, TREM-2 had only been seen on the surface of immune cells; in the new study, we found it floating freely in spinal fluid," says lead author Laura Piccio, M.D., Ph.D., postdoctoral fellow. "This is only speculation for now, but these 'free agent' copies of TREM-2 could be making it harder for the TREM-2 that is attached to immune cells to keep the cells' aggressiveness under control."

    Piccio explains that TREM-2 is a receptor protein, which means that another molecule activates it. Scientists don't currently know what that other molecule is, but the "free agent" TREM-2 in the spinal fluid could be binding to the molecule, reducing the chances that it will bind to and activate TREM-2 attached to immune cells. If Piccio and her colleagues can confirm their theory, the TREM-2 in the spinal fluid or its unknown partner could become targets for new MS treatments. The findings appear in the journal Brain.

    Epidemiologists estimate that 400,000 people in the United States have MS. Symptoms, which often strike in episodic bursts, include bladder and bowel dysfunction, memory problems, fatigue, dizziness, depression, difficulty walking, numbness, pain and vision problems. The disease is more common among Caucasians than any other group and affects two to three times as many women as men.

    TREM-2 first came to MS researchers' attention because of Nasu-Hakola disease, a rare genetic disorder that involves a mutation in the gene for TREM-2. Among other symptoms, Nasu-Hakola causes loss of the same protective sheath around nerve cell branches that is damaged by MS.

    One place where the TREM-2 protein commonly appears is the macrophage, an immune cell that performs a variety of functions, including cleaning up debris and emitting inflammatory signals that escalate immune attacks. Macrophages come in two classes: one that promotes inflammation and one that suppresses it. TREM-2 is present only on the anti-inflammatory macrophages.

    Prior experiments had shown that activation of the TREM-2 receptor can help reduce immune inflammation and promote phagocytosis, a process that lets cells consume things. In the context of the central nervous system, researchers think this allows macrophages to consume dying nerve cells and to perform "housekeeping functions," such as shutting down inflammatory processes.

    "The main thing we knew about MS and the function of TREM-2 before this study was that blocking TREM-2 in a mouse model of MS made their conditions worse," says senior author Anne Cross, M.D., professor of neurology and head of the neuroimmunology section.

    After Piccio identified TREM-2 in the spinal fluid, she compared that form of the protein in patients with various types of MS, patients with other inflammatory diseases of the central nervous system, and patients with non-inflammatory central nervous system diseases. To ensure that the soluble TREM-2 wasn't seeping into the patients' spinal fluid from the bloodstream, they also analyzed TREM-2 levels in blood.

    While there were no differences in blood levels, the soluble form of TREM-2 was significantly higher in the spinal fluid of MS patients.

    Scientists are trying to develop a mouse line where the TREM-2 gene has been disabled to learn more about the protein's contributions to the immune system.

    Source: © 2008 News-Medical.Net (30/09/08)

    Novel mechanism to reduce nervous system inflammation identified by researchers

    Immune Cells

    Researchers at Georgetown University Medical Center have discovered a new way to limit inflammation caused by the activation of microglia - key immune cells in the brain. Although the role of such cells is to "clean up damage" after injury, they often worsen the damage by releasing toxic inflammatory factors.

    In the October issue of the journal Glia, now published online, the scientists say that the type of chemical they used to deactivate these cells could possibly be developed as a drug to treat a variety of acute and chronic disorders marked by brain cell damage - including stroke, head and spinal cord injury, and possibly Alzheimer's disease and Parkinson's disease.

    "Inflammation associated with the activation of microglial cells is an important factor that appears to contribute to tissue damage and disability in many of the important neurodegenerative disorders. By decreasing this inflammatory response, tissue loss after injury can be reduced. Thus, what we found in this study has important potential therapeutic implications for the treatment of a number of important neurological disorders," says the study's senior investigator, Alan I. Faden, M.D., a professor of neuroscience and director of the Laboratory for the Study of Central Nervous System Injury.

    The research, led by investigator Kimberly Byrnes, Ph.D., an assistant professor in Faden's laboratory, centered on microglial cells, which react against pathogens that invade the brain, and also remove foreign material and damaged cells.

    Byrnes describes microglial cells as just a little too good at their jobs. "They overdo it, perhaps because they don't have very good stop signals. They secrete a number of toxic chemicals designed to clear up infections and damaged tissue -- but in the process they can kill sensitive brain cells."

    In this study, Byrnes, Faden and a team of four other researchers looked to see whether microglial cells express a certain receptor on their surface that Faden and his laboratory had previously found could be turned on in brain neurons to prevent cell death in response to injury. The receptor, the group I metabotropic glutamate receptor 5 (mGluR5), which also plays a critical role in modulating pain and addiction, was previously found in other types of brain cells.

    The researchers found the receptor protein in microglia in cell culture. "That's a first," Byrnes says. They then showed that a selective activator of this receptor type, CHPG, could turn off microglial activity. This is the same chemical that Faden discovered could shut down certain kinds of suicide cell death (apoptosis) in neurons.

    "We found that if we stimulate just this receptor, we can markedly reduce microglial release of key inflammatory factors and the ability of activated microglia to kill nerve cells," Byrnes says.

    The receptor, therefore, appears to be a switch-off mechanism, a brake on the damaging effects of microglial activity. "This is possibly a way that the brain has designed to turn microglia off, but the problem is that these cells get many other signals that keep them turned on after injury."

    Treating brain injury with a selective compound may be challenging, the researchers add. "Microglia also releases good chemicals, such as growth factors, to promote nerve cell regrowth and regeneration, so the trick will be to discretely use it after injury for a period of time."

    But brain and spinal cord injury studies in animals, conducted after the present experiments were completed, have been very encouraging, Byrnes says. Those studies have not yet been published.

    Source: Medical News Today © 2008 MediLexicon International Ltd (26/09/08)

    Regulatory immune cells may not be defective in Multiple Sclerosis

    Immune Cells

    Multiple sclerosis (MS) is a chronic inflammatory disease that causes neurodegeneration, resulting in numerous physical and mental disabilities. It is thought to be caused by out of control immune cells that attack the proteins that make up the protective sheath in which nerve cells are encased.

    In addition, it has been reported that a subset of immune cells known as Tregs (characterized by expression of the protein CD4 and high levels of expression of the protein CD25), which suppresses the function of aggressive immune cells, is defective in individuals with MS, and that this contributes to the progression of the disease.

    However, it has recently been shown that if CD4+CD25high cells are divided into cells expressing high and low levels of the protein CD127 only the CD4+CD25highCD127low cells have suppressive capability.

    Thus, Jean-Paul Soulillou and colleagues, at INSERM U643, France, compared the suppressive capabilities of CD4+CD25highCD127low cells from individuals with MS and healthy individuals. Surprisingly, they found that these cell populations were equally effective suppressors of aggressive immune cells when analyzed in vitro.

    These data therefore indicate that the suppressive function of Tregs (when characterized as CD4+CD25highCD127low) is not defective in individuals with MS, suggesting that this defective Treg function is not a factor that contributes to the development of this debilitating autoimmune disease.

    Source: Medical News Today © 2008 MediLexicon International Ltd (05/09/08)

    B cells, Epstein Barr Virus and Multiple Sclerosis

    B Cells


    Clonal expansion of B cells and the production of oligoclonal IgG in the brain and cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) have long been interpreted as circumstantial evidence of the immune-mediated pathogenesis of the disease and suggest a possible infectious cause.

    Extensive work on intrathecally produced antibodies has not yet clarified whether they are pathogenetically relevant. Irrespective of antibody specificity, however, the processes of antibody synthesis in the CNS of patients with MS are becoming increasingly clear. Likewise, targeting B cells might be therapeutically relevant in MS and other autoimmune diseases that are deemed to be driven predominantly by T cells.

    Accumulating evidence indicates that in MS, similar to rheumatoid arthritis, B cells aggregate into lymphoid-like structures in the target organ. The process of aggregation is mediated through the expression of lymphoid-homing chemokines.

    In the brain of a patient with MS, ectopic B-cell follicles preferentially adjoin the pial membrane within the subarachnoid space. Recent findings indicate that substantial numbers of B cells that are infected with Epstein-Barr virus (EBV) accumulate in these intrameningeal follicles and in white matter lesions and are probably the target of a cytotoxic immune response.

    These findings, which await confirmation, could be an explanation for the continuous B-cell and T-cell activation in MS, but leave open concerns about the possible pathogenicity of autoantibodies.

    Going beyond the antimyelin-antibody dogma, the above data warrant further work on various B-cell-related mechanisms, including investigation of B-cell effector and regulatory functions, definition of the consistency of CNS colonisation by Epstein-Barr virus-infected B cells, and understanding of the mechanisms that underlie the formation and persistence of tertiary lymphoid tissues in patients with MS and other chronic autoimmune diseases (ectopic follicle syndromes). This work will stimulate new and unconventional ways of reasoning about MS pathogenesis.

    Source: Lancet Neurology 2008; 7:852-858 © 2008 Elsevier Limited (12/08/08)

    Possible new trigger for Multiple Sclerosis found

    T Cell

    Yale University researchers have discovered a new way that autoimmune diseases like multiple sclerosis (MS) can be triggered, they reported Monday in the journal Proceedings of the National Academy of Sciences.

    Scientists have long known the molecule TGF-Beta (transforming growth factor Beta) plays a pivotal role in preventing T cells from launching an attack on the body's own tissues.

    A team led by Richard Flavell, professor and chairman of Immunobiology at the Yale School of Medicine, investigated whether TGF-Beta might also influence activity of other immune system cells as well.

    Flavell, an investigator for the Howard Hughes Medical Institute, and his colleagues engineered mice in which TGF-Beta was blocked at different places in the immune system. They found that when they blocked TGF-Beta in dendritic cells (DC's) the mice developed lesions on myelin sheathing of central nervous system cells, the hallmark of MS.

    "Previous work suggested that the immune dysfunction seen when TGF-Beta is removed could all be explained by T cells," said Flavell. "Now we know that TGF-Beta control of DC's is important to prevent autoimmunity."

    The PNAS study may explain why efforts to spur TGF-Beta activity only in T cells have had limited effects in treating autoimmune diseases, Flavell said.

    The authors also speculated that bolstering TGF-Beta activity on dendritic cells might have a potentially therapeutic effect on patients with MS and other autoimmune diseases.

    Source: Medical News Today © 2008 MediLexicon International Ltd (29/07/08)

    Cerebrospinal Fluid B Cells Correlate with Early Brain Inflammation in Multiple Sclerosis

    There is accumulating evidence from immunological, pathological and therapeutic studies that B cells are key components in the pathophysiology of multiple sclerosis (MS).

    Methodology/Principal Findings
    In this prospective study we have for the first time investigated the differences in the inflammatory response between relapsing and progressive MS by comparing cerebrospinal fluid (CSF) cell profiles from patients at the onset of the disease (clinically isolated syndrome, CIS), relapsing-remitting (RR) and chronic progressive (CP) MS by flow cytometry. As controls we have used patients with other neurological diseases. We have found a statistically significant accumulation of CSF mature B cells (CD19+CD138) and plasma blasts (CD19+CD138+) in CIS and RRMS. Both B cell populations were, however, not significantly increased in CPMS. Further, this accumulation of B cells correlated with acute brain inflammation measured by magnetic resonance imaging and with inflammatory CSF parameters such as the number of CSF leukocytes, intrathecal immunoglobulin M and G synthesis and intrathecal production of matrix metalloproteinase (MMP)-9 and the B cell chemokine CxCL-13.

    Our data support an important role of CSF B cells in acute brain inflammation in CIS and RRMS.

    Kuenz B, Lutterotti A, Ehling R, Gneiss C, Haemmerle M, et al. (2008 ) Cerebrospinal Fluid B Cells Correlate with Early Brain Inflammation in Multiple Sclerosis. PLoS ONE 3(7): e2559. doi:10.1371/journal.pone.0002559

    Source: Coffee and Sci(ence) (07/07/08)

    Possibility of distinct types of disease in Multiple sclerosis patients with same symptoms
    Results raise prospects for tailoring treatments for patients with MS.

    Animal studies by University of Michigan scientists suggest that people who experience the same clinical symptoms of multiple sclerosis (MS) may have different forms of the disease that require different kinds of treatment. 

