Epstein-Barr Virus

Abstract
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)

Summary: 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.

Source@ PLoS One. 2012;7(2):e32160. Epub 2012 Feb 22. & Pubmed PMID: 22384166 (07/03/12)

Epstein-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)

Western 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)

Report on a focused workshop held in the Centre for Brain Research of the Medical University of Vienna, Austria.

Summary

Recent epidemiological and immunological studies provide evidence for an association between Epstein–Barr virus infection and multiple sclerosis, suggesting a role of Epstein–Barr virus infection in disease induction and pathogenesis.

A key question in this context is whether Epstein–Barr virus-infected B lymphocytes are present within the central nervous system and the lesions of patients with multiple sclerosis.

Previous studies on this topic provided highly controversial results, showing Epstein–Barr virus reactivity in B cells in the vast majority of multiple sclerosis cases and lesions, or only exceptional Epstein–Barr virus-positive B cells in rare cases.

In an attempt to explain the reasons for these divergent results, a workshop was organized under the umbrella of the European Union FP6 NeuroproMiSe project, the outcome of which is presented here.

This report summarizes the current knowledge of Epstein–Barr virus biology and shows that Epstein–Barr virus infection is highly complex.

There are still major controversies, how to unequivocally identify Epstein–Barr virus infection in pathological tissues, particularly in situations other than Epstein–Barr virus-driven lymphomas or acute Epstein–Barr virus infections.

It further highlights that unequivocal proof of Epstein–Barr virus infection in multiple sclerosis lesions is still lacking, due to issues related to the sensitivity and specificity of the detection methods.

Hans Lassmann, Gerald Niedobitek, Francesca Aloisi, Jaap M. Middeldorp and the NeuroproMiSe EBV Working Group

Source: Brain Copyright © 2011 Guarantors of Brain (25/08/11)

Patients with multiple sclerosis (MS) have a decreased frequency of CD8+ T cells reactive to their own Epstein-Barr virus (EBV) infected B cells. We have proposed that this might predispose to the development of MS by allowing EBV-infected autoreactive B cells to accumulate in the central nervous system.

The decreased CD8+ T cell response to EBV results from a general CD8+ T cell deficiency and also a decreased proportion of EBV-specific T cells within the total CD8+ T cell population. Because decreased HLA class I expression on monocytes and B cells has been reported in MS and could influence the generation and effector function of EBV-specific CD8+ T cells, the present study was undertaken to measure the expression of HLA molecules on B cells and monocytes in patients with MS.

Methods: We used flow cytometry to determine the proportions of T cells, natural killer cells, B cells and monocytes in peripheral blood mononuclear cells (PBMC) and to quantify the expression of HLA molecules on T cells, B cells and monocytes of 59 healthy subjects and 62 patients with MS who had not received corticosteroids or immunomodulatory therapy in the previous 3 months.

Results: The levels of HLA classI and class II molecules expressed on T cells, B cells and monocytes were normal in patients with MS, with the exception of two patients with secondary progressive MS with very low class II expression on B cells.

In confirmation of previous studies we also found that the percentage of CD8+ T cells was significantly decreased whereas the percentage of CD4+ T cells and the CD4:CD8 ratio were significantly increased in patients with MS compared to healthy subjects.

Conclusions: The decreased CD8+ T cell response to EBV-infected B cells in MS patients is not due to decreased HLA class I expression on monocytes or B cells. In a small proportion of patients decreased HLA class II expression on B cells might impair the CD8+ T cell response to EBV by reducing CD4+ T cell help.

Authors: Michael Pender, Peter Csurhes, Casey Pfluger,Scott Burrows
Credits: BMC Neurology 2011, 11:95

Source: 7th Space Interactive © 2011 7thSpace Interactive (03/08/11)

New Australian research has found a link between glandular fever and multiple sclerosis (MS).

MS affects 20,000 people in Australia and is a condition where the immune system attacks the brain and spinal cord.

Many of those diagnosed are young, healthy women.

Now a new study from the Australian National University (ANU) has found those who have glandular fever antibodies have a much greater risk of developing multiple sclerosis.

The research, published in the journal Neurology, could lead to new treatments for the condition.

ANU Associate Professor Robyn Lucas studied 300 patients with MS and 500 healthy participants.

She also found a strong relationship between those who had MS and genetic changes relating to the immune system.

Professor Lucas says the findings are consistent with other studies showing an association between markers of past episodes of glandular fever and MS risk.

"We have shown further interaction with other immune system genes in the HLA class 1 region and CLTA-4," she said.

Professor Lucas says the Australian work is promising.

"It starts to bring together the different risk factors that we know are involved in MS. It points us in the right direction for further research to prevent and cure MS," she said.

The research was part of the Ausimmune study, a major study looking at the possible environmental triggers for multiple sclerosis.

Source: ABC News © 2011 ABC (22/07/11)

At present, while there is no cause known for this condition, patients with MS seem to have genetic vulnerability to certain environmental factors that could trigger this condition, such as the Epstein-Barr virus. Scientists at the University of Granada have found a relation between the Epstein-Barr virus – which belongs to the herpes viruses family – and the development of this condition.

The Epstein-Barr (EVB) virus –belonging to the herpes viruses family, which also includes the herpes simplex virus and the cytomegalovirus– is one of the environmental factors that might cause multiple sclerosis, a condition affecting the central nervous system, which causes are unknown. This has been confirmed by University of Granada scientists that analyzed the presence of this virus in patients with multiple sclerosis. Researchers analyzed antibody levels, that is, antibodies that are produced within the central nervous system and that could be directly involved in the development of multiple sclerosis.

Multiple sclerosis is a demyelinating condition affecting the central nervous system. Although the cause for this condition is unknown, patients with MS seem to have genetic vulnerability to certain environmental factors that could trigger this condition.

While other studies have tried to ellucidate whether infection with the Epstein-Barr virus could be considered a risk factor in multiple sclerosis, what University of Granada researchers did was conducting a meta-analysis of observational studies including cases and controls, aimed at establishing such association.

A 151-patient sample

In a sample of 76 healthy individuals and 75 patients with multiple sclerosis, researchers sought a pattern that would show an association between this virus and multiple sclerosis. Thus, they determined the presence of antibodies to Epstein-Barr virus antigens synthetized within the central nervous system. Simultaneously, they identified viral DNA to measure antibody levels to EBV within the central nervous system, and the presence of EBV DNA respectively.

This piece of research was conducted by Olivia del Carmen Santiago Puertas at the Department of Microbiology, University of Granada, and coordinated by professors José Gutiérrez Fernández, Antonio Sorlózano Puerto and Óscar Fernández Fernández.

The researchers found a statistically significant association between viral infection and multiple sclerosis starting from the detection of markers that essentially indicate an infection in the past, while markers that indicate recent infection or reactivation are not relevant.

The researcher Olivia del Carmen Santiago Puertas state that, as the factors triggering this condition are still unknown “studying them is important to try to develop a prevention method”.

This study found an association between MS and some viral infection markers “but, to obtain a definitive conclusion, further research is needed with a significant number of patients that combine different microbiological techniques, where the different viral infection markers are recorded, and assessing patients’ clinical state even years before the onset of the first symptoms of multiple sclerosis”.

References:

- Relation between Epstein-Barr virus and Multiple Sclerosis. Analytic study of scientific production. European Journal of Clinical Microbiology and Infectious Diseases. 2010.

- New Strategies and Patent Therapeutics in EBV-Associated Diseases. Mini-Reviews in Medicinal Chemistry. 2010.

Source: CORDIS wire (17/05/11)

Having a history of mononucleosis and living in an area that gets little sunlight both appear to increase the risk for developing multiple sclerosis, new research finds.

Multiple sclerosis (MS) is far more common in regions that get little sunlight most of the year, such as Scandinavia, Canada, and the Northern U.S.

Exposure to sunlight allows the skin to produce vitamin D, and vitamin D deficiency has been linked to MS in some studies. Having a history of mononucleosis, which is caused by the Epstein-Barr virus, has also long been suspected of being a possible trigger for MS.

In an effort to determine if the two possible risk factors could explain the geographic differences in multiple sclerosis incidence, longtime MS researcher George C. Ebers, MD, and colleagues at the University of Oxford in the U.K. conducted a study in England.

Their earlier studies in France, Scotland, and other regions of Europe suggest that differences in sunlight exposure affect MS risk even within small geographical areas.

For example, MS rates in Scotland were higher in Glasgow than in the sunnier city of Dundee.

“We wanted to find out if having had mononucleosis adds to the multiple sclerosis risk we have documented for low ultraviolet B (UVB) exposure,” Ebers tells WebMD.

Sunlight, Mono Explain 72% of Regional Difference

To do this, the researchers examined all National Health Service (NHS) hospital admissions in England from spring of 1998 to spring of 2005, identifying almost 57,700 cases of multiple sclerosis and 14,600 cases of infectious mononucleosis.

They also used NASA satellite data on UV radiation exposure to calculate sunlight exposure within different areas of the country.

The researchers concluded that sunlight exposure and mononucleosis history together explained 72% of the variance in multiple sclerosis incidence within England during this period.

Exposure to sunlight accounted for about 61% of this variance, with having a history of mononucleosis accounting for the rest of the risk, the researchers found.

