Epstein-Barr virus neutralizing antibody levels and risk of multiple sclerosis

Previous infection with Epstein-Barr virus (EBV) and infectious mononucleosis are established multiple sclerosis (MS) risk factors, and elevated serum titers of anti-EBV nuclear antigen (anti-EBNA) antibodies in healthy adults are strongly correlated with future MS risk. In this prospective study, we investigated the association between EBV neutralizing antibodies and MS risk. MS risk tended to be higher in individuals with high titers of neutralizing antibodies compared to those with low titers (relative risk [RR] = 2.2, 95% confidence interval [CI] 0.97-5.1). This association was attenuated after adjustment for anti-EBNA1 IgG Ab titers (RR = 1.4, 95% CI 0.5-3.5). This preliminary finding warrants further study in a larger population.     

Epstein-Barr virus and multiple sclerosis

Epstein-Barr virus (EBV) is one of the most common and successful human viruses, infecting more than 90% of the world’s adult population. Despite its strong tumorigenic potential, most virus carriers remain healthy due to maintenance of a delicate balance between the host’s immune system, which limits production of virus particles, and the virus, which persists for the duration of the host’s life. New data show that this balance is altered on a subtle level in patients with multiple sclerosis (MS) and other autoimmune diseases who show enhanced as well as less restricted T-cell and antibody responses to EBV-encoded antigens. Such quantitatively and qualitatively distinct immune responses and the virus’ unique ability to immortalize B cells as well as to continuously stimulate strong T-cell responses during persistent infection suggest a possible role for EBV in the initiation and progression of symptomatic autoimmunity. We hypothesize that EBV promotes both autoimmune B and T-cell responses. EBV gene products might stimulate cross-reactive autoimmune B cells directly or increase their survival after infection. In addition, autoimmune T cells could be maintained via molecular mimicry between autoantigens and EBV antigens, and via the Th1 polarizing cytokine milieu of protective antiviral T-cell immunity. A better understanding of how EBV and EBV-specific immune control mechanisms interfere with the evolution of autoimmunity may generate a rationale for novel EBV-targeting therapeutic strategies aimed at the prevention and more efficient treatment of autoimmune diseases.     

Epstein-Barr virus and multiple sclerosis

This review of the considerable evidence linking Epstein-Barr virus (EBV) infection to risk and disease progression in multiple sclerosis (MS) builds on the background to the virus and its interactions with the human host available in the online supplement (see supplement, available online only). The evidence for a similarity in the geographic patterns of occurrence of MS and EBV infection (with infectious mononucleosis or EBV specific serology used as surrogate markers), when reviewed critically, is very limited. There is strong evidence however that people with MS are more likely to report a past history of infectious mononucleosis (thought to represent initial EBV infection at an older age), and higher titres of EBV specific antibodies are associated with an increased risk of developing MS. Elevated levels of the latter are apparent many years before MS onset (compared with non-MS controls) and there is a dose-response relationship between MS risk and antibody titre, with antibodies to the EBV nuclear antigen-1 particularly important. The evidence in relation to EBV DNA load in blood or CSF is conflicting, as is that in relation to T cell responses to EBV. Several hypotheses that have been proposed to explain the links between EBV and MS risk are reviewed and gaps requiring further research are identified.     

Epstein-Barr virus genotypes in multiple sclerosis

Background –  Multiple sclerosis (MS) is associated with Epstein–Barr virus (EBV) infection, but the relationship between the virus and the disease is not clear. As many different types of EBV exist, it is possible that MS is caused by one particular type of EBV.
Objectives –  The aim of this study was to determine whether MS is associated with a particular genotype of EBV.
Materials and methods –  We collected blood from MS patients and controls, amplified and sequenced the latent membrane protein-1 (LMP-1) gene, and compared the groups.
Results –  We found a variety of LMP-1 sequences in both MS and controls, with no significant differences between the groups.
Conclusion –  We conclude that MS is not associated with a particular genotype of EBV.     

Epstein-Barr virus antibodies in multiple sclerosis

Serum antibody titers to Epstein-Barr virus (EBV), an agent that persists in a latent form after the initial infection, were determined in 157 patients with multiple sclerosis and in 81 control subjects. Two patients (1.3%) and five control subjects (6.2%) lacked antibodies to EBV. In the subjects with antibodies, the prevalence of high titers (greater than or equal to 1:160) was significantly greater in patients, 69 (44.5%), than in control subjects, 22 (28.9%). The geometric mean titer of antibodies to EBV was significantly higher in patients, 107.0, than in control subjects, 77.1. There was no association between antibody titers and duration or activity of the disease. These findings further support the contention that patients with multiple sclerosis have a general aberration of the immunological system.     