    The results, if borne out in further studies, point to a time when doctors will be able to target specific inflammatory processes in the body and more effectively help MS patients, using available drugs and new ones in the pipeline.
    Since the 1990s, the treatment picture has brightened for people with multiple sclerosis in its most common form, relapsing-remitting MS. Beta interferon drugs and glatiramer acetate (marketed as Copaxone) have proved effective at decreasing the attack rate and suppressing inflammatory plaque development in many patients with MS. Yet why the drugs help some patients, but not others, has remained a mystery.
    The U-M research team conducted the studies in mice that have a disease similar to MS: experimental autoimmune encephalomyelitis or EAE. The team found that different inflammatory chemicals, whose activity is linked to two different types of immune system T cells, could bring on the same paralysis and other MS-like signs. They also showed that drugs that block one of the inflammation pathways were not effective at blocking the other. The results, published online ahead of print, will appear in the July 7 issue of the Journal of Experimental Medicine.
    “These two forms of disease differ in the specific anti-inflammatory agents that they are responsive to,” says Benjamin Segal, M.D., the study’s senior author and the director of the Multiple Sclerosis Center at the U-M Health System.
    “We already know that some people respond better to the drugs beta interferon or Copaxone than others. Now we’ve shown proof that you can cause MS-like syndrome in mice due to qualitatively different types of inflammatory damage. As a result, these two kinds of inflammation likely require different approaches to treatment,” says Segal. He directs the Holtom-Garrett Program in Neuroimmunology and is the Holtom-Garrett Family Professor of Neurology at the U-M Medical School.
    MS is an inflammatory disease of the central nervous system believed to be autoimmune in nature. Certain cells in the body’s immune system mount an inappropriate response against proteins in the nervous system, in particular myelin, the fatty substance that covers nerve axons. MS affects an estimated 2.5 million people worldwide. Symptoms, which vary widely, include numbness and weakness, incontinence, double vision, tremor, imbalance and pain.
    In 85 percent of MS cases, patients begin with what is called a relapsing-remitting form of the disease. Initially, they have attacks in which they experience symptoms for a time, return to normal, then have attacks again. In the last 15 years, several beta interferon drugs and Copaxone have been effective in many patients at limiting the number of attacks. These drugs also can also decrease damage in the brain as visualized on MRI scans.
    Research details:
    Segal’s research team injected one group of mice with an immune system T helper cell, Th1, long believed to play a role in MS, and another group with a T helper cell, Th17, whose potential role in MS has recently come to light. They measured the activity of specific inflammatory agents that are induced by each type of T cell as the immune system mounts its misguided attack on the myelin sheaths of nerve cells.
    Both groups of mice developed similarly severe and rapid paralysis. But the researchers found clear differences in the inflammatory agents involved, called cytokines and chemokines, and in the resulting damage to the central nervous system.
    Mice injected with Th1 cells showed a pattern of central nervous system inflammation that resembled that of common MS, with lesions filled with macrophages, a type of immune system defender cell. Mice injected with Th17 cells, however, had lesions filled with another immune cell type, neutrophils. In these mice, inflammation reached deep in central nervous system tissues and in the optic nerve.
    In both groups of mice, the scientists tested the effects of neutralizing antibody drugs similar to drugs being developed against autoimmune diseases in humans. Some of the drugs inhibited disease in the Th17 mice, but not in the mice receiving Th1 cells. Other drugs were effective against both types of disease.
    “That’s our proof that these really are different mechanisms of disease,” says Mark Kroenke, the study’s first author and a Ph.D. student in immunology at U-M.
    It’s not yet known whether the same differences will prove true in people with MS. But the study suggests the need to develop drugs tailored to affect distinct inflammation pathways that might drive different forms of relapsing-remitting MS.
    “We speculate at some point being able to identify and measure active inflammatory agents in patients, and to develop customized profiles that would help predict what treatments will be effective,” Segal says.
    In addition, Segal says, the findings may aid the search for effective drugs for two difficult-to-treat diseases closely related to MS: neuromyelitis optica, which affects the optic nerve and spinal cord, and opticospinal MS, most common in Asia. The pattern of inflammation the team saw in the Th17-injected mice resembled the pattern in these variants of MS.
    Other authors include: Anuska V. Andjelkovic, Ph.D., U-M Department of Pathology; and Thaddeus J. Carlson, Ph.D., University of Rochester School of Medicine and Dentistry.
    Segal is on the scientific advisory board of the National MS Society.
    This work was supported by grants from the National Multiple Sclerosis Society and the National Institutes of Health.
    Source: University of Michigan © copyright 2008 Regents of the University of Michigan (02/07/08)

    T regulatory cells that inhibit multiple sclerosis that are not T reg
    Multiple sclerosis is mediated by autoimmune T cell responses against components of the myelin basic sheath, for example myelin basic protein, myelin oligodendrocyte protein, and phospholipid protein. Stem cell therapy, especially with universal donor mesenchymal stem cells or endometrial regenerative cells, has potent for treatment of this disease, however these therapies are still not implimented on a widespread basis. One treatment of multiple sclerosis that has been successful clinically is glatiramer acetate, which is a polymer of repeating peptides. Its mechanism of action was not really figured out although numerous theories exist. Nevertheless it has helped hundreds of thousands of patients.

    In a recent paper (Stern et al. Amino acid copolymer-specific IL-10-secreting regulatory T cells that ameliorate autoimmune diseases in mice. Proc Natl Acad Sci U S A. 2008 Apr 1;105(13):5172-6) immunological mechanisms of glatiramer acetate were examined in detail.

    Mice were immunized with autoantigens and treated with glatiramer acetate and a specific type of it made by Peptimmune called FYAK. T cell lines were made by in vitro restimulation. It was found that the T cell lines were capable of protecting mice when administered into mice with ongoing disease, thus stimulating the authors to call the cells "T regulatory".

    T cell lines responding to the glatiramer acetate were not "true" T regulatory cells since they lacked expression of FoxP3. Interestingly the cells expressed CD30 and GITR, as well as the classical CD4+ CD25+ T regulatory cell markers.

    The T cell lines produced the cytokines IL-10 and IL-13 but little IL-4.

    Most strikingly, the T cells were antigen-nonspecific in their activity, at least in their in vivo activity. The cells blocked autoimmune responses induced by a variety of different autoantigens. These data provide some additional insight as to mechanisms of glatiramer acetate. Given that mesenchymal stem cells stimulate T regulatory cells, it will be interesting to see if synergy of effect can be attained by adding these two approaches.

    Source: © 2006 - 2008 (05/06/08)

    Luteolin Flavonoid In Celery May Impact Multiple Sclerosis
    Researchers at the University of Illinois report this week that a plant compound found in abundance in celery and green peppers can disrupt a key component of the inflammatory response in the brain. The findings have implications for research on aging and diseases such as Alzheimer’s and multiple sclerosis.

    Inflammation can be a blessing or a blight. It is a critical part of the body’s immune response that in normal circumstances reduces injury and promotes healing. When it goes awry, however, the inflammatory response can lead to serious physical and mental problems.

    Inflammation plays a key role in many neurodegenerative diseases and also is implicated in the cognitive and behavioral impairments seen in aging.

    The new study looked at luteolin (LOO-tee-OH-lin), a plant flavonoid known to impede the inflammatory response in several types of cells outside the central nervous system. The purpose of the study was to determine if luteolin could also reduce inflammation the brain, said animal sciences professor and principal investigator Rodney Johnson.

    “One of the questions we were interested in is whether something like luteolin, or other bioactive food components, can be used to mitigate age-associated inflammation and therefore improve cognitive function and avoid some of the cognitive deficits that occur in aging,” Johnson said.

    The researchers first studied the effect of luteolin on microglia. These brain cells are a key component of the immune defense. When infection occurs anywhere in the body, microglia respond by producing inflammatory cytokines, chemical messengers that act in the brain to orchestrate a whole-body response that helps fight the invading microorganism.

    This response is associated with many of the most obvious symptoms of illness: sleepiness, loss of appetite, fever and lethargy, and sometimes a temporary diminishment of learning and memory. Neuroinflammation can also lead some neurons to self-destruct, with potentially disastrous consequences if it goes too far.

    Graduate research assistant Saebyeol Jang studied the inflammatory response in microglial cells. She spurred inflammation by exposing the cells to lipopolysaccharide (LPS), a component of the cell wall of many common bacteria.

    Those cells that were also exposed to luteolin showed a significantly diminished inflammatory response. Jang showed that luteolin was shutting down production of a key cytokine in the inflammatory pathway, interleukin-6 (IL-6). The effects of luteolin exposure were dramatic, resulting in as much as a 90 percent drop in IL-6 production in the LPS-treated cells.

    “This was just about as potent an inhibition as anything we had seen previously,” Johnson said.

    But how was luteolin inhibiting production of IL-6?

    Jang began by looking at a class of proteins involved in intracellular signaling, called transcription factors, which bind to specific “promoter” regions on DNA and increase their transcription into RNA and translation into proteins.

    Using electromobility shift assays, which measure the binding of transcription factors to DNA promoters, Jang eventually determined that luteolin inhibited IL-6 production by preventing activator protein-1 (AP-1) from binding the IL-6 promoter.

    AP-1 is in turn activated by JNK, an upstream protein kinase. Jang found that luteolin inhibited JNK phosphorylation in microglial cell culture. The failure of the JNK to activate the AP-1 transcription factor prevented it from binding to the promoter region on the IL-6 gene and transcription came to a halt.

    To see if luteolin might have a similar effect in vivo, the researchers gave mice luteolin-laced drinking water for 21 days before injecting the mice with LPS.

    Those mice that were fed luteolin had significantly lower levels of IL-6 in their blood plasma four hours after injection with the LPS. Luteolin also decreased LPS-induced transcription of IL-6 in the hippocampus, a brain region that is critical to spatial learning and memory.

    The findings indicate a possible role for luteolin or other bioactive compounds in treating neuroinflammation, Johnson said.

    “It might be possible to use flavonoids to inhibit JNK and mitigate inflammatory reactions in the brain,” he said. “Inflammatory cytokines such as interleukin-6 are very well known to inhibit certain types of learning and memory that are under the control of the hippocampus, and the hippocampus is also very vulnerable to the insults of aging,” he said. “If you had the potential to decrease the production of inflammatory cytokines in the brain you could potentially limit the cognitive deficits that result.”

    Source: Scientific Blogging (21/05/08)

    Possible Antibody to fight Multiple Sclerosis discovered
    An antibody to fight multiple sclerosis may be the first potential treatment coming from a five-year-old state partnership between Mayo Clinic and the University of Minnesota.

    The Minnesota Partnership for Biotechnology and Medical Genomics has sent the antibody, called rHIgM22, to be purified by Biovest, a private company in Minneapolis, in quantities large enough that animal studies and clinical trials can be done, said neuroscientist Art Warrington.

    Multiple sclerosis directs the body to attack the protective myelin sheath around nerves of the brain and spinal cord. Researchers say rHIgM22 appears to counteract that.

    "The importance of the antibody as a promoter of myelin repair (remyelination) was recognized in studies using experimental animal models of multiple sclerosis," says a Mayo statement.

    The Minnesota Partnership fills a void by helping researchers with good ideas but not enough money, Warrington said.

    "It helps academic researchers to avoid this blockade in the road where you have promising data -- where you can run a research grant off that -- but the next step would take several million dollars, or a commercial venture," he said.

    The Minnesota Partnership was instrumental in providing the infrastructure to develop the antibody to this point, said researcher Larry Pease, chairman of immunology at Mayo. "This antibody would not be headed into clinical trials or toward commercialization otherwise."

    The partnership developed a valid process for producing purified antibody developed at Mayo.

    "This is exactly what the partnership is intended to do," Mayo Partnership program director Eric Wieben. "That is to promote interactions between the two leading medical research institutions in Minnesota and to accelerate medical discoveries that can be commercialized for the benefit of patients while improving our state's economy."

    Source: Copyright 2008 Post-Bulletin Company 19/04/08)

    Idera Pharmaceuticals Presents Data from Study of Toll-Like Receptor Antagonist in Preclinical Model of Multiple Sclerosis

    Idera Pharmaceuticals, Inc, today presented data from studies evaluating a Toll-Like Receptor (TLR) antagonist in a preclinical model of multiple sclerosis (MS).

    The presentation entitled "Studies of Oligonucleotide-Based Antagonists of TLR9 in a Mouse Model of Experimental Autoimmune Encephalomyelitis" (Abstract #2049) was made during the 60th Annual Meeting of the American Academy of Neurology.

    In the study, one of the Company's proprietary TLR antagonist candidates was evaluated in a mouse model of experimental encephalomyelitis, a preclinical model of MS. Treatment with this antagonist candidate resulted in reductions of disease symptoms, including leg weakness and inflammatory cell infiltration in and demyelination of the spinal cord.

    "With presentation of the current data, our novel TLR antagonist candidates now have shown activity in preclinical models of multiple sclerosis, lupus and rheumatoid arthritis," commented Sudhir Agrawal, D. Phil, Chief Executive Officer and Chief Scientific Officer. "We are forming an Autoimmune Disease Scientific Advisory Board to assist us in defining clinical development strategy in autoimmune diseases. In 2008, we anticipate initiating preclinical studies of a selected TLR antagonist to support an Investigational New Drug application."

    Source: The Centre Daily Times Copyright 2008 The Centre Daily Times (18/04/08)

    Marie Curie researcher investigates role of innate immune system in Multiple Sclerosis
    Multiple Sclerosis (MS) is a neurological disease and has many faces that researchers still do not fully understand. It is believed to be an autoimmune disease, in which the immune system reacts against components of the brain and spinal cord. Recent research efforts have been looking into the possibility of exploiting the human body's own immune system in MS therapy.