The findings do not prove that either low levels of sunlight exposure or having a history of mononucleosis cause multiple sclerosis. But Ebers says they point to the “pressing need” for larger studies to examine vitamin D, infectious mononucleosis, and MS.

“The evidence implicating UV radiation in MS is pretty strong,” he says. “It is less strong for infectious mononucleosis, but we need to learn more about this.”

Neurologist Recommends Testing, Supplementation

Neurologist Karen Blitz-Shabbir, MD, agrees the evidence suggesting a protective role for vitamin D against MS is convincing, and she believes supplementation may even help patients once they have the disease.

Blitz-Shabbir, who directs the North Shore MS Care Center in East Meadow, N.Y., recommends that her patients take 1,000 international units (IU) of vitamin D a day.

Other than sunlight exposure, supplementation is the most efficient way to get vitamin D. Food sources includes fatty fish and fortified dairy products, but getting vitamin D from food alone would be very difficult.

“It is important for MS patients and family members of patients to have their vitamin D levels checked,” Blitz-Shabbir says. “If vitamin D levels are low, 1,000 IU may not be enough.”

Late last year, the Institute of Medicine weighed in on vitamin D supplementation, concluding that most Americans under the age of 70 need no more than 600 IU of the vitamin per day to maintain health and older people need no more than 800 IU.

The group concluded that the evidence linking higher levels of supplementation to protection against diseases like MS was inconclusive.

Source: WebMD ©2005-2011 WebMD, LLC (19/04/11)

Summary: Epstein Barr virus (EBV) is one of several infective agents that have been suggested to be linked with MS. This study explores the geographical incidence of hospital admissions for infectious mononucleosis (IM), which is caused by EBV and compares the incidence to that of admissions for MS.

The study supports existing data that a significant geographical variance in incidence of MS exists and correlates with the degree of latitude. This correlation remained after adjustment for deprivation and UK birthplace. Furthermore the authors found the geographical distributions of IM and MS were significantly correlated. The authors suggest these results may have implications for defining disease causality and for disease prevention.

Abstract
Objective It is well recognised that variation in the geographical distribution of multiple sclerosis (MS) exists. Early studies in England have shown the disease to have been more common in the North than the South. However, this could be an artefact of inaccurate diagnosis and ascertainment, and recent data on MS prevalence are lacking.

In the present study, data were analysed to provide a more contemporary map of the distribution of MS in England and, as infectious mononucleosis (IM) has been shown to be associated with the risk of MS, the geographical distribution of IM with that of MS was compared.

Methods: Analysis of linked statistical abstracts of hospital data for England between 1999 and 2005.

Results: There were 56 681 MS patients. The admission rate for MS was higher in females (22/10(5); 95% CI 21.8 to 22.3) than males (10.4/10(5); 95% CI 10.2 to 10.5). The highest admission rate for MS was seen for residents of Cumbria and Lancashire (North of England) (20.1/10(5); 95% CI 19.3 to 20.8) and the lowest admission rate was for North West London residents (South of England) (12.4/10(5); 95% CI 11.8 to 13.1). The geographical distributions of IM and MS were significantly correlated (weighted regression coefficient (r (w))=0.70, p<0.0001). Admission rates for MS were lowest in the area quintile with the highest level of deprivation and they were also lowest in the area quintile with the highest percentage of population born outside the UK. A significant association between northernliness and MS remained after adjustment for deprivation and UK birthplace.

Conclusions: The results show the continued existence of a latitude gradient for MS in England and show a correlation with the distribution of IM. The data have implications for healthcare provision, because lifetime costs of MS exceed £1 million per case in the UK, as well as for studies of disease causality and prevention.

Authors: Ramagopalan SV, Hoang U, Seagroatt V, Handel A, Ebers GC, Giovannoni G, Goldacre MJ.
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

Sources: J Neurol Neurosurg Psychiatry. 2011 Jan 6 & Pubmed PMID: 21212107 (12/01/11)

Epstein-Barr virus infection of human brain microvessel endothelial cells: A novel role in multiple sclerosis

Abstract

Multiple sclerosis (MS) is an inflammatory neurological disease that is widely regarded as the outcome of complex interactions between a genetic predisposition and an environmental trigger.

Epstein-Barr virus (EBV) has recently been associated with the onset of MS, yet understanding how it elicits autoimmunity remains elusive.

Neuroinflammation, including the entry of autoreactive T cells, likely follows a breach of the blood-brain barrier (BBB) leading to CNS lesions in MS.

We show that EBV can infect human BBB cells leading to increased production of pro-inflammatory mediators that result in immune cell adherence thus modeling a key step in MS pathogenesis.

Casiraghi C, Dorovini-Zis K, Horwitz MS.

Department of Microbiology and Immunology, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.

Source: J Neuroimmunol. 2010 Sep 6. [Epub ahead of print] Pubmed PMID: 20826008

Both epidemiological and experimental studies have indicated that the ubiquitous herpes virus Epstein - Barr virus (EBV) plays a role in the pathogenesis of multiple sclerosis (MS).

Some features of MS epidemiology, such as the decline in risk among migrants from high to low MS prevalence areas, suggest the presence of variant EBV strains that increase MS risk.

The objective of this study was to investigate whether genetic variability in EBV is associated with MS.

Genes encoding for two EBV antigens (EBNA1 and BRRF2) were sequenced in EBV isolates from 40 MS patients and a similar number of control subjects.

These viral antigens were chosen for analysis because they are known to stimulate atypical immune responses in MS.

Extensive sequence polymorphism was observed within the EBNA1 and BRRF2 genes in isolates from both MS patients and controls.

Interestingly, several single nucleotide polymorphisms within the EBNA1 gene, and one within the BRRF2 gene, were found to occur at marginally different frequencies in EBV strains infecting MS patients versus controls.

Although this study does not find a simple causal relationship between EBV strains and the occurrence of MS, the existence of haplotypes that occur at different frequencies in MS patients versus controls may provide an area for future study of the role of EBV strain variation in multiple sclerosis.

RM Brennan - Queensland Institute of Medical Research and Australian Centre for Vaccine Development, Australia, The University of Queensland, School of Medicine, Australia

JM Burrows - Queensland Institute of Medical Research and Australian Centre for Vaccine Development, Australia

MJ Bell - Queensland Institute of Medical Research and Australian Centre for Vaccine Development, Australia

L. Bromham - Centre for Macroevolution and Macroecology, Research School of Biology, Australian National University, Australia

PA Csurhes - The University of Queensland, School of Medicine, Australia

A. Lenarczyk - The University of Queensland, School of Medicine, Australia

J. Sverndal - Queensland Institute of Medical Research and Australian Centre for Vaccine Development, Australia, Department of Health and Environment, Linköping University, Sweden

J. Klintenstedt - Queensland Institute of Medical Research and Australian Centre for Vaccine Development, Australia, Department of Health and Environment, Linköping University, Sweden

MP Pender - The University of Queensland, School of Medicine, Australia, Department of Neurology, Royal Brisbane and Women's Hospital, Australia

SR Burrows - Queensland Institute of Medical Research and Australian Centre for Vaccine Development, Australia

Source: Multiple Sclerosis, Vol. 16, No. 6, 643-651 (2010)
DOI: 10.1177/1352458510364537 - Sage Journals Online © 2010 by SAGE Publications (23/06/10)

Abstract
To determine whether multiple sclerosis (MS) risk increases following primary infection with the Epstein-Barr virus (EBV), we conducted a nested case-control study including 305 individuals who developed MS and 610 matched controls selected among the >8 million active-duty military personnel whose serum has been stored in the Department of Defense Serum Repository.

Time of EBV infection was determined by measuring antibody titers in serial serum samples collected before MS onset among cases, and on matched dates among controls.

Ten (3.3%) cases and 32 (5.2%) controls were initially EBV negative.

All of the 10 EBV-negative cases became EBV positive before MS onset; in contrast, only 35.7% (n = 10) of the 28 controls with follow-up samples seroconverted (exact p value = 0.0008).

We conclude that MS risk is extremely low among individuals not infected with EBV, but it increases sharply in the same individuals following EBV infection.

Levin LI, Munger KL, O'Reilly EJ, Falk KI, Ascherio A.

Department of Epidemiology, Division of Preventive Medicine, Walter Reed Army Institute of Research, Silver Spring, MD, USA.

Source: Ann Neurol. 2010 Jun;67(6):824-30. Pubmed PMID: 20517945 (07/06/10)

Although studies have found a link between infection with the Epstein-Barr virus and a heightened risk of multiple sclerosis, new findings cast doubt on the theory that the virus helps cause the disease.

In an analysis of spinal fluid and autopsied brain tissue from people with MS, researchers found little evidence of Epstein-Barr genetic material in the samples.

That absence, the researchers say, indicates that the virus is not directly involved in the MS disease process, as a number of other investigators propose.

Multiple sclerosis, or MS, is believed to arise from an abnormal immune system attack on the body's own myelin, a protective sheath surrounding nerve fibers in the brain and spine. This leads to symptoms such as muscle weakness, numbness, vision problems and difficulty with coordination and balance.

Researchers have long suspected that a combination of genetics and an environmental trigger -- such as a virus -- may be to blame for inducing this abnormal immune assault. Studies have particularly focused on Epstein-Barr, an extremely common herpesvirus that causes mononucleosis in some people.