Epstein-Barr virus and disease activity in multiple sclerosis

OBJECTIVES: To study in relapsing-remitting (RR) multiple sclerosis (MS) whether exacerbations and brain activity as measured by magnetic resonance imaging (MRI) are associated with plasma levels of anti-Epstein Barr (EBV) antibodies and EBV DNA. METHODS: This was a prospective study with 73 RR MS patients followed for an average of 1.7 years with frequent neurological examination and blood sampling. Antibodies to various EBV proteins were measured by ELISA and plasma EBV DNA was measured by PCR. RESULTS: All MS patients had IgG antibodies to EBV (viral capsid antigen (VCA) and/or EBV nuclear antigen (EBNA)), irrespective whether samples were taken at stable disease or exacerbation. A significantly elevated percentage of the patients (48%) had antibodies against EBV antigens (early antigen, EA) that indicate active viral replication, compared with the age matched healthy controls (25%). Antibodies against a control herpesvirus, cytomegalovirus, were similar between the two groups. The percentage of EA positive individuals and EA titres did not differ between stable disease or exacerbation. Anti-VCA IgM was positive in three cases, unrelated to disease activity. Using a highly sensitive PCR on 51 samples taken at exacerbation visits, only three patients were found to have one timepoint with viraemia, and this viraemia was unrelated to disease activity. Of special note was the fact that anti-EA seropositive patients remained seropositive during follow up, with stable titres over time. We hypothesised that these patients may constitute a subgroup with higher disease activity, due to the triggering effect of a chronic attempt of the virus to reactivate. The EA positive group did not differ from the EA negative with respect to clinical disease activity or other characteristics. However, in the EA positive group, analysis with gadolinium enhanced MRI indicated more MRI disease activity. CONCLUSIONS: There was no evidence for increased clinical disease activity in the subgroup of MS patients with serological signs of EBV reactivation. However, the observation that chronic EBV reactivation may be associated with increased inflammatory activity as assessed by gadolinium enhanced MRI lesions should be reproduced in a larger and independent dataset.     

The association between multiple sclerosis and infection with Epstein-Barr virus and retrovirus

B-lymphoblastoid cell-lines may develop spontaneously in mononuclear cells from patients with multiple sclerosis, an observation rarely seen in healthy individuals. Examination of such spontaneously established B-cell lines reveal the presence of Epstein-Barr virus and retrovirus particles. We have speculated that in predisposed individuals, a dual infection with retrovirus and late acquired Epstein-Barr virus plays an aetiological role in the development of multiple sclerosis. This hypothesis is supported by a number of observations, including the finding that infection with Epstein-Barr virus may be a prerequisite for developing multiple sclerosis. The association between multiple sclerosis and infection with Epstein-Barr virus and retrovirus is evaluated in this study.     

Symptomatic Epstein-Barr virus infection and multiple sclerosis.

In a case-control study of 214 patients with multiple sclerosis, recall of infectious mononucleosis in subjects seropositive for Epstein-Barr viral capsid antigen was associated with a relative risk of 2.9 (95% CI 1.1 to 7.2). Those who reported having infectious mononucleosis before the age of 18 years had a relative risk of multiple sclerosis of 7.9 (95% CI 1.7 to 37.9). The pathogenesis of multiple sclerosis may involve an age-dependent host response to Epstein-Barr virus infection.     

Quantitative PCR for Epstein-Barr virus DNA and RNA in multiple sclerosis

BACKGROUND: Epstein-Barr virus (EBV) is associated with MS, but it is not clear whether EBV plays a role in the pathogenesis of MS. HYPOTHESIS: We hypothesized that the immune control of EBV might be defective in MS, and that reactivation of EBV might drive the immune response in MS. METHODS: We collected blood from controls and patients with MS, and measured the amounts of EBV DNA and RNA using quantitative PCR. RESULTS: We found that EBV DNA and RNA were frequently detectable in peripheral blood leukocytes from both patients with MS and normal controls. There was no significant difference between patients with MS or controls. Paired samples from a small number of subjects suggest that EBV DNA may increase before and during clinical relapse. CONCLUSIONS: We conclude that the immune control of EBV infection is similar in MS and controls, and that reactivation of EBV may correlate with MS disease activity.     

Environmental risk factors in multiple sclerosis

Objectives –  Multiple sclerosis (MS) likely results from an interaction between genetic and exogenous factors. While genetics shapes the overall population MS susceptibility, observed epidemiological patterns strongly suggest a role for the environment in disease initiation and modulation.
Results –  Findings from studies on seasonality in MS patients' birth, disease onset and exacerbations, as well as apparent temporal trends in incidence and gender ratio support an influential effect of viruses, metabolic and lifestyle factors on MS risk. Epstein–Barr virus, vitamin D status, and smoking are factors that may explain such epidemiological patterns.
Conclusions –  Further epidemiological investigations are encouraged and opportunities to use data from existing cohort studies as well as the design of new studies should be pursued. In particular, the development of new large multicentre population-based case-control studies which incorporate the study of the role of environment and genetics, including epigenetic mechanisms, in determining MS risk is proposed.     

Epstein-Barr nuclear antigen and viral capsid antigen antibody titers in multiple sclerosis

To characterize the antibody response to the Epstein-Barr virus (EBV) in MS, we studied serum anti-EBV nuclear antigen (anti-EBNA) and anti-EBV capsid antigen (anti-EBVCA) titers. Both titers were assayed in 93 age- and sex-matched pairs of MS patients and controls. Anti-EBVCA titers were measured by indirect immunofluorescence and anti-EBNA titers by anticomplement immunofluorescence. The seropositivity rate of both anti-EBVCA and anti-EBNA in MS patients was 100%, compared with 84% in controls (p less than 0.0001). Both anti-EBVCA and anti-EBNA titers were significantly higher in MS patients than in controls (p less than 0.0001). The data suggest that EBV has a significant seroepidemiologic association with MS, but they do not define what role EBV antibodies play in the pathogenesis of the disease.     

间接免疫荧光法研究EB病毒感染类型与多发性硬化发生的关系

目的 用间接免疫荧光法研究EB病毒(EBV)不同感染类型与多发性硬化(MS)发生的关系.方法 采用间接免疫荧光法检测20例MS患者和20例其他神经科疾病(OND)患者脑脊液(CSF)中抗EBV壳抗原(EBV-CA)IgG抗体、抗EBV-CA IgG抗体亲和力、抗EBV-CA IgM抗体、抗EBV早期抗原(EBV-EA)...