    In the framework of the EU's Marie Curie programme, Dr Bruno Gran of the University of Nottingham, UK, is investigating the use of the so-called innate immune system. As opposed to the adaptive immune system, which is in charge of highly specific immune responses, the innate immune system is less specific. It is designed 'to respond quickly to infectious agents such as bacteria and viruses and to recognise patterns that are common to these infectious agents and start a rather potent and quick immune response that is eliminating these pathogens,' Dr Gran explained in a CORDIS News interview.

    In principle, the innate immune system is able to recognise structural components shared by viruses, bacteria and other infectious agents with the help of Toll-like receptors (TRLs). The TRLs as a type of pattern recognition receptor identify structurally conserved molecules derived from infectious agents once they have breached physical barriers such as the skin or intestinal mucosa, and activate immune cell responses. 'When this is initiated, the innate immune system also instructs the adaptive immune system to fine-tune a more specific response.'

    So far, most recent MS research, including Dr Gran's, has been focused on the adaptive immune system. 'This is an initial investigation into the ability of the innate immune system to provoke autoimmune reaction as opposed to the adaptive, from the point of view of disease mechanisms,' he said. 'If we then go on to the innate immune system, there are two aspects. One is the ability to eliminate pathogens by provoking inflammatory immune responses that may then provoke damage to tissues. But also the ability to produce regulatory molecule like the Type 1 Interferons, Interferon-beta and also Interferon-alpha. So, the concept here is that we use some of these molecules to treat MS.'

    Currently, MS is treated with Interferons, most commonly Interferon-beta, a molecule that was initially discovered because of its antiviral properties but was later found to have an effect on the entire immune system. However, the cost of producing Interferon-beta as a drug for injection are high, and the human immune system itself can produce large amounts of Interferon-beta, for instance, during viral infections.

    One year into the two-year project, Dr Gran has just started conducting experiments on mice using the animal model of MS, experimental autoimmune encephalomyelitis (EAE). In vitro experiments on mouse and human cells, however, have already provided promising results: As Dr Gran had expected, toll-like receptor stimuli triggered the production of both pro-inflammatory cytokines, i.e. signalling proteins and glycoproteins essential to cellular communication, and type 1 interferons.

    Yet the aim of the project is to develop TLR agonists, substances that bind to TLRs and trigger a response in the cell, to a stage where they are ready for clinical testing in humans. This will improve quality of life for people suffering from MS and reduce treatment costs at the same time.

    However, there are a number of promising routes for MS treatment being explored at the moment. 'We have had very significant advances in understanding and treatment in the last 15 years,' Dr Gran pointed out, adding that there is still a need to understand the genetic susceptibility better, as well as the interplay between genetics and environmental factors. 'For example, viruses can provoke disease relapses and recently, some very interesting data on the Epstein-Barr virus [a virus of the Herpes family] was published suggesting that it may be one of the pathogens involved in disease susceptibility.' In addition, Dr Gran predicts a gradually more customised, individualised treatment, as well as a greater role for stem cell research.

    Source: Cordis © European Communities, 1990-2008 (31/03/08)

    Liver transplant patient hailed a 'medical miracle'
    Doctors in Sydney may have stumbled across the holy grail of transplant surgery.

    A young liver transplant patient has taken on the immune system of her donor, allowing her to stop taking potentially toxic anti-rejection drugs.

    The doctors aren't exactly sure how it happened, but they do see potential benefits for other transplant patients, as well as for sufferers of auto-immune diseases like multiple sclerosis and type-one diabetes.

    Paula Kruger reports.

    PAULA KRUGER: Demi Brennan is a very grateful 15-year-old.

    DEMI BRENNAN: I'm probably the most grateful person because that has saved my life, that gave me a chance to fulfil my life.

    PAULA KRUGER: But the Sydney teenager isn't just blessed with the donated liver that saved her life six years ago, she is being hailed as a medical miracle.

    Organ transplants have been saving lives around the world for 50 years but patients have had to take toxic anti-rejection drugs - known as immunosuppressant drugs - for the rest of their lives.

    Demi Brennan doesn't. Instead her immune system changed to that of the organ donor.

    It was a development that surprised Dr Michael Stormon, a paediatric hepatologist who treated Ms Brennan at Sydney's Westmead Hospital.

    MICHAEL STORMON: Oh, we were stunned, because we'd never come across this before, we… there was no precedent for this having happened at any other time, so we were sort of flying by the seat of our pants to a certain degree trying to sort this out.

    PAULA KRUGER: When Demi Brennan was nine years old she caught a virus that caused her liver to fail.

    She was given an urgent transplant but became very ill nine months after the operation.

    She suffered a process called haemolysis - her red blood cells were breaking down.

    It was at that point that doctors discovered her blood type and bone marrow had changed to that of the organ donor.

    But the young patient was still gravely ill.

    MICHAEL STORMON: We certainly struggled with this for months and months because of the haemolytic process, she required multiple blood transfusions, we discovered that most but not all of her immune system was also that of the donor.

    But at the same time she was producing some antibodies herself and you know, we as I said, struggled for several months. She spent that time in hospital. We put her on large doses of immunosuppression to try and stop that process.

    And it was then that we decided, you know, one of our other options was actually to stop all her immunosuppression in the hope that she would become, her immune system would become completely that of the donor. And in fact that's what happened.

    PAULA KRUGER: The patient is now a normal healthy 15-year-old.

    But after taking on someone else's immune system she had to be re-vaccinated against the measles and mumps because the donor had never been vaccinated against the diseases.

    Demi Brennan's case is being seen a medical breakthrough, and there are potential benefits for not only transplant surgery but a range of auto-immune diseases too, such as multiple sclerosis and Type 1 Diabetes, if the results can be replicated.

    But her doctors still aren't sure why it happened.

    MICHAEL STORMON: I think it's a combination of factors and I guess that's the million-dollar question because, if we could replicate this then that would be a fantastic achievement, but it's probable that there was a sort of sequence of events that in some way resulted in this occurring.

    PAULA KRUGER: Dr Michael Stormon has co-authored an article on Demi Brennan's remarkable recovery in the New England Medical Journal.

    The latest issue also reports on a similar situation in the United States.

    Researchers from Stanford University in California treated a patient with radiation and a drug that destroyed his T-cells before transplanting a kidney from the patient's brother.

    Along with the transplant was a blood infusion that had been enriched for blood-producing stem cells.

    Two years after the procedure the patient still has his brother's immune cells in his system and there are no signs of organ rejection even though he has stopped taking immunosuppressant drugs.

    The researchers are continuing their study and say that if all goes well with other patients the technique could be generally available within ten years.

    Source: Australia Broadcasting Company © 2008 ABC (28/01/08)

    New therapeutic target for the treatment of multiple sclerosis

    Researchers prove the role of certain leukocyte cell adhesion molecules in the pathogenesis of the disease.

    A study published in the February issue of Nature Immunology provides answers about the role of novel adhesion molecules in the pathogenesis of multiple sclerosis (MS) and suggests new therapeutic targets for its treatment.

    The study, by the team of neurologist Dr. Alexandre Prat, neurologist, researcher at the Centre hospitalier de l'Université de Montréal and professor at the Faculty of Medicine of Université de Montréal, reveals that the adhesion molecule, dubbed ALCAM (Activated Leukocyte Cell Adhesion Molecule), or CD166, which is expressed by the endothelial cells of the brain, plays a major role in the migration of certain types of leukocytes to the brain. Researchers believe that the molecule constitutes a novel target to restrict migration of immune cells to the brain, thus dampening neuroinflammation and decreasing the lesions characteristic of MS. MS is a chronic autoimmune disease of the nervous system that affects approximately 55,000 young adults in Canada.

    Understanding the molecular mechanisms of brain inflammation is essential in the development of new treatments for this degenerative disease. The study was carried out also with researchers at McGill University (Dr. S. David), Université de Montréal (Dr. N. Arbour), the National Research Council of Canada (Dr. D. Stanimirovic) and University of Zurich (Dr. B. Becher).

    The results clearly demonstrate that CD166/ALCAM is involved in the inflammatory process by priming the migration of leukocytes across the blood-brain barrier (BBB). The research project combines results using an in vitro human BBB model and an in vivo experimental autoimmune encephalomyelitis mouse model. Normally, a limited number of immune cells are able to cross the BBB and penetrate the central nervous system. In MS and other neuroinflammatory diseases, the increased permeability of the BBB is associated with an increase in the transmigration of some of these immune cells, which penetrate the central nervous system and cause the demyelinating lesions of MS. A previous study by Dr. Prat's team published in October in Nature Medicine (1), proved that a certain type of leukocyte, the TH17 lymphocyte, produces two critical products, interleukins 17 and 22 (IL-17 and IL-22), which contribute to infiltrating the blood-brain barrier and causing inflammation of the central nervous system.

    "Blocking the migration of immune cells across the BBB has long been considered a promising therapeutic approach to autoimmune diseases of the central nervous system," states Dr. Prat. "This study has given us new insight into the factors involved in the pathogenesis of immune reactions affecting the central nervous system and allowed us to identify potential targets to suppress neuroinflammatory processes."

    An attractive therapeutic target

    Pharmacological agents exist that reduce the transmigration of immune cells by specifically blocking leukocyte adhesion molecules, thus significantly decreasing the extent of CNS inflammation. However, they also impede the immune system's ability to provide protection against chronic viral infections of the central nervous system, such as progressive multifocal leukoencephalopathy, a demyelinating disease of the central nervous system caused by the JC virus. Since ALCAM/CD166 blockade does not affect CD8+ T cell migration, whose main function is to destroy cells infected by viruses and neoplastic cells, the study results suggest that CNS immune protection against viruses would not be compromised by ALCAM blockade in vivo. ALCAM/CD166 could thus be considered as an attractive therapeutic target for multiple sclerosis. This study was funded by the Multiple Sclerosis Society of Canada and by the Canadian Institutes of Health Research (CIHR).

    The blood-brain barrier (BBB)

    The BBB is a membranic structure that controls and limits exchanges between the blood and the brain. Composed of endothelial cells packed tightly within brain capillaries, it maintains the composition of the brain's interstitial spaces by its selective and restrictive permeability. It is almost completely impermeable to various molecules, immune cells and substances circulating in the blood. The BBB thus isolates and protects the brain from the rest of the organism.

    (1) Kebir H., Kreymborg K., Ifergan I., Dodelet-Devillers A., Cayrol R., Bernard M., Giuliani F., Arbour N., Becher B., Prat A. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation (2007). Nat Med, 13(10), 1173-5.

    Source: Centre hospitalier de l'Université de Montréal (22/01/08)

    New Way To Block Destructive Rush Of Immune Cells Found
    Researchers have found a way to selectively block the ability of white blood cells to "crawl" toward the sites of injury and infection when such mobility drives disease, according to a study published January 14 in The Journal of Experimental Medicine. The results suggest a new treatment approach for autoimmune diseases like rheumatoid arthritis, lupus and multiple sclerosis, and for conditions made worse by misplaced inflammation, like atherosclerosis, stroke and transplant rejection, researchers said.

    Where a single-celled amoeba moves to find food, human cells migrate as part of complex bodily functions like immunity. Disease-fighting cells for instance move toward bacteria and cells infected with viruses, which they target for destruction. Unfortunately, the same cells can mistakenly attack the body's own cells or drive inflammation too far, worsening the problem they rushed in to solve.

    A team of researchers at the University of Rochester Medical Center has been studying proteins called integrins that enable T cells, a major subset of immune cells, to migrate. The integrin-related mechanisms described for the first time in the current paper suggest a way to shut down only those T cells currently in the act of disease-related migration, while leaving in place reserves needed in the likely event that another infection occurs during treatment. Making the mechanistic discoveries possible was a successful effort by the team to capture on video the first detailed images of fast-migrating T cells and the behavior of key proteins related to migration, which had been tagged with fluorescence. Twelve videos of T cells, and their key migration proteins, in action are part of the publication and are available online.

    "There are many cases where it would be incredibly useful to precisely block integrin activation, and thus T cell migration," said Minsoo Kim, Ph.D., assistant professor of Microbiology and Immunology within the David H. Smith Center for Vaccine Biology and Immunology at the Medical Center, and lead author of the article. "Good examples include when our immune system attacks our own cells, or rejects a lifesaving transplant or clogs our blood vessels by mistake. The problem is that past, system-wide attempts that block all integrin activation, like the multiple sclerosis drug Tysabri, shut down not only unwanted inflammation in one locale, but also vital immune defenses elsewhere, leaving patients vulnerable to infection."

    The Great Migration

    Two mechanisms make cell migration, or programmed directional movement, possible. The first, called chemotaxis, tells the cell which direction to move in. Cell surface proteins sense and follow chemicals and molecules they are attracted to toward wherever those attractants are most concentrated. T cells, named after the thymus (T) where they mature, move toward the byproducts of bacteria and viruses.