It's believed that nearly everyone -- up to 95 percent of people worldwide -- become infected with Epstein-Barr at some point. After infection, the virus can then take up residence in some of the body's B lymphocytes, a type of immune-system cell, where it dwells in a dormant state.

Some epidemiological studies have found that people with relatively high antibody levels to Epstein-Barr -- possibly indicating a stronger immune response to the infection -- may have a higher risk of MS than people with lower antibody levels.

That, however, is not enough to prove that the virus directly contributes to MS.

For the new study, reported in the journal Neurology, researchers looked for evidence of Epstein-Barr in samples of brain tissue and cerebrospinal fluid from individuals with and without MS.

They found no evidence of Epstein-Barr DNA in B lymphocytes or other cells from MS patients' cerebrospinal fluid. And only a few samples of MS brain lesions harbored genetic material from the virus.

The findings are in line with the majority of published studies looking for evidence of Epstein-Barr in MS brain tissue, according to senior researcher Dr. Donald Gilden, of the University of Colorado School of Medicine in Aurora.

"We feel quite confident that EBV has no role in causing MS," Gilden said in an interview.

He added, however, that he still believes some as-yet-unidentified virus is at work. "I've felt for a long time that a virus is involved in MS," Gilden said. "It's just not Epstein-Barr."

The current findings do conflict, however, with a 2007 study in which researchers found a high rate of Epstein-Barr-infected B lymphocytes in MS brain lesions. Those investigators concluded that "brain infiltration" with those infected cells may be key in the MS process.

For the current study, Gilden and his colleagues included brain-tissue samples from five of the study subjects in the 2007 report (although the specific lesions they examined differed). They failed to find evidence of Epstein-Barr in the samples.

Gilden said the "only explanation" he can think of for the discrepancy is the different techniques the two research teams used to look for Epstein-Barr genetic material. His team used a highly sensitive test called polymerase chain reaction (PCR), which Gilden said is more objective than the technique used in the 2007 study -- known as in situ hybridization.

However, an editorial published with the study asserts that this is far from the end of the story for Epstein-Barr and MS.

Even if the virus is "rare," or only in select types of MS brain lesions, that does not mean Epstein-Barr plays no role in the disease, according to editorialist Dr. Alberto Ascherio of the Harvard School of Public Health in Boston, who has published several studies on the virus and MS.

There are a number of theorized mechanisms by which Epstein-Barr might contribute to MS, write Ascherio and co-author Dr. Amit Bar-Or, of McGill University in Montreal. It's possible, for example, that brain Epstein-Barr-infected B lymphocytes contribute to the disease process earlier on, or transiently.

"These results do not question the importance of (Epstein-Barr) in MS," write Ascherio and Bar-Or, "but rather the predominant anatomic site and disease stage of major (Epstein-Barr) contribution."

But Gilden argued that it is time to look elsewhere for viral culprits in MS. "I would hope that more research in the future will look at other viruses," he said.

If a particular virus were found to contribute to MS, there would be "enormous implications," Gilden said. Such a discovery could, for example, lay the groundwork for a finding a vaccine or drug to help prevent MS.

Source: Reuters © Thomson Reuters 2010 (16/04/10)

OBJECTIVE: Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that becomes latent in B-lymphocytes and has been implicated in the pathogenesis of multiple sclerosis (MS). We searched for latent and active EBV infection in MS brain and CSF.

METHODS: Nested and non-nested real-time PCR were used to detect cell-specific and EBV-specific transcripts in 15 fresh-frozen and 5 formalin-fixed paraffin-embedded MS plaques and in single MS CSF B-lymphocytes and plasma cells. Intrathecal anti-EBV antibody synthesis was measured by ELISA. Immunocytochemistry was used to detect binding of MS CSF and recombinant antibodies (rAbs) generated from clonally expanded plasma cells in MS CSF to EBV-infected cells.

RESULTS: No EBV RNA was found in MS CSF B-lymphocytes or plasma cells. In active MS plaques, EBV-encoded RNA (EBER)-1 was the only and rarely detected transcript. The frequency of detected intrathecal anti-EBV antibody synthesis in patients with MS did not differ from that in non-MS inflammatory CNS disease control patients. Anti-EBV antibodies were detected in the CSF of patients with MS, but MS rAbs did not react with EBV.

CONCLUSIONS: Application of real-time PCR to multiple sclerosis brain and single B-lymphocytes in CSF did not reveal any evidence of active Epstein-Barr virus infection.

Sargsyan SA, Shearer AJ, Ritchie AM, Burgoon MP, Anderson S, Hemmer B, Stadelmann C, Gattenlöhner S, Owens GP, Gilden D, Bennett JL.

From the Departments of Neurology (S.A.S., A.J.S., A.M.R., M.P.B., S.A., G.P.O., D.G., J.L.B.), Microbiology (D.G.), and Ophthalmology (J.L.B.), University of Colorado Denver School of Medicine, Aurora; Department of Neurology (B.H.), Technische Universität, Munich; Universitätsmedizin der Georg-August-Universität Göttingen (C.S.), Göttingen; and Department of Pathology (S.G.), Julius-Maximilians-University, Würzburg, Germany.

Source: Pubmed PMID: 20220124 (17/03/10)

Summary
The cause of MS is yet to be found. However, both environmental and genetic factors are believed to contribute to its pathogenesis.

Amongst the environmental factors, viruses seem to play an important role. The authors of this article suggest that the nature of the immune response to Epstein-Barr virus is associated with the risk of developing MS. Mult Scler. 2010 Mar;16(3):355-8

Details
The objective of this study was to determine the immune responses to candidate viral triggers of multiple sclerosis in patients and healthy siblings raised in the same family household.

Virus antigen-specific IgG responses to Epstein-Barr virus-derived gene products as well as to human herpersvirus-6, human cytomegalovirus, and measles virus were evaluated in 25 multiple sclerosis patients and compared with 49 healthy full-siblings.

IgG responses to the latent Epstein-Barr virus-encoded nuclear antigen-1 (EBNA1) were selectively increased in individuals with multiple sclerosis compared with their unaffected siblings.

We conclude that elevated IgG responses towards EBNA1 are associated with the development of multiple sclerosis.

Source: MS Society of Canada (16/03/10)

Researchers from the Harvard School of Public Health, Walter Reed Army Institute of Research, and a team of collaborators have observed for the first time that the risk of multiple sclerosis (MS) increases by many folds following infection with the Epstein-Barr virus (EBV). This finding implicates EBV as a contributory cause to multiple sclerosis. The study appears in an advance online edition of the journal Annals of Neurology and will appear in a later print edition.

Hundred of thousands of individuals not infected with EBV were followed up for several years through repeated blood samples collections. Researchers were then able to determine the time when individuals developed an EBV infection and its relation to MS onset. "The recruitment of individuals before they were infected with EBV and following up with them for several years is the critical methodological aspect that makes this study qualitatively different from all previous work," said Alberto Ascherio, senior author of the study and professor of epidemiology and nutrition at Harvard School of Public Health and professor of medicine at Harvard Medical School.

MS is a chronic degenerative disease of the central nervous system. Women are more likely than men to get the disease and it is the most common neurologically disabling disease in young adults. Although genetic predisposition plays an important role in determining susceptibility, past studies have shown that environmental factors are equally important.

EBV is a herpes virus and one of the most common human viruses worldwide. Infection in early childhood is common and usually asymptomatic. Late age at infection, however, often causes infectious mononucleosis. In the U.S., upwards of 95% of adults are infected with the virus, but free of symptoms. EBV has been associated with some types of cancer and can cause serious complications when the immune system is suppressed, for example, in transplant recipients. There is no effective treatment for EBV.

This is the first study based on the longitudinal follow-up of several thousand individuals who were not infected with EBV at the time of recruitment. The study population was made up of active-duty US Army, Navy, and Marines personnel who have at least one blood sample in the Department of Defense Serum Repository. The electronic databases of the Physical Disability Agencies of the US Army and Navy were then searched for individuals whose records indicated a possible diagnosis of MS reported between 1992 and 2004.

The researchers selected 305 individuals diagnosed with MS and who had blood specimens collected before the date of their diagnosis. Two controls for each case were then selected from the serum database and matched by branch of service, sex, date of blood collection, and age at time of blood collection.

The study found that MS risk is extremely low among individuals not infected with EBV, but it increases sharply in the same individuals following EBV infection.

"The observation that MS occurred only after EBV is a big step forward," said Alberto Ascherio. "Until now we knew that virtually all MS patients are infected with EBV, but we could not exclude two non-causal explanations for this finding: that EBV infection is a consequence rather than a cause of MS, and that individuals who are EBV negative could be genetically resistant to MS. Both of these explanations are inconsistent with the present findings," said Ascherio.

"The evidence is now sufficiently compelling to justify the allocation of more resources to the development of interventions targeting EBV infection, or the immune response to EBV infection, as these may contribute to MS prevention," he said.

The study was supported by a grant from the National Institute of Neurological Disorders and Stroke.

"Primary Infection with the Epstein-Barr Virus and Risk of Multiple Sclerosis," Lynn I. Levin, Kassandra L. Munger, Eilis J. O'Reilly, Kerstin I. Falk, Alberto Ascherio, Annals of Neurology, online January 20, 2010

Source: ScienceBlog Copyright, Science Blog 2010. (05/03/10)

The same virus that causes relatively mild mononucleosis, the "kissing disease," can also cause severe mono as well as several potentially deadly kinds of cancer.

