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    You are here : Home » MS Research News » Potential Viral Causes Of MS

    Potential Viral Causes Of MS

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    More news can be found in New Pathways Magazine, our bi-monthly publication, and also check daily at MSRC: Latest MS News.

    MS less common with cytomegalovirus exposure

    CMVAlthough theories that multiple sclerosis arises from viral infections are alive and well, exposure to one virus -- cytomegalovirus (CMV) -- is associated with reduced risk for the disease, a researcher said here.

    In a study of 669 MS patients and 786 controls who did not have MS, individuals testing positive for anti-CMV antibodies were about 30% less likely to have MS, reported Ingrid Kockum, PhD, of the Karolinska Institute in Stockholm.

    The finding stayed significant and robust after adjustment for gender, body mass index, ethnic origin, and age at sampling and at disease onset, she told attendees at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

    A number of earlier studies have implicated Epstein-Barr virus (EBV) as a possible cause of MS, largely on the basis of epidemiological associations, but also in research that found, for example, EBV genetic elements lurking in MS patients' brain lesions.

    So-called endogenous retroviral elements in the human genome have also been linked to MS, according to Renaud Du Pasquier, MD, of Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, who preceded Kockum at the ECTRIMS podium.

    That link appears strong enough to prompt clinical trials with a monoclonal antibody targeting these elements, he noted.

    CMV, as another common viral infection, has also been looked at previously for possible associations with MS, but there's been no consensus on its role. Kockum pointed to one study that found a dramatically lower risk of paediatric MS in children with prior CMV exposure, while another found a modest increase in risk of adult MS in CMV-seropositive individuals.

    She and her colleagues analyzed data from two cohorts of patients and controls participating in a Swedish epidemiological study of MS called EIMS.

    This study, begun in 2005, has recruited a total of about 2,000 patients and 3,000 controls, all of whom completed questionnaires and provided a blood or saliva sample for genetic analysis.

    The data confirmed the positive association of EBV exposure with MS risk. More than two-thirds of the 669 patients in the EIMS cohorts had anti-EBV antibody titres higher than the median among controls.

    But the presence of anti-CMV antibodies was significantly lower in patients than controls, Kockum reported.

    After adjusting for gender imbalances, the odds ratio for MS among CMV-seropositive individuals in the first EIMS cohort was 0.69 (95% CI 0.52 to 0.90, P=0.007), and in the second cohort it was 0.65 (95% CI 0.52 to 0.82, P=0.0002).

    CMV seropositivity was not evenly distributed among patients or controls. It was more common among women, individuals of lower socioeconomic status, those with higher body mass index values, and older participants.

    But the association between CMV exposure and MS remained significant irrespective of gender, BMI, socioeconomic status, and age.

    In a multivariate analysis that adjusted for these factors, the odds ratio for MS in CMV-seropositive participants in both cohorts combined was 0.73 (95% CI 0.57 to 0.91).

    The association was also unaffected by participants' genotype, smoking status, or anti-EBV antibody titers, Kockum said.

    But she cautioned that the study results did not prove that CMV infection is somehow protective against MS. How such an effect might work is unknown, she said, although the infection is known to leave a lasting imprint on immune cell distributions and activity.

    The study was funded by the Wallenberg Foundation, the Swedish Research Council, the Swedish Council for Working Life and Social Research, and the Swedish Association of Persons with Neurological Disabilities.

    Study authors reported relationships with Biogen Idec, Sanofi, Merck Serono, and Bayer Schering.

    Du Pasquier reported serving on scientific advisory boards for Biogen Idec, Merck Serono, Teva, and Novartis and has received funding for travel, speaker honoraria, or support for research from Abbott, Bayer Schering Pharma, Biogen Idec, Merck Serono, Teva, and ViiV.

    Primary source: European Committee for Treatment and Research in Multiple Sclerosis
    Source reference:
    Sundqvist E, et al "Cytomegalovirus seropositivity is associated with lower multiple sclerosis risk" ECTRIMS 2012.

    Source: MedPage Today © 2012 MedPage Today, LLC (12/10/12)

    Low vitamin D & EBV immune activity may be key to MS breakthrough within 2–3 years

    Epstein-Barr VirusAbstract:
    Objective: Vitamin D deficiency and Epstein-Barr virus (EBV) infection may be associated with the development of multiple sclerosis (MS).

    We investigated serum 25-hydroxyvitamin D (25-OH-D) levels and anti-EBV immunoreactivity in 25 individuals before the first clinical manifestation of MS.