    The second migratory mechanism is propulsion. In between infections and injuries, inactive T cells ride along with the bloodstream. T cells "realize" when they pass by part of a blood vessel wall close to the site of an injury or infection. Integrins on their surfaces unfold and grab onto key proteins on the surface of blood vessel wall cells (e.g. ICAM), resisting the surrounding blood flow. The T cells then pass through the vessel wall, and once outside the bloodstream, crawl along the tissue scaffolding toward the site of injury.

    In a T cell at rest, integrins are distributed evenly over the entire surface of the T cell. When the cell gets ready to move, however, activated integrins cluster on the leading edge of the cell in the direction the cell wants to move in. They bind to their counterpart adhesion proteins like ICAM on the surface that the T cell is moving across. The T cell then contracts using its cell skeleton to pull itself over the leading edge integrins. Finally, the integrins on the trailing edge of the cell let go. Without precise changes that enable the front end to gain traction, and the tail to let go, the cell cannot migrate.

    Kim's team found that a subset of integrins, including lymphocyte function--associated antigen-1 (LFA-1), control whether or not the tail end of the T cell can "let go" (de- adhesion). Data revealed for the first time that a protein called non-muscle myosin heavy chain-IIA (MyH9) is recruited to LFA-1 at the trailing end of migrating T lymphocytes. Experiments that interfered with the association between MyH9 and the LFA-1 integrin were found to prevent the trailing edge of the crawling T cell from letting go, dramatically reducing the ability of T cells to move. Myosins are motor proteins that expend energy to enable cell skeletons to contract.

    That contraction creates force that is used in many cases to move muscle fibers, but in the case of MyH9, to rip the trailing end of a migrating T cell foot away from the surface it is migrating across by breaking integrin-ICAM bonds. The results provide the first evidentiary support of the longstanding theory that cell skeleton contractile force is used to drive T cell migration, with MyH9 as the mechanical link. Captured images show fluorescently tagged actin (which partners with LFA-1 to grip the surface) gathering at the front end of the cell, and fluorescently tagged MyH9 gathering at the tail end in cycles, each time the cell takes a "step."

    The study was a joint effort by the Department of Surgery at Rhode Island Hospital, Brown Medical School, the Department of Physics at Brown University, the CBR Institute for Biomedical Research at Harvard Medical School and the departments of Chemical Engineering, Biomedical Engineering and Department of Microbiology and Immunology at the University of Rochester. The project was supported by the American Heart Association, the Rhode Island Foundation, the National Institutes of Health, the National Science Foundation and the Brown University Seed Grant.

    In the next phase, the team will seek to develop better-targeted, anti-integrin therapies, with MyH9 among the rational targets for new classes of drugs. Toward that end, experiments currently underway are designed to determine which molecules regulate MyH9 activity during T cell migration.

    "Initial clinical studies on T cell migration focused on overall blocking of migration, but general inhibition is a blunt tool," said Tim Mosmann, Ph.D., director of the David H. Smith Center for Vaccine Biology and Immunology. "As studies such as Dr. Kim's help us to understand the process more precisely, we should be able to design much more precise methods to block migration in the selected circumstances that cause problems, without crippling the essential immune responses to infections."

    Source: Science Daily Copyright © 1995-2007 ScienceDaily LLC (15/01/08)

    A Promising Therapeutic Approach for Multiple Sclerosis: Recombinant T-Cell Receptor Ligands Modulate Experimental Autoimmune Encephalomyelitis by Reducing Interleukin-17 Production and Inhibiting Migration of Encephalitogenic Cells into the CNS
    Recombinant T-cell receptor ligands (RTLs) can prevent and reverse clinical and histological signs of experimental autoimmune encephalomyelitis (EAE) in an antigen-specific manner and are currently in clinical trials for treatment of subjects with multiple sclerosis (MS). To evaluate regulatory mechanisms, we designed and tested RTL551, containing the 1 and ß1 domains of the I-Ab class II molecule covalently linked to the encephalitogenic MOG-35-55 peptide in C57BL/6 mice.

    Treatment of active or passive EAE with RTL551 after disease onset significantly reduced clinical signs and spinal cord lesions. Moreover, RTL551 treatment strongly and selectively reduced secretion of interleukin-17 and tumor necrosis factor by transferred green fluorescent protein-positive (GFP+) MOG-35-55-reactive T-cells and almost completely abrogated existent GFP+ cellular infiltrates in affected spinal cord sections.

    Reduced inflammation in spinal cords of RTL551-treated mice was accompanied by a highly significant downregulation of chemokines and their receptors and inhibition of VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) expression by endothelial cells.

    Thus, RTL therapy cannot only inhibit systemic production of encephalitogenic cytokines by the targeted myelin oligodendrocyte glycoprotein-reactive T-cells but also impedes downstream local recruitment and retention of inflammatory cells in the CNS.

    These findings indicate that targeted immunotherapy of antigen-specific T-cells can result in a reversal of CNS lesion formation and lend strong support to the application of the RTL approach for therapy in MS.

    Sushmita Sinha,1,2 Sandhya Subramanian,1 Thomas M. Proctor,1,7 Laurie J. Kaler,1 Marjorie Grafe,3,4 Rony Dahan,2,3 Jianya Huan,2,7 Arthur A. Vandenbark,1,2,5,7 Gregory G. Burrows,2,6,7 and Halina Offner1,2,4,7

    1Neuroimmunology Research, Veterans Affairs Medical Center, Portland, Oregon 97239, and Departments of 2Neurology, 3Pathology, 4Anesthesiology and Perioperative Medicine, 5Molecular Microbiology and Immunology, and 6Biochemistry and Molecular Biology and 7Tykeson MS Research Laboratory, Oregon Health & Science University, Portland, Oregon 97239

    Source: The Journal of Neuroscience Copyright © 2007 by Society for Neuroscience. (15/11/07)

    Clinical and neuroimaging correlates of antiphospholipid antibodies in Multiple Sclerosis: A preliminary study
    The presence of antiphospholipid antibodies (APLA) in multiple sclerosis (MS) patients has been reported frequently but no clear relationship between APLA and the clinical and neuroimaging features of MS have heretofore been shown. We assessed the clinical and neuroimaging features of MS patients with plasma APLA.

    A consecutive cohort of 24 subjects with relapsing-remitting (RR) MS were studied of whom 7 were in remission (Rem) and 17 in exacerbation (Exc). All subjects were examined and underwent MRI of brain. Patients' plasma was tested by standard ELISA for the presence of both IgM and IgG antibodies using a panel of 6 targets: cardiolipin (CL), beta2 glycoprotein I (beta2GPI), Factor VII/VIIa (FVIIa), phosphatidyl choline (PC), phosphatidyl serine (PS) and phosphatidyl ethanolamine (PE).

    In exacerbation up to 80% of MS subjects had elevated titers of IgM antibodies directed against the above antigens. However, in remission, less than half of MS patients had elevated titers of IgM antibodies against one or more of the above antigens. This difference was significant, p<0.01, for all 6 target antigens. Interestingly, none of the MS patients had elevated plasma titers of IgG against any of the target antigens tested. Correlation analysis between MRI enhancing lesions and plasma levels of APLA revealed high correlation for aPC, aPS and FVIIa (p<0.0065), a trend for aPE and aCL (p = 0.056), and no correlation for abeta2GP1. The strongest correlation was for FVIIa, p = 0.0002.

    The findings of this preliminary study show that increased APLA IgM is associated with exacerbations of MS. Currently, the significance of this association or role of these autoantibodies in pathogenesis of MS remains unknown. However, systematic longitudinal studies to measure APLA in larger cohorts of patients with relapsing-remitting MS, particularly before and after treatment with immunomodulatory agents, are needed to confirm these preliminary findings.

    Carlos J. Bidot , Lawrence L. Horstman , Wenche Jy , Joaquin J. Jimenez , Carlos Bidot Jr , Yeon S. Ahn , J. Steven Alexander , Eduardo Gonzalez-Toledo , Roger E. Kelley and Alireza Minagar

    Source: BMC Neurology 2007, 7:36doi:10.1186/1471-2377-7-36 (19/10/07)

    Antibody leads to repair of myelin sheath in lab study of multiple sclerosis and related disorders
    Mayo Clinic researchers have found that a human antibody administered in a single low dose in laboratory mouse models can repair myelin, the insulating covering of nerves that when damaged can lead to multiple sclerosis and other disorders of the central nervous system.

    The study will be presented on Oct. 9 at the American Neurological Association meeting in Washington, D.C.

    “The repair of chronic spinal cord injury is seldom modeled in laboratory studies, but it is an important reality for the treatment of humans. The concept of using natural human antibodies to treat disease of this kind has not yet been tested in humans, but these research findings are very promising,” says Moses Rodriguez, M.D., a Mayo Clinic neurologist and the study’s corresponding author. “The findings could eventually lead to new treatments that could limit permanent disability,” states Arthur Warrington, Ph.D., a Mayo Clinic scientist and study author.

    Myelin repair normally occurs spontaneously, but in multiple sclerosis and other disorders of the central nervous system, the myelin repair process occurs very slowly or fails altogether. Researchers are trying to determine how to speed up the myelin healing process, which they hope will eventually lead to new treatments for patients.

    The antibody, which was genetically engineered from a single cell, binds to myelin and the surface of cells in the brain and spinal cord, then it triggers the cells to begin the repair process called remyelination. This antibody is the first known reagent designed to induce repair by acting within the central nervous system at the damage sites on cells responsible for myelin synthesis.

    The study uses laboratory mouse models of chronic progressive multiple sclerosis in humans. The severity of the disease and also success of the treatment were largely defined by how naturally active the mice were, particularly during the night because mice are nocturnal and are especially active at this time. They received a single dose of the antibody. A minimum of 25 mcg/kg was needed to trigger remyelination, which is equivalent to about 2 mg in the average adult, considered a very low dose. The myelin repair plateaued after five weeks in the mice models.

    In addition, when combined with daily methylprednisolone, (an immune modulating steroid) the antibody still promotes remyelination in mouse models. This is an important fact because the first multiple sclerosis patients treated with the antibody will have been treated first with methylprednisolone.

    As a naturally occurring protein of the immune system, antibodies do not appear to carry any side effects, nor are they toxic -- even when administered at 4,000 times the minimal effective dose -- though the concept has not yet been tested in humans, the researchers say.

    In summary, this antibody:

    Promotes remyelination with a single dose as low as 25 mcg/kg in mice models The remyelination plateaus at five weeks after a single dose Converts a model of chronic immune mediated demyelination to one that repairs with the speed of a toxin induced model of demyelination In terms of replicating the findings in humans, the researchers have already produced the antibody through genetic engineering and conducted preliminary toxicology experiments in mice showing that 1,000 times the therapeutic dose is not toxic. The study continues to be explored in animal models and eventually, in clinical trials.

    In short, the critical finding is that when combined with methylprednisolone, the antibody still effectively promotes remyelination and does not make the mice worse, Dr. Warrington states.

    Source: The Mayo Clinic (09/10/07)

    Anti-aquaporin 4 antibody in selected Japanese multiple sclerosis patients with long spinal cord lesions
    Multiple sclerosis (MS) in Asian populations is often characterised by the selective involvement of the optic nerve (ON) and spinal cord (SP) (OSMS) in contrast to classic MS (CMS), where frequent lesions are observed in the cerebrum, cerebellum or brainstem.

    In Western countries, inflammatory demyelinating disease preferentially involving the ON and SP is called neuromyelitis optica (NMO).

    Recently, Lennon et al. discovered that NMO-IgG, shown to bind to aquaporin 4 (AQP4), could be a specific marker of NMO and also of Japanese OSMS whose clinical features were identical to NMO having long spinal cord lesions extending over three vertebral segments (LCL).

    To examine this antibody in larger populations of Japanese OSMS patients in order to know its epidemiological and clinical spectra, we established an immunohistochemical detection system for the anti-AQP4 antibody (AQP4-Ab) using the AQP4-transfected human embryonic kidney cell line (HEK-293) and confirmed AQP4-Ab positivity together with the immunohistochemical staining pattern of NMO-IgG in approximately 60% of Japanese OSMS patients with LCL.

    Patients with OSMS without LCL and those with CMS were negative for this antibody. Our results accorded with those of Lennon et al. suggest that Japanese OSMS with LCL may have an underlying pathogenesis in common with NMO.

    Source: Multiple Sclerosis 2007; 13: 850—855 (07/10/07)

    UC researchers land grant to study 'natural killer cells' in Multiple Sclerosis
    University of Cincinnati researchers will use a $1.7 million grant to see if natural killer cells, a first line of defense against infection, also provide protection against multiple sclerosis and related chronic inflammation.

    The National Institute of Neurological Disorders and Stroke awarded the five-year grant to Dr. Bibiana Bielekova, a UC associate professor of neurology and director of the Waddell Center for Multiple Sclerosis.

    MS is an autoimmune disease, occurring when the body's own natural defense system starts attacking the myelin sheath -- or outer lining -- of nerves and neurons.

    Patients with MS often have defects in the number or function of natural killer (NK) cells in their body.