Now researchers think they can kiss a stealthy form of Epstein-Barr virus (EBV) goodbye - or at least shut it down enough to successfully treat several of the dangerous diseases it causes.

Using a class of drugs being clinically tested to treat other kinds of cancer, researchers at the University of Wisconsin School of Medicine and Public Health found that the drugs were the first to stop the latent form of EBV infection from causing disease.

The drugs, Hsp90 inhibitors, prevented human EBV-related tumors from growing in mice, protected immune cells from transforming into tumors and killed established tumor cells at low, non-toxic doses.

Until now, there have been no effective drugs for treating latent EBV infection in any of the EBV-associated diseases, which in addition to mono include a subset of stomach cancers, certain types of nose-throat cancer and lymph node cancers such as lymphoproliferative disease, says lead author Shannon C. Kenney, MD.

"This discovery suggests a new way of treating patients with severe mononucleosis, which in rare circumstances can be fatal, and patients with EBV-driven cancers, particularly immuno-compromised AIDS and transplant patients," says Kenney, an infectious disease expert at UW Hospital and Clinics.

The study appears in the current (Jan. 25, 2010) Proceedings of the National Academy of Sciences.

Kenney, also a professor of oncology at the McArdle Laboratory for Cancer Research and of medicine, has studied EBV for nearly 30 years. Most of her work has focused on the form of EBV that actively produces infection, but recently she turned to the so-called latent form.

"The latent infection form actually is not so latent," says Kenney, a member of the UW Carbone Cancer Center. "This is the form of EBV that is most closely associated with cancer development."

Latently infected cells express transforming viral proteins that can change normal cells into cancer cells. One key viral protein, EBNA-1, is required for EBV to live long-term in host cells. Many scientists and drug companies are looking for ways to block this viral protein, expressed in every EBV-infected cell.

Kenney and her team had been using Hsp90 (heat shock protein 90) inhibitors as they studied the infectious form of EBV.

"Normal cells can survive when treated with Hsp90 inhibitors," Kenney says. "In contrast, Hsp90 inhibitors are toxic to certain types of cancer cells, which often are more dependent upon high levels of Hsp90."

After they discovered that EBNA-1 itself must have Hsp90 in order to function in cells, the Wisconsin researchers conducted three different experiments to see what the effect of exposing EBV-infected cells to Hsp90 inhibitors would be.

In all three experiments, the results showed a dramatic reduction in EBNA-1-related activity. The drugs killed EBV-induced tumor cells in one experiment, halted the growth of EBV-induced tumors in mice in another and protected normal immune cells from becoming transformed to tumor cells in the third.

And while the drugs were highly toxic to EBV-infected cells, they had very little effect on normal cells at the doses used in the experiments.

The researchers found the underlying explanation to be that EBNA-1 could not be processed - synthesized and translated - to any degree when Hsp90 inhibitors were present.

Kenney expects the inhibitors-geldanamycin, 17-AAG and 17-DMAG-may be useful for most but not all kinds of EBV-induced cancers as well as severe mono.

In fact, the drugs may be even more widely useful, says Kenney, because clinicians are seeing that people older than age 70 are getting certain forms of EBV-induced cancers more frequently.

"There also is tantalizing early evidence that EBV may contribute to auto-immune diseases such as lupus and multiple sclerosis," she says.

And what about the possibilities for standard mono?

"The majority of healthy humans will get over mono with no treatment after a month or two," says Kenney. "But Hsp90 inhibitors could potentially help, in terms of getting people back to school or work sooner. Clinical trials will need to be performed in patients to determine if these drugs are useful in severe mononucleosis."

Source: PhysOrg.com © PhysOrg.com 2003-2009 (26/01/10)

Possible connection to Chronic Cerebrospinal Venous Insufficiency (CCSVI) explained.

Re: Epstein–Barr virus is associated with grey matter atrophy in multiple sclerosis
R Zivadinov, M Zorzon, B Weinstock-Guttman, M Serafin, A Bosco, A Bratina, C Maggiore, A Grop, M A Tommasi, B Srinivasaraghavan, M Ramanathan
J Neurol Neurosurg Psychiatry 2009;80:620-625 Published Online First: 23 January 2009 doi:10.1136/jnnp.2008.154906

Dear Editor,

I read the article by Zivadinov ⁽¹⁾ with reference to the association of Epstein-Barr virus (EBV) to gray matter atrophy in multiple sclerosis (MS) patients.

Accumulation of EBV infected B cells in meninges and perivascular regions of MS lesions in 21 or 22 patients with MS ⁽²⁾ was noted as well, indicating direct involvement of the brain and perivascular spaces by EBV in MS patients..

A recent study has indicated chronic cerebrospinal venous insufficiency with multiple extracranial venous strictures in MS patients ⁽³⁾.

EBV appears to infect endothelial cells ⁽⁴⁾, and may be important in the pathology of EBV virus.

EBV virus has been found to cause deep venous thrombosis in a patient with hereditary thrombophilia ⁽⁵⁾.

EBV may infect the venous endothelium causing venous thromboses and strictures in the cranial and spinal venous drainage system and perivascular regions of MS lesions in patients with MS.

Such venous involvement may be implicated in MS disease involvement.

Chronic EBV infection may involve the venous system with secondary effects on the brain and spinal cord in MS.

References

^1.Zivadinov R, Zorzon M, Weinstock-Guttman B, Serafin M, Bosco A, Bratina A, et al.
Epstein-Barr virus is associated with grey matter atrophy in multiple sclerosis
J Neurol Neurosurg Psychiatry 2009; 80: 620 -625.

^2.Serafani B, Rosicarelli B, Franciotta D, et al.
Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain.
J Exp Med 2007; 204:2899-2912.

^3. Zamboni P, Galeotti P, Menegatti E, Malagoni AM, Tacconi G, et al.
Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis.
J Neurol Neurosurg Psychiatry 2009: 80: 392-398.

^4. Jones K, Rivera C, Sgadari C, Franklin J, Max EE, et al.
Infection of human endothelial cells with Epstein-Barr virus.
J Exp Med. 1995; 182: 1213-1221.

^5. Mashav N, Saar N, Chundadze T, Steinvil.
Epstein-Barr virus associated thromboembolism: A case report and review of the literature.
Thromb Res. 2008; 122: 570-571.

No conflict of interest.

Steven R Brenner, Neurologist
St. Louis VA Medical Center and Dept Neurology and Psychiatry at St. Louis University

Source: J Neurol Neurosurg Psychiatry © 2009 by the BMJ Publishing Group Ltd

Over the last 40 years, Epstein-Barr virus (EBV) has been repeatedly associated with multiple sclerosis and other autoimmune diseases. During the 2nd European Congress of Immunology ECI 2009 held in Berlin, Francesca Aloisi, Istituto Superiore di Sanità, Rome, will present new data* that further support the link. In the brain lesions of patients with multiple sclerosis her team found abnormal accumulation of EBV infected B lymphocytes. Similar findings were made in the pathological tissues of patients with other autoimmune diseases.

Multiple sclerosis is the most common inflammatory disease of the central nervous system affecting young adults. Similarly to other chronic inflammatory diseases, like rheumatoid arthritis and systemic lupus erythematosus, multiple sclerosis is thought to result from an inappropriate attack of the immune system toward selected body components, a process named autoimmunity. In the case of multiple sclerosis, the immune system is thought to attack myelin, the lipid-rich sheath coating our nerves.

To date neither the causes nor the cure of this highly disabling disease have been identified. A detailed knowledge of the cause(s) and the pathogenesis is needed to develop effective new options for therapy and prevention. Viruses have always attracted the interest of immunologists as possible triggers of autoimmune diseases due to their ability to interfere with the host’s immune system. One of the most ubiquitous viruses, EBV, which infects up to 95 % of the human population worldwide, has been repeatedly associated with multiple sclerosis through epidemiological and serological studies, but direct proof of its involvement was missing. The virus has the ability to hide in a particular population of immune cells, the B lymphocytes, remaining in a relatively dormant state for the entire life of the host. However, when not properly controlled by the immune system, EBV can reactivate causing tumours.

At the end of 2007, Aloisi and co-workers showed that EBV is present in brain lesions of patients with multiple sclerosis and that the virus is brought into the central nervous system by B lymphocytes, which behave as Trojan horses for the virus. They also showed that the infected B cells present in the brain become the target of an immune attack, thus promoting the chronic inflammation which leads to tissue destruction. "This raises the suspicion that EBV and its Trojan horses are the main cause of brain damage in multiple sclerosis", Aloisi says.

The scientists demonstrated that abnormal accumulation of EBV infected B lymphocytes is also found in pathological tissues in other autoimmune diseases. "These findings reinforce the long-held view that EBV might be involved in several autoimmune diseases and represent a step forward in the effort to understand the mechanisms underlying the development of autoimmunity. One of the main challenges for the future will be to understand whether preventing or counteracting EBV infection will have a beneficial impact on autoimmune diseases."

*This project is supported by the FP6 EU Programme

Source: Science Daily © 1995-2009 ScienceDaily LLC (15/09/09)

Scientists have discovered a blood test that could predict the course of multiple sclerosis (MS), or even indicate who is likely to develop the condition after a first MS-like attack.

The results of the study suggest that differing antibody levels produced in response to the common virus Epstein Barr Virus (EBV), may predict the course of MS.