    Patients and methods:

    • 56 serum samples of 25 individuals who had donated blood prior to the first clinical MS manifestation (clinically isolated syndrome (CIS))

    • Four male subjects, 21 female subjects,

    • Mean age 31.5 years at time of pre-CIS blood sampling;

    • Mean age at disease onset 33.4 years…

    ….were available, covering an interval of 7.3 years-2 months (mean 31.5 months) before CIS.

    In 18 of 25 patients serum samples were also obtained after established diagnosis of MS.

    Longitudinal age- and gender-matched healthy blood donors (four male subjects, 21 female subjects, 39 samples, mean age 32.5 years) served as controls.

    Serum 25-OH-D was measured by isotope dilution-liquid chromatography-tandem mass spectrometry. 25-OH-D levels were deconvoluted using published seasonal coefficients from a German population.

    Immunoglobulin G (IgG) against Epstein-Barr virus nuclear antigen-1 (EBNA1) were assessed using commercially available ELISA.

    Results:

    • Low 25-OH-D levels were observed during the 24-month pre-CIS interval (47.8 (32.5-77.2) nmol/l, median (IQR); healthy controls: 81.6 (57.7-98.5), p=0.004,

    • However, still higher than after established diagnosis (24.5 (13.7-47.7), p<0 .0001) compared with controls).

    • IgG against EBNA1 during the 36-month pre-CIS interval was increased (185.9 (91.2–460.0) IU/ml, median (IQR); healthy controls 63.7 (29.5–121.6), p=0.002).

    Conclusions: Low vitamin D and remote EBV infection may be associated with clinical MS breakthrough within 2–3 years.

    By Brenard F Decard, Andrew Chan, et al

    Source: Journal of Neurology, Neurosurgery and Psychiatry, Aug 11, 2012. PMID:22888143

    Source: ProHealth Copyright © 2012 ProHealth, Inc (20/08/12)

    Autonomic dysfunction: A unifying MS theory, linking CCSVI, vitamin D3, and Epstein-Barr virus

    MS MRIAbstract
    Multiple sclerosis (MS) is a disease with multiple etiologies. The most recent theory of the vascular etiology of MS, Chronic Cerebrospinal Venous Insufficiency (CCSVI), suggests that cerebral venous obstruction could lead to cerebral venous reflux, promoting local inflammatory processes.

    This review article offers strong evidence that the route of the observed narrowing of cerebral veins arises from autonomic nervous system dysfunction, particularly cardiovascular autonomic dysfunction.

    The dysfunction of this system has two major effects: 1) the reduction of mean arterial blood pressure, which has the potential to reduce the cerebral perfusion pressure and the transmural pressure, and 2) the failure of cerebral autoregulation to maintain constant cerebral blood flow in the face of fluctuations in cerebral perfusion pressure. Alterations in cerebral autoregulation could in turn raise the critical closure pressure, indicated to be the cerebral perfusion pressure at which the transmural pressure will be sub-sufficient to overcome the active tension imparted by the smooth muscle layer of the vessel. These two effects of autonomic nervous system dysfunction (reduction in arterial blood pressure and alterations in cerebral autoregulation), when combined with inflammation-induced high levels of nitric oxide in the brain, will lower transmural pressure sufficiently to the point where the threshold for critical closure pressure is reached, leading to venous closure.

    In addition, cerebral vessels fail to overcome the closure as a result of low central venous pressure, which is also regulated by autonomic nervous system function. Furthermore, through their neuroregulatory effects, infectious agents such as the Epstein-Barr virus and vitamin D3 are able to alter the functions of the autonomic nervous system, influencing the rate of CCSVI occurrence.

    The absence of CCSVI specificity for MS, observed in recent clinical studies, may stem from a high prevalence of autonomic nervous system dysfunction in control groups which were recruited to these studies. Future studies should investigate CCSVI in relation to cardiovascular autonomic function.

    Abbreviations
    ANS, autonomic nervous system; BBB, blood brain barrier; BP, blood pressure; CCSVI, chronic cerebrospinal venous insufficiency; CIS, clinically isolated syndrome; CP, chronic progressive; CrCP, critical closure pressure; EBV, Epstein-Barr virus; EDSS, expanded disability status scale; HR, heart rate; IJV, internal jugular vein; MBP, myelin basic protein; PTA, percutaneous transluminal angioplasty; RR, relapsing remitting; SLE, systemic lupus erythematosus; Vit D, 1,25-dihydroxyvitamin D

    Zohara Sternberg, Department of Neurology, Baird MS center, Jacobs Neurological Institute, 100 High St. Buffalo, NY 14203, USA

    Full Article

    Source: Autoimmunity Reviews Copyright © 2012 Published by Elsevier B.V. (08/05/12)

    Could a virus be the cause of MS?