    "We aren't sure if NK cell deficiencies in MS cause the disease, or if the disease causes the deficiencies," Bielekova said in a press release. "But we do know that the medications out there that successfully alleviate MS symptoms have been found, in essence by accident, to improve NK cell activity."

    Bielekova added: "Our ultimate goal now is to understand how NK cells work in the immune response and create more tolerable therapeutics that boost their regulatory action."

    Source: Business Courier © 2007 American City Business Journals, Inc. (05/10/07)

    Early Research Into A Treatment For Progressive Multiple Sclerosis
    Scientists in Scotland may be on the way to discovering the cause of long term disability in people with multiple sclerosis (MS).

    New research carried out at the University of Aberdeen in Scotland, led by Professor Chris Linington, showed that some people with MS have specific antibodies (a type of immune molecule) which attack nerve fibres.

    The newly identified antibodies recognise and attack a protein called neurofascin-186 which makes up part of the nerve fibre. Higher levels of these antibodies were discovered in a small study of people with MS who have a particularly degenerative type of MS.

    Researchers are now planning a larger study and if further research showed the antibody to be responsible, it may be possible to remove these antibodies from the blood of people with MS to slow disease progression.

    Professor Linington said 'I am particularly encouraged because there are already treatments available for other antibody mediated conditions. These type of therapies could be very rapidly translated and applied to MS if we confirm our findings'.

    Millions of nerve fibres are responsible for transmitting messages from our brain to the rest of our body and these nerves are covered in a protective coating called myelin which wraps in bundles around nerve fibres. The gaps which exist between these bundles are very important to allow transmission of nerve impulses along nerve fibres. The neurofascin antibodies can attack the nerve fibres between these gaps in the myelin..

    In a rat model of MS the attacking antibodies interrupted nerve impulse transmission and worsened disease symptoms by damaging nerve fibres.

    Dr Laura Bell, research communications officer at the MS Society, said: 'Nerve fibre loss is thought to be the primary cause of long term disability in MS though little is known about what causes that loss. This early research provides potential insight into the process and I look forward to seeing the results of the next stage of the study.'

    Source: Medical News Today © 2007 MediLexicon International Ltd

    Multiple sclerosis: T-cell receptor expression in distinct brain regions
    Multiple sclerosis (MS) is an inflammatory demyelinating disease where T cells attack the brain and the spinal cord. It is known that often particular T-cell clones are expanded in the target tissue, but it is still unknown, whether identical T-cell clones are present at distinct anatomical sites, or whether the T-cell spectrum is locally diverse. Therefore we compared the T-cell receptor (TCR) repertoire in distinct lesions and normal-appearing white matter (NAWM) from post-mortem brains of four MS patients. We analysed 19 lesions (inactive demyelinated, 15; slowly expanding chronic, 3; active lesions, 1) and 5 NAWM regions.

    The TCR ß-chain repertoire was investigated by CDR3 spectratyping. For each anatomical site 325 semi-nested PCR reactions were performed. About 800 Vß-NDN-Jß combinations were sequenced. Each of the four patients had distinct T-cell clones that were present in more than two anatomically distinct regions. These clones were not restricted to lesions, but were also present in NAWM. Some clones were present in all investigated lesions, and additionally, in NAWM sites. A single T-cell clone was detected in nine different sites in one patient. None of the clones was shared among different patients.

    Thus, pervasive T-cell clones exist in distinct regions of MS brain, and these clones are ‘private’ (unique) to individual patients. Analysis of the hypervariable NDN region revealed ‘silent’ nucleotide exchanges, i.e. nucleotide exchanges that code for identical amino acids. Such silent nucleotide exchanges suggest that the corresponding T-cell clones were recruited and stimulated by particular antigens. To attribute some of the pervasive clones to particular T-cell subsets, we isolated individual CD8+ T cells from cryosections by laser microdissection and characterized their TCR by single-cell PCR. These experiments revealed that at least some of the pervasive T-cell clones belonged to the CD8+ compartment, supporting the pathogenic relevance of this T-cell subset.

    Andreas Junker1,*, Jana Ivanidze1,2,*, Joachim Malotka2, Ingrid Eiglmeier1, Hans Lassmann3, Hartmut Wekerle2, Edgar Meinl1,2, Reinhard Hohlfeld1,2 and Klaus Dornmair1,2

    1Institute for Clinical Neuroimmunology, Ludwig Maximilians University, D-81377 Munich, 2Department of Neuroimmunology, Max-Planck-Institute for Neurobiology, D-82152 Martinsried, Germany and 3Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria

    Source: Brain Copyright © 2007 Guarantors of Brain (24/09/07)

    Autoimmune Response in Multiple Sclerosis
    In multiple sclerosis (MS), the myelin that surrounds the axons of nerve cells is attacked by the body’s own T cells, resulting in slowed and disrupted nerve impulses and, ultimately, axon loss.

    Myelin basic protein (MBP) is a major component of the myelin sheath and when used as an antigen will induce experimental autoimmune encephalitis (EAE) in mice, which is used as an animal model of human MS.

    Interestingly, myelin-specific T cells are found in both healthy individuals as well as patients with MS, thus researchers have been working to determine what specific characteristic of these destructive T cells is dominant in driving the development of EAE/MS.

    In a study appearing online on July 12 in advance of publication in the August print issue of the Journal of Clinical Investigation, Eli Sercarz and colleagues from the Torrey Pines Institute for Molecular Studies immunised mice with an epitope of MBP known as Ac1–9, which resulted in a single episode of EAE in these animals, followed by recovery and resistance to any reinduction of disease.

    The authors then went on to characterise the Ac1–9–specific T cells present during the induction, onset, and recovery from disease. They identified two distinct subsets of T cells, or clonotypes, soon after immunisation and prior to disease onset: BV8S2/BJ2S7 and BV16/BJ2S5.

    The BV8S2/BJ2S7 clonotype was found in far greater excess, disappeared with disease recovery, and was found to transfer disease to other healthy mice.

    The second clonotype, BV16/BJ2S5, persisted following recovery, consistent with the hypothesis that the other, BV8S2/BJ2S7 T cell clonotype, is the driver of disease and necessary for EAE/MS persistence. The identification of this T cell subset suggests that these cells may be critical targets valuable to the design of therapies for autoimmune diseases such as MS.

    Source: Medindia © All Rights Reserved 1997 - 2007 (14/07/07)

    AnaSpec Introduces New Anti-MOG (35-55) Antibody
    Leveraging its portfolio of MOG (35-55) and other multiple sclerosis (MS) experimental autoimmune encephalomyelitis (EAE)-related peptides, AnaSpec has introduced its new Rabbit Anti-MOG (35-55) antibody.

    Myelin oligodendrocyte glycoprotein (MOG), a member of the immunoglobulin superfamily, is expressed exclusively in central nervous system myelin. Recent studies suggest that MOG may function in the completion, compaction, and maintenance of myelin in the central nervous system. Even though MOG physiological function is not entirely understood, studies have correlated the immune response of MOG to autoimmune mediated demyelination in several species. MOG is able to induce encephalitogenic T cell response, autoantibody response, and produce relapsing-remitting neurological disease with an extensive plaque-like demyelination. The autoantibody response to MOG [anti-MOG protein and anti-MOG (35-55) peptide] has been seen in MS patients and EAE-induced mice. This phenomenon suggests that MOG may have an important role in the development of MS and EAE, an experimental in vivo animal model for MS.

    Rabbit anti-MOG (35-55) polyclonal antibody was raised against a synthetic peptide from the N-terminus corresponding to amino acids 35-55 of mouse and rat MOG. There is only one amino acid residue difference between the mouse/rat and human MOG (35-55) peptide. ELISA results show that Anti-MOG (35-55) cross-react with human. The antibodies were also evaluated by Western blot.

    Source: Medical News Today © 2007 MediLexicon International Ltd (27/06/07)

    Natural immune-control system may aid treatment of autoimmune disease and tissue rejection
    The immune system’s ability to police itself may offer a new method of arresting the cells responsible for autoimmune diseases such as multiple sclerosis and for the rejection of transplanted organs and tissues, scientists at Dana-Farber Cancer Institute report in a study in the May issue of the journal Immunity.

    Because the technique utilises the body’s own mechanism for controlling the immune system, it may prove more effective and less prone to side effects than current therapies, which take a less direct approach, the study authors indicate. Although the research was done in mouse cells, it is likely to apply to humans because of strong similarities between mouse and human immune cells.

    "We found that when we block a key interaction between two types of immune system cells, one of those types -- which is often associated with autoimmune disease and tissue rejection -- is attacked and dies," says senior author Harvey Cantor, MD, of Dana-Farber. "The fact that this approach uses the body's natural system for regulating the immune response encourages us that it can be the basis of an effective therapy for a variety of immunological conditions."

    Autoimmune disease and tissue rejection pose a complex challenge to scientists. Both problems result from an attack by immune system cells -- which are trained to detect and destroy infected or diseased tissue -- on parts of the body where it isn't wanted. In the case of rejection, they recognise transplanted tissue as foreign and mount an assault on it. In autoimmune diseases, they attack the body’s own tissue as through it were foreign.

    Conventional therapies for these conditions can have serious drawbacks. Many of them rely on natural substances called antibodies, which wedge inside “receptors” on immune system T cells. The coupling blindfolds T cells to the presence of foreign or diseased tissue, blunting their ability to spark an immune attack.

    Antibody-based treatments fall short for a variety of reasons: the antibodies often fail to fit securely inside T cells receptors, so the immune response is only slightly reduced; or the antibodies succeed in blocking the receptor, but that inadvertently causes the T cells to launch a more ferocious attack. In other cases, antibodies work too well, suppressing the entire immune system, rather than just a portion of it, leaving patients susceptible to dangerous infections.

    To overcome these problems, researchers have tried to harness the body's natural system for quieting the immune response. One intriguing approach involves the immune system's "natural killer," or NK, cells. Scientists have long known that some NK cells can kill a class of T cells -- known as CD4 T cells -- that have been activated to fight infection, but that NK cells are often restrained from doing so.

    Cantor and his colleagues theorised that when a tiny hook, or ligand, called Qa-1–Qdm on activated CD4 T cells latches onto the NKG2A receptor on NK cells, the T cells are protected from destruction. To test this, they produced activated T cells that either lacked the Qa-1–Qdm receptor or had a faulty version of it, preventing them from binding to the NKG2A receptor. The result was that the T cells became vulnerable to attack from a set of NK cells. Using an antibody to block the connection between Qa-1–Qdm and NKG2A had the same result.

    "Our findings suggest that it is possible to use antibodies to trigger the body's own mechanism for suppressing the immune response," Cantor remarks. "The results serve as a proof of principle that this approach can be applied to the treatment of conditions characterised by an excessive or unwanted immune response."

    While the work was done with mouse cells, the Qa-1–Qdm ligand has the same shape and structure in human and mouse T cells, raising hopes that the approach will prove effective in humans as well, adds Cantor, who is also a professor of pathology at Harvard Medical School.

    The research was supported by grants from the National Institutes of Health, the National Multiple Sclerosis Society, the Claudia Adams Barr Foundation, and a fellowship from Taiho Pharmaceuticals of Japan.

    The lead author of the study is Linrong Lu, PhD, of Dana-Farber. Co-authors include Koichi Ikizawa, PhD, Dan Hu, PhD, Miriam Werneck, and Kai Wucherpfennig, MD, PhD, all of Dana-Farber.

    Source: Dana-Farber Cancer Institute (17/05/07)

    Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology

    Intrathecal antibody production is a hallmark of multiple sclerosis and humoral immunity is thought to play an important role in the inflammatory response and development of demyelinated lesions. The presence of lymphoid follicle-like structures in the cerebral meninges of some multiple sclerosis patients indicates that B-cell maturation can be sustained locally within the CNS and contribute to the establishment of a compartmentalised humoral immune response. In this study we examined the distribution of ectopic B-cell follicles in multiple sclerosis cases with primary and secondary progressive clinical courses to determine their association with clinical and neuropathological features.

    A detailed immunohistochemical and morphometric analysis was performed on post-mortem brain tissue samples from 29 secondary progressive (SP) and 7 primary progressive (PP) multiple sclerosis cases. B-cell follicles were detected in the meninges entering the cerebral sulci of 41.4% of the SPMS cases, but not in PPMS cases. The SPMS cases with follicles significantly differed from those without with respect to a younger age at multiple sclerosis onset, irreversible disability and death and more pronounced demyelination, microglia activation and loss of neurites in the cerebral cortex.

    Cortical demyelination in these SPMS cases was also more severe than in PPMS cases. Notably, all meningeal B-cell follicles were found adjacent to large subpial cortical lesions, suggesting that soluble factors diffusing from these structures have a pathogenic role. These data support an immunopathogenetic mechanism whereby B-cell follicles developing in the multiple sclerosis meninges exacerbate the detrimental effects of humoral immunity with a subsequent major impact on the integrity of the cortical structures.