If proven in further studies, this would be the first credible biological indicator, or biomarker, identified for MS that could predict disability progression from a simple blood test.

The innovative work was carried out at the Institute of Neurology, UCL and the Institute of Cell and Molecular Biology, Barts and The London and was funded by the MS Society.

It is hoped the findings will aid the development of better ways to predict who goes on to develop MS after initial MS-like symptoms and help in identifying more effective therapies for the 100,000 people living with MS in the UK.

The paper's lead author, Clinical Research Fellow Dr Rachel Farrell, said: "All the participants in our study had previous history of infection with EBV, which has been shown in other studies and is not surprising given that a large majority of the adult population is infected with EBV.

"What was surprising is that the levels of a molecule in the blood called anti-EBNA-1 IgG, induced by the virus, were associated with the activity of MS.

"The results of this work show that those participants who had new areas of MS damage in the brain also had high levels of the anti-EBNA-1 IgG molecule in their blood.

"In addition, participants with higher levels of EBNA-1 in the bloodstream were more likely to have an increase over time in the disability associated with MS."

The researchers received funding of nearly £35,000 from the MS Society's Innovation Research grant scheme and looked at 100 participants, 50 of whom had a single MS-like attack but no diagnosis of MS, 25 people with relapsing-remitting MS and 25 with primary progressive MS.

They tested participants for evidence of EBV infection in the blood and also looked for anti-EBNA-1 IgG and other EBV induced antibodies. MRI brain scans of each participant were taken over a five year period and the scientists also measured disability progression.

The authors of the study, published in the journal Neurology, concluded that anti-EBNA-1 IgG is a potential biomarker in MS that might be useful in predicting disability and progression.

They added that the work needed to be validated in larger studies and in combination with other as yet unidentified biomarkers.

Dr Susan Kohlhaas, Research Communications Officer at the MS Society said, "We're delighted that such an interesting study has produced these valuable results that will give scientists a new avenue of MS research to explore.

"Identifying biomarkers of MS is a key area of research and this work is a stepping stone on the path to mapping out the course of the condition and potentially determining prognosis.

"People with MS find the uncertainty of what the future holds very daunting so more knowledge about what might lie in store could be a big help."

Source PR Newsire (31/08/09)

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system (CNS) that is thought to be caused by a combination of genetic and environmental factors.

To date, considerable evidence has associated Epstein-Barr virus (EBV) infection with disease development. However, it remains controversial whether EBV infects multiple sclerosis brain and contributes directly to CNS immunopathology.

To assess whether EBV infection is a characteristic feature of multiple sclerosis brain, a large cohort of multiple sclerosis specimens containing white matter lesions (nine adult and three paediatric cases) with a heterogeneous B cell infiltrate and a second cohort of multiple sclerosis specimens (12 cases) that included B cell infiltration within the meninges and parenchymal B cell aggregates, were examined for EBV infection using multiple methodologies including in situ hybridization, immunohistochemistry and two independent real-time polymerase chain reaction (PCR) methodologies that detect genomic EBV or the abundant EBV encoded RNA (EBER) ¹, respectively.

We report that EBV could not be detected in any of the multiple sclerosis specimens containing white matter lesions by any of the methods employed, yet EBV was readily detectable in multiple Epstein-Barr virus-positive control tissues including several CNS lymphomas.

Furthermore, EBV was not detected in our second cohort of multiple sclerosis specimens by in situ hybridization. However, our real-time PCR methodologies, which were capable of detecting very few EBV infected cells, detected EBV at low levels in only 2 of the 12 multiple sclerosis meningeal specimens examined.

Our finding that CNS EBV infection was rare in multiple sclerosis brain indicates that EBV infection is unlikely to contribute directly to multiple sclerosis brain pathology in the vast majority of cases.

Willis SN, Stadelmann C, Rodig SJ, Caron T, Gattenloehner S, Mallozzi SS, Roughan JE, Almendinger SE, Blewett MM, Brück W, Hafler DA, O'Connor KC.

¹ Department of Neurology, Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA.

Source: Pubmed PMID: 19638446 (05/08/09)

The cause of MS is not known but many factors, including viruses, could play a role. The authors investigated whether infections such as measles, mumps, rubella, varicella and infectious mononucleosis, or vaccinations for these infections, were involved in the development of MS. They found that infectious mononucleosis was associated with higher MS risk.

Viral infections are probably involved in the pathogenesis of multiple sclerosis (MS).

A recent cohort study in the Gothenburg population revealed no change in MS incidence associated with the introduction of the Swedish measles, mumps and rubella vaccination programmes.

The aim of the present study was to clarify whether these infections or vaccinations, and two other infections, varicella and infectious mononucleosis, influence MS risk.

We performed a population-based case-control study in Gothenburg that included 509 MS cases and 2,067 controls, born 1959-1986.

Data on infections and vaccinations were obtained from questionnaires and from child health and school health records.

We found no significant associations between measles, mumps, rubella or varicella and MS risk. These results were consistent between the two source materials.

Infectious mononucleosis was associated with significantly higher MS risk (odds ratio 2.03, 95% CI 1.52-2.73).

Overall, there was no significant association between measles-mumps-rubella (MMR) vaccination and MS risk, while those MMR vaccinated before age ten only were at significantly higher MS risk (odds ratio 4.92, 95% CI 1.97-12.20).

Those MMR vaccinated both before and after age ten had intermediate MS risk.

Infection with measles, mumps, rubella and varicella did not influence MS risk in contrast to infectious mononucleosis which conferred doubled MS risk.

The association with 'early' MMR vaccination only was an isolated finding, limited by a small number of subjects and multiple testing. Most likely this was a chance finding.

Future studies could investigate it on an a priori basis.

Ahlgren C, Torén K, Odén A, Andersen O.

Institute of Clinical Neuroscience, Sahlgrenska University Hospital, 413 45, Gothenburg, Sweden.

Source: Pubmed PMID: 19633994 (05/08/09)

Multiple sclerosis has been linked to several infectious organisms and the canine distemper virus is one of these organisms. Ongoing research could aid in curing MS.

Multiple sclerosis (MS) in people is a neurological disease with an autoimmune component and a multifactorial cause. One recent theory discussed by Dr. JA Lincoln and his associates in the August, 2008 Neurol Clin proposes that adult exposure to an infectious organism could lead to an immune response which could subsequently cause symptoms of MS. They also theorize that exposure to these infectious agents early in life could lead to protection against multiple sclerosis later in life.

The Link Between Canine Distemper Virus and Multiple Sclerosis
Dr. Lincoln and his associates have examined the Epstein-Barr virus (EBV) and the canine distemper virus (CDV) as potential candidates for playing a part in the development of multiple sclerosis. Their epidemiologic data seem to support a link between both the EBV virus and the CDV virus and the development of clinical multiple sclerosis.

•The incidence of multiple sclerosis is lower in developing countries than in more industrialized countries, leading researchers to believe that less effective sanitation, which leads to exposure to greater numbers of infectious agents, may result in fewer cases of multiple sclerosis.

•Areas experiencing lower prevalences of multiple sclerosis generally have exposure to the Epstein-Barr virus at an earlier age, whereas those areas in which infection with Epstein-Barr virus occurs later in life have higher prevalences of multiple sclerosis.

•Clusters of cases of multiple sclerosis have been documented in areas which have also experienced outbreaks with the Epstein-Barr virus.

•Some patients experiencing onset of multiple sclerosis reported increased exposure to dogs prior to onset of disease.

•Some patients experiencing multiple sclerosis had contact with dogs infected with the canine distemper virus.

•There is a possible increase in multiple sclerosis prevalence in areas where dogs are kept indoors more frequently.

This evidence is far from being conclusive of the theory of a link between multiple sclerosis and canine distemper virus or Epstein-Barr virus and more research is necessary. However, identification of an infectious agent could aid researchers in finding effective therapeutic options or even a cure for multiple sclerosis.

Source: Suite101.com Copywrite Suite101.com Media Inc. (01/06/09)

Infection with Epstein-Barr virus appears to raise the risk of developing multiple sclerosis (MS), Boston researchers report.

The findings offer the strongest evidence to date implicating the virus as a trigger for the chronic progressive autoimmune disorder of the brain and spinal cord that affects more than 350,000 Americans, says Lily Jung, MD, medical director of the neurology clinic at the Swedish Neurology Institute in Seattle. Jung was not involved in the study.

Almost everyone is infected with Epstein-Barr virus (EBV) by the time they reach adulthood. Infection early in childhood typically does not cause severe illness, although infection that occurs in adolescence often leads to mononucleosis.

Researchers have searched for decades for a viral or bacterial agent that may trigger MS in people who are genetically susceptible. Epidemiology professor Alberto Ascherio, MD, DrPH, and colleagues at the Harvard School of Public Health in Boston have published several studies suggesting that the Epstein-Barr virus may be that agent.

The new study shows "that people who are not infected with Epstein-Barr virus do not get MS," Ascherio tells WebMD. "All 100% of people who got MS in our study were infected with Epstein-Barr virus," he says.

The findings were presented at the annual meeting of the American Academy of Neurology.

MS Risk and Epstein-Barr Virus Antibodies
For the study, the researchers were granted access to more than 7 million blood specimens stored in the Department of Defense Serum Repository. The U.S. military maintains service members' medical records in electronic databases.