    MS GeneticsMight some forms of neurological illness, such as multiple sclerosis and schizophrenia, be caused at least partly by bacteria, viruses or other parasites? A largely Danish team has recently published evidence of a strong association between multiple sclerosis and a retrovirus, together with hints that a gene called TRIM5, which is used by cells to fight viruses, is especially active in people with MS.

    Other illnesses have unexpectedly turned out to be caused by parasites. In the 1980s, Barry Marshall of the University of Western Australia ran into a brick wall of official disbelief for suggesting that a bacterium caused stomach ulcers. Only by deliberately infecting and then curing himself did he finally get the medical establishment's attention (and eventually the Nobel Prize).

    The virus implicated in multiple sclerosis is called HERV-Fc1, a bizarre beast called an "endogenous" retrovirus. What this means is that its genes are part of the human genome. For millions of years, they have been integrated into our own DNA and passed on by normal heredity. It was one of the shocks of genomic science to find that the human genome contains more retroviral than "human" genes: some 5% to 8% of the entire genome.

    Normally, the genes of endogenous retroviruses remain dormant, but—a bit like a computer virus that springs into action on a trigger—something wakes them up sometimes, and actual viruses are made from them, which then infect other cells in the body. The Danish scientists suggest that this is what happens in multiple sclerosis. Bjørn Nexø of Aarhus University writes that "retroviral infections often develop into running battles between the immune system and virus, with the virus mutating repeatedly to avoid the immune system, and the immune system repeatedly catching up. One can see the episodic nature of multiple sclerosis as such a running battle."

    The possibility that you can inherit the genes of a virus blurs the distinction between a genetic and an infectious disease. The HERV-Fc1 genes lie on the X chromosome. Since women have twice as many X chromosomes as men, this might explain why some forms of MS are more common in women. Dr. Nexø concludes hopefully: "The finding that a disease is caused by an infectious agent is an encouraging one. These are the diseases which we know best how to treat."

    Source: The Wall Street Journal Copyright ©2012 Dow Jones & Company (12/03/12)

    Epstein-barr virus stimulates torque teno virus replication: a possible relationship to MS

    Epstein-Barr VirusSummary: This very interesting article from Germany investigates a potential interplay between two viruses previously implicated in MS pathogenesis; The torque teno virus (TTV) and Epstein-Barr virus (EBV). The authors report that viral replication, as measured by genome amplification, as well as quantitative PCR of two TTV-HD14 isolates isolated from multiple sclerosis brain was significantly higher in EBV-positive cell lines than a EBV-negative Burkitt's lymphoma cell line. The authors suggest that possible interaction of EBV and TTV may exist in the aetiology and progression of multiple sclerosis.

    Abstract
    Viral infections have been implicated in the pathogenesis of multiple sclerosis. Epstein-Barr virus (EBV) has frequently been investigated as a possible candidate and torque teno virus (TTV) has also been discussed in this context. Nevertheless, mechanistic aspects remain unresolved.

    We report viral replication, as measured by genome amplification, as well as quantitative PCR of two TTV-HD14 isolates isolated from multiple sclerosis brain in a series of EBV-positive and -negative lymphoblastoid and Burkitt's lymphoma cell lines.

    Our results demonstrate the replication of both transfected TTV genomes up to day 21 post transfection in all the evaluated cell lines.

    Quantitative amplification indicates statistically significant enhanced TTV replication in the EBV-positive cell lines, including the EBV-converted BJAB line, in comparison to the EBV-negative Burkitt's lymphoma cell line BJAB. This suggests a helper effect of EBV infections in the replication of TTV.

    The present study provides information on a possible interaction of EBV and TTV in the etiology and progression of multiple sclerosis.

    Borkosky SS, Whitley C, Kopp-Schneider A, Zur Hausen H, Devilliers EM.

    [email protected] PLoS One. 2012;7(2):e32160. Epub 2012 Feb 22. & Pubmed PMID: 22384166 (07/03/12)

    Latent virus sparks inflammation in MS

    Epstein-Barr VirusEpstein-Barr virus may play a role in multiple sclerosis (MS) by activating innate immune responses, researchers found.

    Examination of postmortem brain tissue turned up RNA segments of the virus specifically in areas of active MS lesions overexpressing an inflammatory cytokine involved in innate immunity, according to a study by Ute C. Meier, DPhil, of Queen Mary University of London, and colleagues.

    That cytokine, interferon-alpha, was overexpressed in active areas of white matter MS lesions but not in inactive lesions, normal-appearing white matter, or normal brain tissue from controls, the group reported online in Neurology.