    Roberta Magliozzi 1,2, Owain Howell 2, Abhilash Vora 2, Barbara Serafini 1, Richard Nicholas 2, Maria Puopolo 1, Richard Reynolds 2,* and Francesca Aloisi 1,*

    1Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Rome, Italy and 2Department of Cellular and Molecular Neuroscience, Imperial College Faculty of Medicine, London, UK

    Source: Brain Copyright © 2007 Guarantors of Brain (08/05/07)

    Allergy/autoimmunity link found
    A link between allergic diseases like eczema, and autoimmune diseases has been found by scientists at the University of Washington in Seattle.

    "Our study implies that allergic and inflammatory diseases may actually trigger autoimmune diseases by relaxing the controls that normally eliminate newly produced, self-reactive B cells," said researcher David Rawlings. "Many autoimmune diseases are caused by self-reactive antibodies produced by such B cells."

    Rawlings, the head of immunology at UW and Seattle's Children's Hospital and Regional Medical Center, explained that autoimmune diseases are a group of more than 80 disorders that occur when the immune system -- designed to detect and destroy foreign invaders in the body -- begins destroying the body's tissues instead.

    Such diseases can affect the nervous system (multiple sclerosis), gastrointestinal system (Crohn's disease), and endocrine systems (Grave's disease), as well as the skin, connective tissue, eyes, blood, and blood vessels, he said. The principal attackers are B and/or T immune cells.

    Rawlings said his team is currently focused on where the "relaxation" in the control of B cell autoimmunity occurs, and are looking at drugs that can counter some of the adverse effects of that process.

    The research is published in the April 1 edition of Nature Immunology.

    Source: United Press International © Copyright 2007 United Press International, Inc. All Rights Reserved. (04/04/07)

    Attacking Autoimmunity: Penn Researchers Discover New Molecular Path to Fight Autoimmune Diseases
    One cause of an immune regulatory cell malfunction, which underlies many autoimmune diseases, is when a mutation in a gene called FOXP3 disables the immune cells’ ability to function.

    Researchers at the University of Pennsylvania School of Medicine found that when enzymes known as histone acetyl transferases are turned on, or when the histone deacetylases are turned off, the immune regulatory cells work better and longer.

    The research will be published online next week in the Proceedings of the National Academy of Sciences.

    Multiple sclerosis, diabetes, and arthritis are among a variety of autoimmune diseases that are aggravated when one type of white blood cell, called the immune regulatory cell, malfunctions. In humans, one cause of this malfunction is when a mutation in a gene called FOXP3 disables the immune cells’ ability to function. In a new study published online next week in the Proceedings of the National Academy of Sciences, researchers at the University of Pennsylvania School of Medicine have discovered how to modify enzymes that act on the FOXP3 protein, in turn making the regulatory immune cells work better. These findings have important implications for treating autoimmune-related diseases.

    “We have uncovered a mechanism by which drugs could be developed to stabilise immune regulatory cells in order to fight autoimmune diseases,” says senior author Mark Greene, MD, PhD, the John Eckman Professor of Pathology and Laboratory Medicine. “There’s been little understanding about how the FOXP3 protein actually works.” First author Bin Li, PhD, a research associate in the Greene lab has been working on elucidating this process since FOXP3’s discovery almost five years ago. Li discovered that the FOXP3 protein works via a complex set of enzymes. One set of those enzymes are called histone deacetylases, or HDACs. These enzymes are linked to the FOXP3 protein in association with another set of enzymes called histone acetyl transferases that modify the FOXP3 proteins. Li found that when the histone acetyl transferases are turned on, or when the histone deacetylases are turned off, the immune regulatory cells work better and longer. As a consequence of the action of the acetylating enzyme, the FOXP3 protein functions to turn off pathways that would lead to autoimmune diseases.

    “I think this simple approach will revolutionise the treatment of autoimmune diseases in humans because we have a new set of enzymatic drug targets as opposed to the non-specific therapies we now use,” says Greene. Non-specific therapies include the use of steroids and certain chemotherapy-like drugs that act on many cell types and have significant side effects. “Before this work FOXP3 was thought essential for regulatory T-cell function, but how FOXP3 worked was not known,” says Li. “Our research identifies a critical mechanism. Based on this mechanism, treatments could be developed to modulate this regulatory cell population.”

    “In this line of investigation, we have learned how to turn on or off this regulatory immune cell population – which is normally needed to prevent autoimmune diseases – using drugs that are approved for other purposes, but work on these enzymes” notes co-author Sandra Saouaf, PhD, a research associate at Penn. Li, Greene, Saouaf and Penn colleagues Wayne Hancock and Youhai Chen are now extending this research directly to several mouse models of autoimmune diseases.

    Additional co-authors are Arabinda Samanta, Xiaomin Song, Kathryn T. Iacono, Kathryn Bembas, Ran Tao, Samik Basu, and James Riley, all from Penn.

    Source: Penn Medicine © 2007, The Trustees of the University of Pennsylvania (07/03/07)

    IL-4 Expression By Mast Cells Modifies The Immune Response In Multiple Sclerosis
    IL-4 is expressed by many types of immune cells and it can act on a variety of other immune as well as non-immune cells to modulate the immune response. This broad range of effects necessitates strict control of IL-4 expression as inappropriate IL-4 expression is associated with allergic disease, autoimmunity, and an inability to clear some infections.

    In a study appearing online in April, in advance of print publication in the May issue of the Journal of Clinical Investigation, Melissa Brown and colleagues demonstrate that IL-4 expression by mast cells is regulated by proteins known as Ikaros and GATA, and this expression contributes to the development of a multiple sclerosis-like autoimmune disease in mice. Interestingly, the authors found that IL-4 expression by mast cells differed in different strains of mice. In sum, the study further points to the role of the mast cell in sophisticated gene regulation relevant to the immune response.

    TITLE: Mast cell IL-4 expression is regulated by Ikaros and influences encephalitogenc Th1 responses in EAE

    AUTHOR CONTACT: Melissa A. Brown Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

    View the PDF of this article at:

    Source: Allergy and Immunology (03/03/07)

    Edmond scientist discovers hidden antibodies in mice
    A discovery by an Oklahoma Medical Research scientist has discredited the 50-year-old accepted dogma that disease fighting cells in the body carry only one protein.

    Edmond’s Patrick Wilson has discovered that B cells can make a mistake when the cells bind to human tissue and change receptors. Cells changing receptors sometimes may result in a second allele (chromosome) producing a second antibody protein, he found. Wilson revealed that 10 percent of mouse models use both alleles.

    Wilson’s research paper appears in a recent issue of The Journal of Experimental Medicine. An editorial in that publication by Rockefeller University researcher Ruth Williams described Wilson’s discovery as tantamount to exposing “a wolf in sheep’s clothing.”

    Wilson’s wife, Nai-Ying Zheng, manages the lab at OMRF and was part of Wilson’s research team. Dr. Rafael Casellas of the National Institutes of Health in Bethesda, Md., was Wilson’s major collaborator in the project. Other participants were Qingzhao Zhang, Melissa D. Mathias and Kenneth Smith.

    “It changes the paradigm of immunology. It changes our idea of it,” said Wilson, who earned his doctorate from the University of Texas Southwestern Medical Center in Dallas and did his postdoctoral studies at the Rockefeller University in New York City.

    “It’s not true one B cell is always expressing a single receptor. Many B cells can express two. These potentially are the ones that cause autoimmune disease later.”

    B cells are white blood cells that defend the human body by creating antibody proteins to protect people with immune protection from disease and infection. Antibodies bind to bacteria, viruses and pathogens, thus blocking their ability to attach to tissue.

    “The other thing it does — it tells our body (B cells) are there and other cells will then destroy the pathogens,” Wilson explained.

    For the system to work properly, every healthy B cell produces only one antibody protein so it can be deleted if it binds to human tissue.

    Despite these mechanisms, 28 million people a year are diagnosed with an autoimmune disease, Wilson said. Autoimmune diseases include a variety of diseases such as lupus, rheumatoid arthritis, multiple sclerosis and Graves disease — among others.

    His research shines new light on how cells survive in spite of being autoreactive.

    “One thing that’s important to figure out is how are these B cells are escaping these mechanisms. How are they avoiding either changing their receptor or just being auto reactive and still surviving — not being removed from the repertoire so they can be dangerous,” Wilson said.

    The next step of his investigation will try proving if these are indeed the cells causing autoimmune disease in the mice models. A third step will involve looking for the same disease processes in humans.

    It remains too early to envision creating specific pharmacological drugs based on the research to fight autoimmune diseases, he said. But his basic scientific research may be the first step in finding new, successful treatments.

    Source: The Edmond Sun - Associated Press content © 2007. All rights reserved.(29/01/07)

    Immune system 'brakes' found
    Scientists say they have learnt how the body controls the machinery it uses to fight infections and foreign invaders.

    The advance, published in the journal Nature, may one day help find ways to tackle unwanted immune reactions following transplant surgery.

    The Johns Hopkins University researchers say a protein molecule called carabin may be the body's way of restraining its defences.

    The US-based team describes it as a 'built-in timer' for the immune system.

    Immunity is vital to human survival - the body is constantly confronted with things that should not be there, including bacteria and viruses.

    The system is constantly adapting when faced with new threats from unknown organisms.

    However, an over-powerful or runaway immune response can be a disadvantage too, as some illnesses involve the immune system attacking parts of our own bodies after failing to recognise them.

    Damping down

    The Johns Hopkins team, led by Professor Jun Liu, has been hunting for body chemicals that might shed light on how the immune system is controlled.

    They found that a protein called carabin appeared to be important, latching onto microscopic cells active during an infection.

    It is made by white blood cells, one of the most important immune system cells.

    However, its role actually appears to restrict their ability to mount a response to infection.

    They found that when there was more carabin in a cell, it appeared to 'damp down' its activity.

    Professor Liu said: "It acts like an internal brake to dial down the speed and intensity of an immune response so that it doesn't go too fast or too far, or career out of control and attack healthy cells.

    "It's like having a built-in timer to keep the immune system in check."

    Carabin appears to work in a similar manner to drugs such as cyclosporin, which are used to control rejection of transplanted organs.

    Professor Liu suggested that one eventual use might be a new drug to do this, and perhaps also help control 'auto-immune' illnesses such as multiple sclerosis.

    Drug alternative

    Dr Peter Peachell, a pharmacologist from Sheffield University said that the paper offered "interesting possibilities".

    But he cautioned that the practical difficulties of developing and manufacturing a drug incorporating a large molecule such as carabin could be substantial.

    He said: "Carabin appears to act on the same target as immune suppressing drugs such as cyclosporin, so offers a potential alternative.

    "What this research does is tell us more about how the immune system is regulated, so it brings the possibility of more effective treatments for a variety of autoimmune diseases, although this is certainly some way off."

    He said that in some circumstances, there might be benefits to switching carabin off, not increasing it - such as in the early stages of infection by viruses such as HIV, when a robust and sustained immune response might be useful.

    Source: BBC News Copywrite BBC MMVII (28/01/07)

    Antibodies to Myelin Don't Signal MS

    Contrary to a previous report, the presence in the blood of two types of antibodies to myelin is not diagnostic of multiple sclerosis, investigators here reported.

    Nor does the presence of the antibodies indicate a risk of progression to clinically definite MS, found Jens Kuhle, M.D., of University Hospital here, along with European and Canadian investigators.

    Although other investigators have found that the patients with serum antibodies against myelin oligodendrocyte glycoprotein and myelin basic protein were at increased risk for MS, Dr. Kuhle and colleagues could find no such link, they reported in the Jan. 25 issue of the New England Journal of Medicine.

    In a study of 462 patients with a first clinical event suggestive of MS and at least two silent brain lesions on MRI, there was no association between serum levels of either of two antimyelin antibody types and risk of progression to clinically definite MS.

    "Our results strongly suggest that antimyelin antibodies have no role in the diagnosis of multiple sclerosis or in the identification of patients at high risk for the development of clinically definite disease," the investigators wrote. "Alternatively, there may be a role for such antibodies, but we may need more sophisticated methods to detect them."

    The investigators used serum samples from the 462 patients enrolled in the BENEFIT study, a randomised double-blind, placebo-controlled, phase III trial evaluating Betaseron (interferon beta-1b) at a dose of 250 μg subcutaneously every other day in patients with a first clinical episode suggestive of MS, and at least two clinically silent lesions detected on MRI scans of the brain.

    They measured serum anti-myelin oligodendrocyte glycoprotein and anti-myelin basic protein at baseline by Western blot analysis, and compared the results with the time and rate of progression to clinically definite multiple sclerosis, or to a diagnosis of multiple sclerosis as defined by an international panel (the McDonald criteria).

    The patients had regular visits for the assessment of neurologic impairment and for MRI before treatment and at months three, six, nine, 12, 18, and 24.

    They used chi square analysis and the Kruskal-Wallis test to compare the baseline characteristics of the patients in the placebo and treatment groups according to antibody status.