The researchers identified 305 service members who were diagnosed with MS plus had up to three blood samples taken prior to diagnosis. Researchers compared these blood specimens with samples from 610 people who did not develop MS but were similar in age, race, sex, and other characteristics to those who did.

The initial blood sample tested negative for EBV-fighting antibodies in 10 (3.2%) of people who developed MS and 32 (5.3%) of people who didn't. Measuring antibodies, which are proteins produced by the body to fight specific infections, is one way to determine the intensity of infection.

Importantly, all 10 of the people who developed MS went on to test positive for Epstein-Barr virus antibodies before the onset of neurological symptoms, Ascherio says. They tested EBV-positive an average of four years before symptoms of the disorder first appeared.

In contrast, only 30% of the people who didn't develop MS later tested positive for Epstein-Barr virus.

Further analysis showed about a 50-fold increased risk of MS among people with the highest levels of EBV antibodies, compared with those with the lowest levels.

Ascherio says that Epstein-Barr virus most likely works in concert with environmental factors to trigger MS in people who are genetically vulnerable to the disease. "We think one of those factors may be vitamin D deficiency," he says.

Source: WebMD © 2009 WebMD, LLC (05/05/09)

Epstein-Barr virus (EBV), the pathogen that causes mononucleosis, appears to play a role in the neurodegeneration that occurs in persons with multiple sclerosis, researchers at the University at Buffalo and the University of Trieste, Italy, have shown.

Multiple sclerosis (MS) is an autoimmune disease that can cause major disability. There currently is no cure.

"This study is one of the first to provide evidence that a viral agent may be related to the severity of MS disease process, as measured by MRI," said Robert Zivadinov, M.D., Ph.D., associate professor of neurology in UB's Jacobs Neurological Institute (JNI) and first author on the study.

The research appears in the Online First section of the Journal of Neurology, Neurosurgery and Psychiatry.

"A growing body of experimental evidence indicates that past infection with EBV may play a role in MS," said Zivadinov, "but the relationship of EBV and the brain damage that can be seen on MRI scans had not been explored."

The study involved 135 consecutive patients diagnosed with MS at the Multiple Sclerosis Center of the University of Trieste. Evaluations of the MRI scans were carried out at the University of Trieste and at the JNI's Buffalo Neuroimaging Analysis Center (BNAC), which Zivadinov directs.

The Buffalo researchers measured total brain volume, as well as the decrease in grey matter, at baseline and three years later.

Results showed that higher levels of anti-EBV antibody measured at the beginning of the study were associated with an increased loss of grey matter and total brain volume over the three-year follow-up.

The researchers now are carrying out prospective longitudinal studies in patients who experienced a condition called "clinically isolated syndrome," a first neurologic episode that lasts at least 24 hours, and is caused by inflammation/demyelination in one or more sites in the central nervous system. If a second episode occurs, the patient is diagnosed with MS.

The study will investigate the relationship of anti-EBV antibody levels to development of grey matter atrophy, neurocognitive function and disability progression over time.

UB and Trieste researchers also are investigating interactions between environment, certain genes and EBV antibodies and the association with MRI injury in MS. A paper on this work is "in press" in the Journal of Neuroimmunology.

Marino Zorzon, M.D., from the University of Trieste, is second author on the Journal of Neurology, Neurosurgery and Psychiatry study. Murali Ramanathan, Ph.D., from the UB School of Pharmacy and Pharmaceutical Sciences and the JNI, is co-corresponding author with Zivadinov. The BNAC and JNI are located in Kaleida Health's Buffalo General Hospital.

Additional contributors to the study are Bianca Weinstock-Guttman, M.D., from UB; Maurizia Serafin, M.D., from Cattinara Hospital in Trieste; and Antonio Bosco, M.D., Ph.D., Alessio Bratina, M.D., Cosimo Maggiore, M.D., Attilio Grop, Maria Antonietta Tommasi, M.D., all from the University of Trieste, and Bhooma Srinivasaraghavan, from the BNAC.

The study was supported in part by the Consortium for International Development of the University of Trieste, Italy. The researchers also gratefully acknowledge additional support from the National Multiple Sclerosis Society and a Pediatric MS Center of Excellence Center Grant.

The University at Buffalo is a premier research-intensive public university, a flagship institution in the State University of New York system and its largest and most comprehensive campus. The School of Medicine and Biomedical Sciences is one of five schools that constitute UB's Academic Health Center. UB's more than 28,000 students pursue their academic interests through more than 300 undergraduate, graduate and professional degree programs. Founded in 1846, the University at Buffalo is a member of the Association of American Universities.

Source: News-Medical.Net © 2009 News-Medical.Net (03/03/09

Background: Both human leukocyte antigen (HLA)-DRB1*15 and Epstein-Barr virus infection presenting as infectious mononucleosis (IM) are recognized as risk factors for multiple sclerosis (MS). However, their combined effect and possible interaction on MS risk is not known.

Objective: To assess the association between HLA-DRB1*15 and risk of MS in persons with and without IM.

Methods: We compared the prevalence of DRB1*15 in MS patients with (n = 76) and without (n = 1,836) IM with the corresponding distributions in blood donors with (n = 62) and without (n = 484) IM histories. This allowed us to estimate the relative risk of MS associated with DRB1*15 in the presence and absence, respectively, of previous IM. We then estimated the interaction between DRB1*15 and IM as the ratio of the two individual odds ratios.

Results: In IM-naïve individuals, DRB1*15 carried a 2.4-fold (95% confidence interval [CI], 2.0-3.0) increased MS risk. In contrast, among persons with IM history, DRB1*15 was associated with a 7.0-fold (95% CI, 3.3-15.4) increased MS risk. Thus, the MS risk conferred by HLA-DRB1*15 was 2.9 (95% CI, 1.3-6.5)-fold stronger in the presence than in the absence of IM. Combined with previous results, this result indicates that DRB1*15-positive persons with a history of IM may be at a 10.0-fold (95% CI, 6.0-17.9) increased risk of MS compared with persons who are DRB1*15 and IM-naïve.

Conclusion: DRB1*15 and IM may act in synergy causing MS.

Source: Pubmed PMID: 19153174 (04/02/09)

The cause of MS is not known but many factors are implicated including possibly viruses. The authors investigated immunity to in people with MS and found fewer immune cells, suggesting that it might somehow be involved.

OBJECTIVE: To investigate T-cell and antibody immunity to Epstein-Barr virus (EBV) in multiple sclerosis (MS).

METHODS: Immunoglobulin G (IgG) immunity to EBV nuclear antigen 1 (EBNA1) and viral capsid antigen was measured by enzyme-linked immunosorbent assays, and T-cell immunity was assessed using enzyme-linked immunospot assays to measure the frequency of peripheral blood mononuclear cells (PBMC) producing interferon-gamma in response to autologous EBV-infected B-cell lymphoblastoid cell lines (LCL) in 34 EBV-seropositive healthy subjects and 34 EBV-seropositive MS patients who had not received immunomodulatory therapy in the previous 3 months.

RESULTS: MS patients had increased levels of anti-EBNA1 IgG but a decreased frequency of LCL-specific T cells, compared to healthy subjects. Using purified populations of CD4+ T cells and CD8+ T cells we showed that the LCL-specific response resides predominantly in the CD8+ population, with a frequency 5-7 fold higher than in the CD4+ population. The decreased CD8+ T-cell response to LCL in MS was not due to decreased HLA class I expression by LCL, and LCL from MS patients could be killed normally by HLA-matched EBV-specific cytotoxic CD8+ T-cell clones from healthy subjects. Furthermore, the decreased CD8+ T-cell immunity to EBV was not due to a primary defect in the function of CD8+ T cells because EBV-specific cytotoxic CD8+ T-cell lines could be generated normally from the PBMC of MS patients.

CONCLUSION: This quantitative deficiency in CD8+ T-cell immunity to EBV might be responsible for the accumulation of EBV-infected B cells in the brains of MS patients.

Authors: Pender MP, Csurhes PA, Lenarczyk A, Pfluger CM, Burrows SR

The University of Queensland, Australia.

Source: Pubmed PMID: 19015225 (03/12/08)

The debilitating disease multiple sclerosis, which affects more than 18,000 Australians, could be prevented with a vaccine being trialled in Europe.

Researchers from the University of Queensland yesterday confirmed a link between the Epstein-Barr virus, which causes glandular fever and is carried by more than 90 per cent of the world's population, and multiple sclerosis, saying the vaccine, developed to combat glandular fever, could save thousands of lives.

But some doctors are cautious, warning that the vaccine has not been fully tested as a preventive for multiple sclerosis and does not take into account the influence of genetic and environmental factors which can also trigger the disease.

Previous studies have shown that people with a parent, child or sibling with multiple sclerosis are at a greater risk of contracting the disease themselves, and the further someone lives from the equator, the higher their risk, indicating that exposure to sunlight and vitamin D play a significant role.

In people with multiple sclerosis, the body's immune system attacks the nervous system, causing bladder and bowel dysfunction, memory loss, tremors, vision problems, hearing loss, anxiety, depression, dizziness and difficulty in walking.

There is no cure and medications can only ease symptoms.

More than 99 per cent of people with multiple sclerosis have been infected with Epstein-Barr virus during their lifetime but those who contract the virus in the first few years of life, such as children in developing countries where the virus is endemic, show no symptoms.