    Significantly higher densities of cells labeling for interferon-alpha were present in acute MS lesions (130 ± 9.4 cells/mm2) and active borders of chronic active MS lesions (114.8 ± 9.7 cells/mm2) compared with inactive MS lesions (18.22 ± 2.8 cells/mm2), normal-appearing white matter (4.4 ± 1.2 cells/mm2), and control tissue (12.25 ± 2 cells/mm2, P<0.0001).

    "Perhaps [the subtle role] is not too surprising as Epstein-Barr virus is a persistent virus with the aim to coexist rather than eradicate the host," the authors wrote.

    The virus has a strong epidemiologic link to MS, they pointed out.

    Individuals who have had a symptomatic case of infectious mononucleosis from Epstein-Barr virus are twice as likely to later develop MS, with risk appearing higher for smokers.

    Determining the mechanism for the link to Epstein-Barr virus could aid in developing better treatments for the neurodegenerative disease, Meier's group suggested, and there could be broader implications as well.

    "Our study casts new light on mechanistic interactions of viral RNAs and innate immune activation in the [central nervous system], and may highlight the propensity of latent viral infections to contribute to neuroinflammation in the CNS, not only in multiple sclerosis but also in other neuroinflammatory diseases," they wrote.

    Their study revitalizes debate over how common Epstein-Barr virus-infected B cells are in MS brains and whether they are a driving factor, Jan D. Lünemann, of the University of Zurich, Switzerland, noted in an accompanying editorial.

    But even if the accumulation of Epstein-Barr virus-infected B cells in such lesions represent merely bystanders, that doesn't necessarily make them silent and innocent, he wrote.

    Rather than requiring active infection, the latent infection in these immune cells appeared to stimulate or maintain innate immune responses contributing to the inflammatory milieu in MS lesions.

    In the seven MS patients' postmortem brain tissue studied, active MS lesions (defined by the presence of dense lymphocytic infiltrates with numerous B cells) all contained Epstein-Barr virus infected cells.

    But few of those infected cells expressed a viral protein indicating active replication, suggesting "that viral gene expression is limited to a few proteins that are expressed during latent infection," Lünemann explained.

    Such cells weren't unique to MS, but were also detected in CNS tissue from two control patients with stroke, which the researchers pointed out is also a disease in which inflammation plays an important role.

    Notably, Epstein-Barr virus-positive cells were present in much higher numbers in active MS lesions than expected in peripheral blood B cells, "which suggests that these cells are recruited to or accumulate in CNS infiltrates," Lünemann noted.

    Meier's group also tested the process by infecting human embryonic kidney cells with Epstein-Barr virus-encoded RNA and found that this significantly stimulated interferon-alpha production.

    Interferon-alpha showed up in macrophages and microglia suggesting local production as part of an acute inflammatory process.

    "Thus even latent Epstein-Barr virus infection can trigger interferon-alpha production observed in active multiple sclerosis lesions, and therefore contribute to the neuroinflammation," the investigators concluded.

    The study was supported by AIMS2CURE, the Roan Charitable Trust, and grants from the Medical Research Council, UAEU FMHS Project, and the Wellcome Trust.

    Meier reported receiving research support from British Technology Group, ABN/MS Society, Aims2Cure, and the Roan Charitable Trust.

    Lünemann reported receiving research support from Baxter International, the Swiss National Science Foundation, the Gemeinnutzige Hertie-Stiftung, the Swiss Multiple Sclerosis Foundation, the Betty and David Koetser Foundation, and the Ernst Schering Foundation.

    Primary source: Neurology
    Source reference:
    Tzartos JS, et al "Association of innate immune activation with latent Epstein-Barr virus in active MS lesions" Neurology 2012; 78: 15-23.

    Additional source: Neurology
    Source reference:
    Lünemann JD "Epstein-Barr virus in multiple sclerosis: A continuing conundrum" Neurology 2012; 78: 11-12.

    Source: Medpage Today © 2012 Everyday Health, Inc. (04/01/12)

    Genetic variations and glandular fever narrow down MS likelihood

    Epstein-Barr VirusWestern Australian scientists are helping to solve the mysteries of multiple sclerosis (MS) with research finding a link between MS development and past infection with glandular fever.

    Combined with genetic variations in the immune system, glandular fever has been found to be one of the factors believed to greatly increase the risk of developing MS.

    A Murdoch University study is working to find out how these factors affect the development of MS.

    Led by Associate Professor David Nolan and funded by the McCusker Charitable Foundation, the study will work with collaborators who will provide specialist medical care for hundreds of men and women affected by MS in Western Australia.