    They used Kaplan-Meier analysis to calculate cumulative risk of progression to clinically definite multiple sclerosis, or multiple sclerosis as defined by the McDonald criteria), and created Cox proportional-hazards models adjusted for potential confounding variables to assess whether antibody status predicted the development of MS.

    They controlled for age, sex, use of corticosteroid treatment for the first event, the effect of treatment with Betaseron, multifocal or monofocal disease presentation, and the number of gadolinium-enhancing lesions on T1-weighted MRI scans and the number of hyperintense lesions on T2-weighted scans.

    During the two-year study, 150 patients (32%) were diagnosed with clinically definite multiple sclerosis, and 331 (72%) were diagnosed with MS according to the McDonald criteria.

    The authors found that "there was no increase in the risk of clinically definite multiple sclerosis or of multiple sclerosis according to the McDonald criteria among patients who were positive for anti-myelin oligodendrocyte glycoprotein antibodies, anti-myelin basic protein antibodies, or both," the authors wrote.

    "This was true for both IgM and IgG antibodies not only in the total study population but also in all subgroups analysed: patients receiving placebo or interferon beta-1b, patients with positive cerebrospinal fluid findings, patients who had received corticosteroid treatment, and patients with shorter or longer intervals between the initial clinical event and blood collection."

    "Finally, we were unable to confirm the previously reported association between the number of lesions seen on gadolinium-enhanced MRI brain scans and the anti-myelin oligodendrocyte glycoprotein or anti-myelin basic protein antibody status," they added.

    They noted that time of blood sample collection--for example, within a few days of the first manifestation of clinical disease and before corticosteroids--could have had an influence on the results.

    They also acknowledged that the follow-up in the study, which was limited to two years, may have been too short to detect a positive correlation between the antibodies and MS.

    "However, in view of the number of patients in whom clinically definite multiple sclerosis or multiple sclerosis according to the McDonald criteria was diagnosed during the two-year follow-up period, a major change in the results with longer follow-up would be highly improbable, " they wrote.

    The study was supported in part by Schering AG, which sponsored the BENEFIT study, and by a grant from the Swiss Multiple Sclerosis Society.

    Neil Osterweil, Senior Associate Editor, MedPage Today
    Reviewed by Rubeen K. Israni, M.D., Fellow, Renal-Electrolyte and Hypertension Division, University of Pennsylvania School of Medicine.

    Source: MedPage Today © 2004-7 MedPage Today, LLC. All Rights Reserved. (25/01/07)

    Chopping off protein puts immune cells into high gear
    St. Jude study shows LAG-3 protein on activated T lymphocytes slows replication until ADAM10 and ADAM17 enzymes cleave it off to allow these cells to reproduce rapidly.

    The complex task of launching a well-organised, effective immune system attack on specific targets is thrown into high gear when either of two specific enzymes chop a protein called LAG-3 off the immune cells leading that battle, according to investigators at St. Jude Children's Research Hospital.

    These cells, called T lymphocytes, are key to the body’s ability to fight off infections, tailoring the immune response so it focuses on specific targets. When activated, certain T lymphocytes called effector T cells reproduce, increasing their numbers and enhancing their ability to protect the body.

    The St. Jude finding is important because it represents a new concept in how T cells are regulated, according to Dario Vignali, Ph.D., associate member of the St. Jude Department of Immunology. The study offers the first example of a protein that is required for dampening T cell activity being controlled by getting chopped off at the T cell’s surface. Certain drugs that inhibit metalloproteases now under development as treatments for multiple sclerosis and arthritis appear to work by keeping T cells on a tight leash, Vignali noted. The new discovery could demonstrate an additional way in which these drugs work. Vignali is senior author of a report on this work that appears in the January 24 issue of The EMBO Journal.

    The investigators performed their studies using animal cells that were genetically modified to carry LAG-3 on their surface; the researchers also used drugs that inhibit enzymes that chop off LAG-3. The team demonstrated that the two enzymes that cleave LAG-3 are controlled by of distinct but overlapping signals generated from the T cell receptor, a specialised protein that allows T lymphocytes to “see” the outside world. The investigators showed that the T cell receptor generates a different, specific signal to control the activity of these metalloprotease enzymes, called ADAM10 and ADAM17.

    Specifically, the team demonstrated that ADAM10 normally cleaves LAG-3 even before the T cells are activated. After the T cell receptor receives signals from the immune system, it causes the gene for ADAM10 to make much more of this enzyme, substantially increasing the rate of LAG-3 cleavage. However, ADAM17 is inactive until the T cell receptor triggers a molecule called protein kinase C theta to activate this enzyme. In either case, when metalloproteases remove LAG-3, the brakes are taken off T cell activity.

    “Appropriate control of T cell expansion during an immune response is critical,” Vignali said. “We have uncovered a new paradigm in which specialised cell surface enzymes control this process by modulating the expression of a molecule, LAG-3, that acts as an immunological molecular brake. In turn, this process is controlled by the strength of the T cell receptor signal—the immunological ‘accelerator.’ So the more the T cell ‘accelerates,’ the more the ‘brake’ is released.”

    The St. Jude team previously reported that regulatory T cells, which prevent effector T cells from running out of control and causing damage to the body, use LAG-3 to rein in these activated effector T cells.

    The current study in EMBO extends that finding by showing that cleavage of LAG-3 proteins on the surface of T cells allows them to greatly increase their proliferation rate during such a battle. The team also showed that cleaved pieces of LAG-3 do not contribute to T cell control, but are rather “waste” products that are swept away later.

    The other authors of the paper include Nianyu Li (formerly at St. Jude; now at Amgen Inc., Thousand Oaks, Calif.), Yao Wang, Karen Forbes, Kate Vignali and Creg J. Workman (St. Jude); Bret S. Heale and John J. Rossi (Beckman Research Institute of the City of Hope, Duarte, Calif.); Paul Saftig (Christian-Albrechts University, Kiel, Germany); Dieter Hartmann (Leuven and Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium); Roy Black (Amgen Inc.; Seattle); Carl P. Blobel (Weill Medical College of Cornell University, New York); and Peter J. Dempsey (University of Washington, Seattle).

    This work was supported in part by the National Institutes of Health, a Cancer Center Support CORE grant, ALSAC and the German Research Foundation.

    St. Jude Children's Research Hospital is internationally recognised for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organisation.

    Source: St. Jude Children's Research Hospital (25/01/07)

    Lack of Association between Antimyelin Antibodies and Progression to Multiple Sclerosis


    Background: Patients with a single episode of neurologic dysfunction and brain magnetic resonance imaging (MRI) scans suggestive of multiple sclerosis are at high risk for clinically definite multiple sclerosis, but the outcome for individual patients is unpredictable. An increased risk of progression to clinically definite multiple sclerosis in patients with serum antibodies against myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP) has been reported.

    Methods: We measured serum anti-MOG and anti-MBP IgG and IgM antibodies in 462 patients with a first clinical event suggestive of multiple sclerosis and at least two clinically silent lesions on brain MRI. The patients were participating in a multicenter trial of treatment with interferon beta-1b. Antibodies were assessed by Western blot analysis at baseline, and the results compared with the time and rate of progression to clinically definite multiple sclerosis or a diagnosis of multiple sclerosis as defined by an international panel (the McDonald criteria). Regular visits were scheduled for the assessment of neurologic impairment and for MRI before treatment and at months 3, 6, 9, 12, 18, and 24.

    Results:No associations were found between the presence of anti-MOG and anti-MBP IgM and IgG antibodies and progression to clinically definite multiple sclerosis or a diagnosis of multiple sclerosis according to the McDonald criteria, either in the entire cohort or in any subgroups of the study population.

    Conclusions: Serum antibodies against MOG and MBP, as detected by Western blot analysis, are not associated with an increased risk of progression to clinically definite multiple sclerosis in patients who have had a clinically isolated syndrome suggestive of multiple sclerosis.

    Jens Kuhle, M.D., Christoph Pohl, M.D., Matthias Mehling, M.D., Gilles Edan, M.D., Mark S. Freedman, M.D., Hans-Peter Hartung, M.D., Chris H. Polman, M.D., Ph.D., David H. Miller, M.D., Xavier Montalban, M.D., Frederik Barkhof, M.D., Ph.D., Lars Bauer, M.D., Susanne Dahms, Ph.D., Raija Lindberg, Ph.D., Ludwig Kappos, M.D., and Rupert Sandbrink, M.D., Ph.D.

    Source : The New England Journal of Medicine © 2007 Massachusetts Medical Society. (25/01/07)

    T For Two: Scientists Show How Immune System Chooses Best Way To Fight Infection
    A new study has suggested a novel way of combating diseases related to the immune system, including cancer and autoimmune diseases such as type I diabetes and arthritis. The study, funded by the Wellcome Trust, appears online in the journal Nature.

    T cells are produced by the body to fight infection. Scientists previously identified two types of T cell, both produced in the thymus: "effector T cells", which attack infected cells, and "regulatory T cells", which suppress the immune system, protecting the body from inflammatory damage during infection. Regulatory T cells, if given to individuals receiving transplants, may help suppress the rejection response.

    Now, a team of researchers has discovered a novel mechanism determining whether a maturing T cell is likely to emerge from the thymus as an effector cell or a regulatory cell. The research suggests that new treatments could be developed to deliberately affect the type of T cells produced, allowing scientists to tackle a number of diseases which are influenced by these different types of T cells.

    "Our team has shown that a process known as 'trans-conditioning', which we knew to be involved in T cell development, actually has a profound influence on whether a T cell becomes an effector or a regulatory cell," explains Professor Adrian Hayday of King's College London. "This may be clinically significant; if we can find a way to influence this process, it may be possible to make the body produce effector T cells in a cancer patient or regulatory T cells in someone suffering from autoimmune disease, both of which are caused by the immune system malfunctioning."

    Professor Hayday and his team believe that the findings may also answer one of medical research's mysteries: why autoimmune diseases in women commonly go into remission in pregnancy.

    "We believe that trans-conditioning is less active during pregnancy," says Professor Hayday. "This means that most T cells emerging at that time will be regulatory. Regulatory T cells prevent an over-active immune system from causing inflammatory damage to the body. This may be one of the key steps in preventing the mother from rejecting the foetus growing inside her."

    The research was carried out at the King's College London School of Medicine at Guy's Hospital and was co-lead by Dr Daniel Pennington, a Wellcome Trust VIP awardee and now at Queen Mary, University of London. Collaborating researchers were based at Faculdade de Medicina de Lisboa, Lisbon; University College, London; Yale University School of Medicine; Institute for Animal Health; and Imperial College London.

    Source: ScienceDaily Copyright © 1995-2006 ScienceDaily LLC (27/12/06)

    Molecule linked to autoimmune disease relapses identified
    The ebb and flow of such autoimmune diseases as multiple sclerosis, lupus and rheumatoid arthritis has long been a perplexing mystery. But new findings from the Stanford University School of Medicine bring scientists closer to solving the puzzle, identifying a molecule that appears to play a central role in relapses.

    The study, to be published in the Dec. 3 advance online edition of Nature Immunology, lays the groundwork for a way to determine when a relapse is about to occur, and could eventually lead to a treatment to prevent relapses. “Right now, there is no good blood test to evaluate when a person is going to have a flare-up,” said senior author Larry Steinman, MD, professor of neurology and neurological sciences. “If we had one, we might be able to give them prophylactic preventive medication.”

    The current study had its genesis five years ago: In a paper published in 2001 in the journal Science, Steinman found that a protein called osteopontin was abundant in multiple sclerosis-affected brain tissue, but not in normal tissue. Since then, other groups have confirmed that osteopontin is elevated just prior to and during a relapse of the disease in MS patients.

    Although the protein had been known to play a role in bone growth, it was unclear why it would be associated with multiple sclerosis, which results when the immune system attacks the protective myelin sheath surrounding nerve cells.

    To explore this question, Eun Mi Hur, PhD, who was then a graduate student in Steinman’s lab, began using a mouse model of multiple sclerosis (experimental autoimmune encephalomyletis, or EAE) to investigate how osteopontin could cause these flare-ups. She and Steinman gave osteopontin to mice that had already experienced paralysis, similar to that of an M.S. patient, and found that the mice then experienced a relapse of the disease.

    The researchers also found that the relapse would occur sometimes in an area of the brain other than the site of the original attack. For example, after receiving the osteopontin, some animals that had previously suffered paralysis became blind from a condition called optic neuritis. One feature of multiple sclerosis is that the flare-ups can affect different parts of the nervous system at different times.

    “When I saw that all mice with EAE relapsed and died from the disease after about a month of osteopontin administration, I was surprised,” said Hur, the study’s first author who is now a postdoctoral scholar at Caltech. “I got a strong belief that a high level of osteopontin in patients’ blood and tissue is a major contributor of the relapse and progression of the disease.”

    Through the mouse studies and molecular characterisations, Hur and Steinman showed that osteopontin - produced by immune cells and brain cells themselves - promotes the survival of the T cells that carry out the damaging attack on myelin; by increasing the number of these T cells, osteopontin increases their destructive potential. These results could be applicable to many other autoimmune diseases, including rheumatoid arthritis, type-1 diabetes and lupus.