Those who contract the virus in their teens or early 20s, as in most Western countries, usually develop glandular fever, or infectious mononucleosis, and suffer from extreme fatigue, muscle aches, headaches, throat inflammation and weight loss. Research has shown those people are more likely to go on to develop multiple sclerosis later in life.

The study's lead researcher and a neurologist at Royal Brisbane and Women's Hospital, Michael Pender, said yesterday the glandular fever vaccine, once fully tested, could be included in Australia's childhood vaccine program for people who had a diagnosed relative.

"It may only help some people, but it is a step in the right direction," he said.

But Robert Booy, a professor in paediatrics with the National Centre for Immunisation Research at the Children's Hospital at Westmead, said yesterday it was still too early to label the Epstein-Barr virus as the main driver behind the disease, and until scientists could establish the exact cause, it was impossible to ensure a vaccine did not contain proteins which could trigger multiple sclerosis.

The scientific chairman of MS Research Australia, Bill Carroll, agreed, saying he was excited that the link between Epstein-Barr and multiple sclerosis had been further confirmed, but remained cautious about the efficacy of a vaccine.

"EBV is an important prerequisite in multiple sclerosis but it is not the only factor which causes the disease. There is also often a 20-year time lag between contracting EBV and MS, so it is impossible to say that other factors, influenced by genetics and the environment, do not come into play during that time and can still result in a person developing the disease," Dr Carroll said.

Source: The Sydney Morning Herald © 2008. The Sydney Morning Herald. (19/11/08)

Background: It remains uncertain whether the presence of serum anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in healthy individuals contributes to predict their risk of developing multiple sclerosis (MS).

Methods: Prospective, nested case-control study of more than 7 million US military personnel who have serum samples stored in the Department of Defense Serum Repository. A total of 126 MS cases and 252 controls matched by age, sex, race/ethnicity, and dates of blood collection were included in the analysis. An ELISA was used to detect IgM and IgG antibodies to MOG. Analyses were conducted with and without adjustment for serum titers of antibodies to the Epstein-Barr nuclear antigen (EBNA), which are an established risk factor for MS.

Results: The presence of anti-MOG IgG antibodies in serum was associated with an increase in risk of developing MS (relative risk for anti-MOG IgG+/IgM– vs seronegativity to both anti-MOG IgM and IgG: 2.03; 95% CI: 1.19–3.46; p = 0.01). This association, however, was attenuated and no longer significant after adjustment for titers of antibodies to EBNA, which were higher among individuals positive for anti-MOG antibodies.

Conclusion: Our findings suggest that although individuals with anti-myelin oligodendrocyte glycoprotein (MOG) antibodies have an increased risk of developing multiple sclerosis, this association may at least in part reflect cross-reactivity between MOG and Epstein-Barr nuclear antigen.

H. Wang, MD, PhD, K. L. Munger, MSc, M. Reindl, PhD, E. J. O’Reilly, MSc, L. I. Levin, PhD, MPH, T. Berger, MD, MSc and A. Ascherio, MD, DrPH

From the Departments of Nutrition (H.W., K.L.M., E.J.O., A.A.) and Epidemiology (A.A.), Harvard School of Public Health, Boston; Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School (A.A.), Boston, MA; Clinical Department of Neurology (M.R., T.B.), Innsbruck Medical University, Austria; and Division of Preventive Medicine (L.I.L.), Walter Reed Army Institute of Research, Silver Spring, MD.

Source: NEUROLOGY 2008;71:1142-1146 © 2008 American Academy of Neurology (07/10/08)

Summary

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)

A team from the Higher Health Institute (ISS) led by Francesca Aloisi and AIDS-virus Barbara Serafini have proved that a common human virus called Epstein Barr Virus (EBV) causes the brain-damaging condition.

EBV, a virus of the herpes family, had long been a suspect in MS. The ISS team has now shown how it causes the typical brain injuries found in MS.

A study on 22 MS patients demonstrated for the first time that EBV is present in the lesions called plaques that attack a nerve-insulating substance called myelin.

“It sparks the inflammatory response that causes the brain damage,” she said.

She confirmed that MS was an autoimmune disease in which the body, through its immune system, launches a defensive attack against its own tissues.

The ‘non-aggression pact’ between the body and its immune system goes awry. The immune system wrongly identifies parts of the body as a foreign threat and declares war.

In the case of MS, EBV is carried across the blood-brain barrier by lymphocytes B - the cells of the immune system that make anti-bodies, Aloisi said.

“This is an extraordinary result,” said ISS President Enrico Garaci.

“For the first time, the observation of a virus in the brain of MS patients has enabled researchers to explain both the characteristics and the mechanisms of the disease”.

“This means that from today we will be better able to assess therapies that are currently available as well as possible prevention strategies,” Garaci said.

MS is a lifelong chronic disease diagnosed primarily in young adults, who retain a virtually normal life expectancy.

Estimates suggest that there are 2.5 million people living with MS and that women are twice as likely to be affected than men.

Persons living with MS describe changes in sensations, visual problems, muscle weakness, depression, loss of bladder control, dizziness, pain and difficulties with walking, clumsiness and halting speech.

Scientists have learnt a great deal about MS in recent years. But its cause has remained elusive - until now.

Multiple sclerosis can range from relatively benign to devastating, as communication between the brain and other parts of the body is disrupted. There are also different forms of the disease.

Twenty years ago, MS sufferers faced a hopeless future of long confinement to a wheelchair within 30 years of diagnosis.

However, in the last decade, treatment has changed dramatically. There is still no cure but disease-modifying drugs now slow the progression and control symptoms of the disease.

The new Italian study is published in The Journal of Experimental Medicine.

Source: Italy © Copyright 2007 Poundbury Publishing. All rights reserved. (10/11/07)

Abstract
Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain.

Epstein-Barr virus (EBV), a ubiquitous B-lymphotropic herpesvirus, has been associated with multiple sclerosis (MS), an inflammatory disease of the central nervous system (CNS), but direct proof of its involvement in the disease is still missing.

To test the idea that MS might result from perturbed EBV infection in the CNS, we investigated expression of EBV markers in postmortem brain tissue from MS cases with different clinical courses.

Contrary to previous studies, we found evidence of EBV infection in a substantial proportion of brain-infiltrating B cells and plasma cells in nearly 100% of the MS cases examined (21 of 22), but not in other inflammatory neurological diseases. Ectopic B cell follicles forming in the cerebral meninges of some cases with secondary progressive MS were identified as major sites of EBV persistence. Expression of viral latent proteins was regularly observed in MS brains, whereas viral reactivation appeared restricted to ectopic B cell follicles and acute lesions. Activation of CD8(+) T cells with signs of cytotoxicity toward plasma cells was also noted at sites of major accumulations of EBV-infected cells.

Whether homing of EBV-infected B cells to the CNS is a primary event in MS development or the consequence of a still unknown disease-related process, we interpret these findings as evidence that EBV persistence and reactivation in the CNS play an important role in MS immunopathology.

Serafini B, Rosicarelli B, Franciotta D, Magliozzi R, Reynolds R, Cinque P, Andreoni L, Trivedi P, Salvetti M, Faggioni A, Aloisi F. Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, 00161 Rome, Italy.

Source: The Journal of Experimental Medicine (10/11/07)

Scientists say that if the results from their research with mice hold true for humans, it could redefine what makes a healthy immune system.

Most healthy adults — an estimated 80 percent to 95 percent — carry multiple herpes viruses, including one or both of those that cause mononucleosis. The researchers, led by Dr. Herbert W. "Skip" Virgin, found that some of those viruses actually rev up the immune system, protecting against a food poisoning bacterium and a bacterium that causes the plague.

Those findings suggests that herpes viruses are a crucial part of a well-tuned immune system, he said. The study appeared Thursday in the journal Nature. Virgin said scientists who are developing vaccines against the mononucleosis viruses should consider whether wiping out such infections could have negative consequences for the immune system. His group is now investigating how herpes viruses help protect against other infections.

He also is trying to determine whether herpes could get the immune system too keyed up — causing autoimmune diseases, such as lupus, multiple sclerosis or rheumatoid arthritis.

Herpes viruses come in several varieties and can cause cold sores, chicken pox and genital herpes, as well as mononucleosis.

Some of the viruses produce only a mild fever or no symptoms. Other people get very sick or die from the infections.

"These are much more live-and-relate viruses than slash-and-burn viruses," Virgin said.

Unlike flu or cold viruses, herpes viruses remain in the body for a long time, hiding out in nerve cells. The viruses rouse periodically from their dormant state. When that happens, the body makes a hormone called interferon-gamma, which sends out a red-alert against bacterial invaders.

When the body's first line of defense, immune cells called macrophages, get the alarm, they turn into ruthless bacteria-killers.

Source: azstarnet.com Copyright © 2007 (20/05/07)

While “mono” has been linked with MS before, “little is known about the characteristics of this association,” write Dr. Trine Rasmussen Nielsen, of Statens Serum Institut, Copenhagen, and colleagues.

The researchers monitored a group of 25,234 Danish patients who had had mononucleosis for the development of MS, starting on April 1, 1968 or in January the year after mononucleosis was diagnosed. The main outcome measure was the ratio of observed to expected MS cases (standardised incidence ratio).