    “We will be able to examine interactions between infections, genetic and environmental risk factors, all of which appear to be important in the disease process,” A/Prof Nolan says.

    Professor Nolan and colleagues hope the research will lead to new innovations and developments in MS diagnosis and treatment.

    “Our sincere hope is that this research will lead to new diagnostics for people at risk of developing MS, and better therapies for those with active disease.”

    The McCusker Charitable Foundation will donate $900,000 over three years to support Murdoch University’s Integrated Health Research Institute (IHRI), with the funding used to study MS among other issues including exercise physiology, diabetes and chronic viral diseases.

    IHRI Director Professor Cassandra Berry says the MS project—in partnership with the Australian Neuro-muscular Research Institute (ANRI)—will look at factors that could increase the risk of developing the disease.

    “This is a really exciting collaborative project which will hopefully lead to new diagnostic and treatment methods,” she says.

    “More people are now developing the disease than 30 years ago and the aim is to be able to predict progression to multiple sclerosis earlier in life.”

    Another study from the Australian National University (ANU), headed by Associate Professor Robyn Lucas found those who have the glandular fever antibodies have a greater risk of developing MS.

    This finding is consistent with other studies showing a connection between markers of previous episodes of glandular fever and MS.

    “What we have shown is that people who develop central nervous system demyelination are more likely to report a past history of glandular fever,” Prof Lucas says.

    According to the ANRI, MS onset usually occurs in young adulthood, is more common in women and affects around 18,000 people across Australia with more than 30 affected in every 1,000 people in WA.

    Source: Science Network Western Australia © Copyright Science Network 2011 (11/11/11)

    New research to look for viral cause of Primary Progressive MS

    MS MRIA team of investigators from the University of Utah has received a two-year, $275,000 grant from the National Institutes of Health (NIH) to fund novel research that may help to uncover a viral cause for the most acute and severe form of multiple sclerosis.

    These studies will use an advanced technology called deep sequencing to analyze brain tissue from patients who died of primary progressive multiple sclerosis.

    Multiple sclerosis (MS), which affects an estimated 2.5Million people world-wide and 400,000 people in the United States, is an autoimmune disease that leads to nerve damage in the brain and spinal cord. This damage is caused by inflammation that occurs when the body's own immune system attacks the myelin sheath, a fatty protective covering that surrounds nerve cells. Loss of myelin affects the ability of nerve cells in the brain and spinal cord to conduct the electrical signals needed for them to communicate with each other. To date, it is not known what prompts the damaging inflammation, but many investigators believe there is an environmental trigger, possibly a viral or other infection.

    "Our preliminary data has already led to identification of a virus in the brain of one patient who died of primary progressive MS," says John D. Kriesel, M.D., research associate professor in the Division of Infectious Diseases at the University of Utah School of Medicine. "Using a technology called deep sequencing, we will now be studying brain tissue from a group of primary progressive MS patients, with the hope of isolating one or more viruses that might prove to be the cause of this severe type of MS."

    Deep sequencing, otherwise known as high-throughput sequencing, is a technology that allows scientists to sequence very large amounts of DNA more quickly and at a lower cost than traditional sequencing methods. Kriesel and his colleagues will utilize deep sequencing to study the brain tissue of 15 patients who died of primary progressive MS and compare it to brain tissue from a population of controls, including normal patients and people with other neurologic diseases.

    The sequencing data generated will then be analyzed for viral genetic material in order to identify viruses that are unique to the brain tissue of people with primary progressive MS.

    MS is classified into four types, which differ in symptom intensity and rate of disease progression. While treatment has been effective for some forms of MS, the standard medications for MS have not been shown to slow the progression of neurologic decline in people with primary progressive multiple sclerosis (PPMS). Identifying viruses that might play a role in the development of PPMS could eventually lead to the development of screening tests, prevention, or anti-viral treatments for the disease.

    "Currently, there is no approved or highly effective treatment for PPMS," says Kriesel. "The goal of our research is to define a cause for PPMS, so that future investigation can be directed at developing medicines that can slow or stop the progression of this devastating neurologic disease."

    Kriesel's collaborators include Brad Cairns, Ph.D., Jon & Karen Huntsman Presidential Professor in Cancer Research and professor in the University of Utah Department of Oncological Sciences, and Kael Fischer, Ph.D., research associate professor in the University of Utah Department of Pathology and scientific director of the Pathogen Microarray laboratory at ARUP Laboratories.

    Source: Eureka Alert! (13/10/11)

    © Multiple Sclerosis Resource Centre

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