    Indeed, the effect of osteopontin may severely alter the way the immune system works. Normally, after the immune system does its job - eradicating a microbe, for instance - the response is then dialed down. If this didn’t happen, the immune response would go on indefinitely. Imagine a cold or an attack of poison oak that would last forever.

    One of the ways that the immune response is muffled is that the activated T cells die in a process known as apoptosis. That is precisely what osteopontin seems to prevent. Osteopontin lets the T cells linger in the blood, ready to attack again. “We don’t know exactly what triggers that new attack but the cells certainly are around and ready to do it,” said Steinman. So scientists now face the challenge of figuring out how and why osteopontin is produced. “We’re back to the chicken-and-the-egg problem,” said Steinman. “We know the egg, so why did the chicken lay it” That is a trickier problem to work out.”

    Even without knowing the answer to that question, there is one inviting practical use of their observations: Osteopontin could be used as a marker of an impending relapse. What’s more, if the protein could be blocked, it might thwart the relapse from ever occurring. Steinman’s lab is working to develop antibodies to inactivate the protein’s effect. “It’s still a long road between saying we want to do it and getting the antibodies, getting it approved by the FDA and getting it tested,” said Steinman, “but we are determined to do that.”

    Still, Steinman offered a caveat. Researchers may find that blocking osteopontin has undesirable side effects. The protein may serve other purposes in addition to promoting survival of immune cells. It could also be vital to the body’s ability to produce myelin, a function that could cause severe problems if disrupted. “Like a lot of important biological molecules, osteopontin has a Janus-like quality - a bad side and a good side,” Steinman said. “We’re going to be extremely lucky if we give the antibody opposing osteopontin and derive just the good side: We stop the autoimmune attack but don’t interfere with the survival of other cells.”

    Further study will determine whether thwarting osteopontin’s effect yields new types of treatments for autoimmune diseases, but regardless, it is likely to lead to discoveries in a host of areas. “I think osteopontin will turn out to be important in a lot of processes, spanning autoimmunity to stem cells,” said Steinman. “It’s probably going to turn out to be a very basic growth factor.”

    Source: Stanford University Medical Center (04/12/06)

    Why MS attacks the 'wiring' of the body

    A German team has found a new clue to the cause of MS, one that could lead to new treatments, says Roger Highfield

    Molecules in the body that are thought to attack the “insulation” in nerves to cause multiple sclerosis have been identified by scientists, providing a new way to diagnose and treat some people who have the devastating degenerative disorder.

    Multiple Sclerosis is the most common disabling neurological disease among young adults and affects around 100,000 people in the UK. Inflammation leads to unsheathing of the myelin coating of nerve cells, so they degenerate, causing weakness, fatigue and dependency.

    Antibodies, mistakenly generated by the body against its own proteins, have been thought to contribute to the inflammation and brain damage in MS but the exact nature of what the antibodies attack on the myelin has been mysterious. In the Proceedings of the National Academy of Sciences, Prof Bernhard Hemmer of the Heinrich Heine-University, Düsseldorf, Germany and colleagues suggest that in some patients the disease can be caused when antibodies attack MOG, a protein embedded in the myelin sheath.

    Using a novel approach which allowed them to measure antibodies which bind to the MOG protein in the brain they found evidence of circulating antibodies directed against MOG in patients with MS. When these antibodies were exposed in the test tube to cells that made the MOG protein on their surface, the cells died. And rats exposed to the anti-MOG antibodies suffered nerve damage, again implicating them in the disease.

    The researchers conclude that, at least in a subgroup of MS patients, antibodies directed against MOG strip nerve cells of their insulation. At present there is no drug that specifically blocks the anti-myelin MOG antibodies but there are therapies that act on antibodies or B cells, which produce the antibodies, said Prof Hemmer.

    The new finding means that measuring anti-myelin antibodies might allow doctors to work out which patients may profit from such treatments. And, in the longer term, drugs could be designed to interfere with the MOG antibodies, turning off the attack on the nervous system. “Development of such specific therapies is in an early stage,” said Prof Hemmer.

    Source: © Copyright of Telegraph Media Group Limited 2006. (29/11/06)

    Mulltiple Regulatory Cell Types Can't Keep Self-destructive Immune Cells Under Control

    TITLE: Alterations in CD46-mediated Tr1 regulatory T cells in patients with multiple sclerosis

    Multiple sclerosis (MS) is an autoimmune disease that occurs when cells of the immune system attack nerves in the brain. Although it is not clear exactly why this self destruction is able to occur, it has been shown that other immune cells that normally keep the destructive ones in check (known as regulatory T cells) are impaired in individuals with MS. Previous studies have focused on a regulatory T cell subset known as the CD4+CD25high regulatory T cell subset, but in a study which appeared online on November 9, in advance of publication in the December print issue of the Journal of Clinical Investigation, researchers from Harvard University, now show that IL-10 producing regulatory T cells (Tr1 cells) are also impaired in individuals with MS.

    David Hafler and colleagues showed that T cells from patients with MS produced substantially less IL-10 when stimulated ex vivo with antibodies specific for CD3 and CD46 than T cells from healthy individuals. This inability to induce a Tr1 cell phenotype was associated with altered expression of CD46 cytoplasmic isoforms upon activation. This study shows that a second regulatory T cell population (the Tr1 cells) is impaired in individuals with MS and the authors speculate that, as for the CD4+CD25high regulatory T cell subset, this defect is likely to be observed in patients with other autoimmune diseases, such as rheumatoid arthritis.

    David A. Hafler
    Brigham and Women's Hospital and Harvard Medical School, Boston,
    Massachusetts, USA.

    Anne L. Astier
    Brigham and Women's Hospital and Harvard Medical School, Boston,
    Massachusetts, USA.

     JCI table of contents: November 9, 2006

    Source: Medical News Today © 2006 MediLexicon International Ltd(15/11/06)

    Antibody Test May Help Point to MS Early On: Docs
    by John C. Martin

    A newly developed test may be the key to predicting MS even before symptoms are apparent, say doctors in a new research paper.1

    Predicting MS Early On
    The test effectively detects antibodies to a myelin protein in the body, say investigators at the University of California at San Francisco, who published results of a study involving both people and animals in the early edition of the journal Proceedings of the National Academy of Sciences.

    The research team developed the test that specifically targets antibodies to myelin oligodendrocyte glycoprotein, or MOG, which is active in myelin. Myelin is a fatty-like substance that covers and protects nerve fibers in the central nervous system. When MS strikes, it is myelin that is damaged by certain cells of the immune system. When this happens, the nerve fibers are unable to effectively transmit nerve impulses between one another, which manifests itself as the disease’s symptoms.2

    MOG antibodies have been difficult to characterize in people, explained Patrice Lalive of UCSF. That’s because current tests don’t take into account the form that the protein takes when it is active in the myelin cell membrane.

    Antibodies Detected
    The test accurately identified antibodies to MOG in patients with relapsing MS, but only in small amounts in those with secondary-progressive multiple sclerosis. Blood samples from patients with primary progressive MS did not contain antibodies to MOG.

    In marmosets with inflammatory demyelination, a condition similar to MS, the researchers found that the test identified the disease long before full blown symptoms appeared. The findings show that the antibodies detected by the test represent the earliest stages of the immune response against myelin, and could be a useful marker to predict the development of the disease when symptoms aren’t present.

    Thus, this test could be used to either “diagnose MS or MS risk,” Lalive and her colleagues wrote.

    1. Lalive PH, Menge T, Delarasse C et al. Antibodies to native myelin oligodendrocyte glycoprotein are serologic markers of early inflammation in multiple sclerosis. Proc Natl Acad Sci USA 2006 Feb 3;[Epub ahead of print]. 2. National Multiple Sclerosis Society.

    John Martin is a long-time health journalist and an editor for CuraScript. His credits include overseeing health news coverage for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.

    Copyright © 2005 CuraScript, Inc. All Rights Reserved (12/02/06)

    Key Antibody Found in Severe MS

    American researchers have identified a key antibody called anti-MOG in cases of severe MS.

    They don't know yet whether this antibody is a cause or a by-product of nerve damage. But the finding should open new areas for investigation and potential therapy.

    Blood tests to measure anti-MOG antibodies could help diagnose the more severe forms of MS, says researcher Claude Genain, MD, from the University of California, San Francisco.

    "This appears to be the first simple, reliable, and inexpensive blood test that correlates so strongly with MS," says Genain. "It would significantly enhance our understanding of what causes the different forms of MS and how they should be treated."

    Genain and colleagues have been searching for molecules, like antibodies, that help identify the targets of the immune system.

    MOG is an antibody to a component of myelin. It's already known to play a role in destroying myelin in mice with MS, reports Genain, but how it works in people is less clear.

    Ref: American Neurological Association annual meeting, New York (10/01/06)

     Llamas produce simpler antibodies than humans Llamas could point the way to new ways of tackling human diseases, according to a Canadian-Belgian team.

    The animals produce antibodies which the company and researchers behind the work say could be used to treat conditions such as Alzheimer's disease.

     They say these "nanobodies" are smaller and more stable than human antibodies and may provide cheaper and more effective treatments.

     However, UK experts warned that the research was at a very early stage.

    A number of research teams around the world are investigating the potential benefits of antibody therapy.

    Tissue penetration

    This research is being carried out by the National Research Council of Canada and the Belgian company Ablynx.

     Antibodies are complex protein molecules which attack foreign substances (antigens) in the body.

    The researchers say animals in the camelid family, such as llamas, produce a much simpler type of antibody than humans.

    Because the animals' antibodies are much more simply constructed, they say, it is easier to take a small fragment which can then be used as a therapeutic treatment.

    The researchers say that the nanobodies' size - over 10 times smaller than a full-size human antibody - means they are better able to penetrate tissues.

    In addition, they say they are more stable than human complex antibodies because they have developed in animals which are exposed to extremely harsh conditions.

    Llamas are given antigens to trigger antibody production.

    The researchers can then identify which nanobodies bind to certain antigens.

    These nanobodies are then cultivated in larger numbers in bacteria in the laboratory.


    The Canadian team have used imaging techniques in the laboratory to show that a specific nanobody can cross the barrier between the blood system and the brain.

    This exists to prevent toxic substances getting into the brain, but can mean it is difficult to deliver medication.

    Dr Danica Stanimirovic, who led the research, said the next step would be to find a way to "piggyback" drugs into the brain.

    Ablynx is investigating other nanobodies which could be used in the treatment of neurological disease.

    The have carried out laboratory experiments which showed one nanobody binds to the protein which causes deposits, or plaques, to form in the brains of Alzheimer's patients.

    Simon Kerry, director of business development for the company, said animal experiments to begin to assess the potential therapeutic benefits were the next step.

    "We hope we will show that it is possible to disrupt plaque development, or formation."

    Clive Ballard, of the UK's Alzheimer's Society, said: "There has been a lot of interest in antibody approaches, and this new development might be something that will provide further opportunities to look at novel antibody therapies."

    But he added: "The researchers don't look at the potential immune response. That would be the concern."

    Source: BBC News (30/05/05)

    © Multiple Sclerosis Resource Centre

    Related Items
    Abnormal Liver Tests and MS
    Aluminium and Multiple Sclerosis
    Antagonist compounds
    Apolipoprotein D
    Bacteria & MS
    Biomarkers and MicroRNA
    Blood tests
    Bone Marrow Cells and MS Treatment
    Bowmann-Birk Inhibitor Concentrate (BBIC)
    Brain Atrophy, Lesion Loads, White and Grey Matter
    Brain Inflammation
    Brain Iron Deposits
    Calcium Binding Proteins
    Cerebro-Spinal Fluid & Spinal Cord
    Chronic Cerebrospinal Venous Insufficiency (CCSVI)
    CXCL1, 7, 12
    Cytokines & Chemokines
    Dendritic Cells
    Estrogen Receptors
    Fibrinogen, Mac-1 and Microglia
    Histamine and MS
    Hormones And MS Research
    Infections and Multiple Sclerosis Relapses
    JAK-STAT inhibitors
    Kallikrein 6
    Lipids & MS
    Medical Imaging
    Mycoplasmas And Bacteria
    N-acetylglucosamine (GlcNAc) & Glucosamine
    Natural Interferon Beta
    Natural Killer Cells
    Nerve and Brain Cell Research
    Olig 1 Gene Discovery
    Oligodendrocytes and Astrocytes
    Pesticides and Multiple Sclerosis
    Plasma Exchange
    Potential Viral Causes of MS
    Recombinant Human Erythropoietin
    Regeneration Research
    RNA and RNAi
    Synthetic Small Molecules
    Tetanus Vaccine and Possible MS Protection
    The Blood Brain Barrier
    Tremors And MS
    Uric Acid
    Urinary Problems
    Vascular Function And MS
    Vision and MS

    Did you find this information useful? Would you like to comment on this page? Let us know what you think! We welcome all comments and feedback on any aspect of our website - please click here to contact us.