There were 104 MS cases observed versus 45.91 MS cases expected—or 58 more cases than normal. This corresponds to a standardised incidence ratio of 2.27, or more than twice the risk of MS, Nielsen’s team reports.

The increased MS risk continued for more than 30 years after infectious mononucleosis. No differences in MS risk were seen according to sex or age, and the severity of mononucleosis did not appear to influence risk.

The investigators hypothesise that this long-term continuation of MS risk “may reflect a change in immunological status” after mononucleosis, which should be further explored.

SOURCE: Archives of Neurology, January 2007.

"Multiple sclerosis is a complicated disease, probably caused by a combination of factors," lead author Evan L. Thacker from the Harvard School of Public Health, Boston, told Reuters Health. "It is likely that some viral infections, such as infectious mono, play a role in determining whether multiple sclerosis will occur."

Similarities in the patterns of infectious mononucleosis and MS led the researchers to consider EBV as a cause of MS, Mr. Thacker and two colleagues from Harvard point out in the Annals of Neurology.

Both conditions occur in young adults, both are more prevalent in certain geographic locations and both are rare in populations in which infections occur at an early age, suggesting that late infection with EBV, evidenced by occurrence of infectious mononucleosis, is an important causal factor in MS," they explain.

However, studies that have evaluated the relationship between infectious mononucleosis and MS risk have produced inconsistent results.

Against this backdrop, the Harvard group systematically identified and statistically combined 14 relevant studies conducted in the US, Europe, and Australia to come up with an overall picture of the connection between infectious mono and MS.

"The most important observation in our study was that people who got infectious mono while growing up were about twice as likely to get multiple sclerosis later, compared to people who never got infectious mono," Thacker told Reuters Health.

"The potential implication of our observation is that some cases of multiple sclerosis could probably be averted through the prevention of infectious mono," he said. "One way to accomplish this might be to develop a safe and effective vaccine against Epstein-Barr virus."

SOURCE: Annals of Neurology, March 2006 and Reuters Health © Reuters 2006. All Rights Reserved.

The molecule is a protein called ZEBRA, which the virus brings along as it infects human cells. ZEBRA is essential to switching the virus from its latent to its active state. "During an infection, EBV inserts its own DNA into the nucleus of human cells. This information contains the codes for about 100 genes," says Christoph Müller, head of an EMBL research lab in Grenoble. "Less than 10 genes are sufficient for the virus during its latent state, whereas all others are necessary to produce new viruses and to infect new host cells. Those have to be switched on, and ZEBRA functions as the switch which turns the cell into a factory to manufacture thousands of copies of the virus."

One result is the disease infectious mononucleosis – called the "kissing disease" because EBV is transmitted in saliva – whose symptoms resemble that of a cold. But in rare cases activation of the virus also leads to EBV associated cancers, especially in people with immune deficiencies.

Researchers have focused on ZEBRA because of its ability to activate so many genes. It does so by recognizing specific strings of chemical "letters" in the DNA, docking onto them and allowing the information to be read and transformed into raw materials to make new viruses.

"A good strategy in fighting viruses is to block the activation of viral genes," says Patrice Morand, a physician at the University hospital and the IVMS. "The drugs we currently use against EBV work that way. The problem is that they only interrupt the late phase of the viral cycle. Since ZEBRA is essential to the first steps, waking the virus, blocking it would be much better."

To identify weak points of ZEBRA as potential drug targets Morand and Carlo Petosa from Müller's group created a high-resolution map of the protein's structure. Using the unique technology "platforms" that EMBL and the IVMS have set up in partnership with the neighbouring institutes, they obtained crystals of ZEBRA.

Examining these crystals with high-intensity X-rays at the European Synchrotron Radiation Facility (ESRF) in Grenoble, the scientists found that ZEBRA binds to DNA in a complex of two molecules. A detailed map of the interface between the two ZEBRA molecules revealed that one copy of ZEBRA plugs a large side chain into a deep pocket in the other. "This is an ideal type of structure to try to target with a drug," Petosa says. "If we can find a molecule to block access to the cavity, the copies wouldn't be able to bind to each other and dock onto DNA."

Morand and his colleagues carried out a close study of the pocket, which gave them good idea of what a "plug" would have to look like. The next step will be to screen likely molecules in hopes of finding an inhibitor. "We have been trying to develop an effective way to treat EBV infections for over 20 years, without major successes," Morand says. "Thanks to this partnership between medical research and structural biology that has grown on the Grenoble Polygone Scientifique campus, we are closer than ever before."

Source: ScienceDaily - Copyright © 1995-2006 ScienceDaily LLC

"Earlier studies suggested a relationship between childhood exposure to Epstein-Barr virus and the risk of developing MS. This is virtually impossible to quantify in adult MS patients, as nearly 90 per cent of the healthy adult population in Western countries has been exposed to EBV. In the paediatric patients, we can study viral exposures more easily, as children have fewer viral exposures due to their young age," said Dr. Brenda Banwell, the study's principal investigator, a Sick Kids neurologist and associate scientist, and an assistant professor in the Department of Paediatrics at the University of Toronto.

The research team found that 83 per cent of the paediatric MS patients showed evidence of a past EBV infection, compared with 42 per cent for the healthy control group. The paediatric MS patients also were less likely than the control subjects to have been exposed to herpes simplex virus. Epstein-Barr virus is very common and transmissible virus in the herpes family that causes infectious mononucleosis.

"We think the Epstein-Barr virus plays an important role in the development of MS, as the genetic code of the virus contains sequences that are identical to genetic sequences in the myelin basic protein, which is expressed in the brain, and destroyed in MS. It is conceivable that the immune system mounts a response to that genetic sequence in EBV, then sees it in myelin and targets it as well," added Dr. Banwell.

Multiple sclerosis (MS) is a disease of the brain, spinal cord, and optic nerves that can cause problems with muscle control and strength, vision, balance, sensation (such as numbness or tingling in your feet or hands), and mental functions such as thinking ( cognition) and moods.

The symptoms of MS are caused by inflammation of the central nervous system and the destruction of myelin, the protein coating that surrounds and protects nerve fibres (axons).

MS is believed to involve a complex interplay between environmental triggers (such as infections), genetic predisposition, and an abnormal autoimmune response. At least five per cent of all MS patients experience the onset of their disease before the age of 18. It is estimated that 50,000 Canadians have MS. Multiple sclerosis is the most prevalent in countries that are furthest from the equator, such as Canada, northern Europe, and Australia.

"We suspect that it is the sequence and timing of viral exposure and how this modifies an individual's immune response that is important," said Dr. Banwell. "Children with MS are the closest to the biological onset of the disease, which allows us to look at a whole host of causative factors that are very difficult to study in adults."

Other members of the research team included Dr. Suad Alotaibi (now at the Al-Sabah Hospital in Kuwait), and Julia Kennedy, Dr. Raymond Tellier, and Derek Stephens, all from The Hospital for Sick Children.

This research was supported by The Hospital for Sick Children Foundation.

The Hospital for Sick Children, affiliated with the University of Toronto, is Canada's most research-intensive hospital and the largest centre dedicated to improving children's health in the country. Its mission is to provide the best in family-centred, compassionate care, to lead in scientific and clinical advancement, and to prepare the next generation of leaders in child health. For more information, please visit http://www.sickkids.ca

Source: Copyright © 1995-2006 ScienceDaily LLC

Researchers suggest that increased levels of immune antibodies that fight Epstein-Barr Virus (EBV), the virus that causes infectious mononucleosis and other disorders, may be associated with an increased risk of developing multiple sclerosis..........

Full story from link above.

Yet again, scientists have found a firm link between the Epstein Barr Virus and multiple sclerosis.

In a study published in the prestigious Journal of the American Medical Association, scientists found that a diagnosis of MS followed on average four years after infection with the Epstein-Barr Virus.

From more than 3 million military personnel with blood samples collected between 1988 and 2000, 83 cases of MS were identified. These were tested for the Epstein-Barr virus and matched against controls.

Ref: The Journal of the American Medical Association Vol 289, No 12. 1533-1536

Another study has found a link between the Epstein-Barr virus and MS.

Harvard researchers found higher levels of immune antibodies against Epstein-Barr virus (EBV) in people who went on to develop MS than in people who did not.

EBV is one of the most common human viruses. Most people in the world become infected with it at some point during their lives. Most of the time, EBV infection is silent. But in adolescence or young adulthood, EBV can result in infectious mononucleosis (glandular fever) almost half of the time.

Researchers have been following the health of 230,000 female American nurses since 1976. They looked for evidence of exposure to EBV and other viruses, both before and after MS diagnosis. The nurses who went on to develop MS had, on average, higher levels of EBV antibodies in their blood than those who did not develop MS. The team also analyzed the blood of 126 women with MS whose blood was collected after the onset of MS - and found significantly higher levels of antibodies than in women without MS.

While EBV has been proposed as a possible infectious trigger for MS in the past, this is the first published study in which exposure to the virus was determined prior to diagnosis.

Other studies have shown associations of MS with EBV and many other viral and bacterial infections. None, including this most recent study, has been able to prove a causative link.

The Harvard team, noting that exposure to EBV is common in most adults, suggests that EBV may be one of several factors that determine MS. More research is needed to determine whether EBV has a direct role.

Ref: Journal of the American Medical Association, December 26, 2001.
Ref: InsideMS, Winter 2002, Vol. 20, Issue 1.