Epstein–Barr virus in the development of multiple sclerosis

In contrast to previous smaller studies, Aloisi and colleagues have recently reported the presence of large numbers of Epstein–Barr virus (EBV) infected B cells in the brains of a large majority of patients with multiple sclerosis (MS) [1]. These cells were more numerous in areas with active inflammatory infiltrates, where cytotoxic CD8+ T cells displaying an activated phenotype were seen contiguous to the EBV-infected cells. Independent confirmation of these findings would lead to the beginning of a new era in MS research. Whereas these pathological findings alone may provide only suggestive evidence for a causal role of EBV in MS, their convergence with the epidemiological evidence accumulated over the past several years [2] is so striking that noncausal explanations, such as infiltration of EBV-infected B cells being a secondary phenomenon, would become improbable. The prevailing view that MS is a T-cell mediated autoimmune disease will have to be modified to accommodate EBV-infected B cells on the central stage.

That MS is most likely a rare complication of a widespread infection was postulated over 40 years ago, largely on the basis of its geographical distribution, evidence of a change in risk among migrants [3] and the possible, albeit controversial, occurrence of epidemics [4]. Many years elapsed, however, without a specific infectious agent being identified, and multiple unsubstantiated claims implicating a broad variety of microorganisms led to widespread skepticism. An alternative hypothesis emerged, often named the ‘hygiene hypothesis’, according to which protection against MS is conferred by persistent effects on the immune responses of a heavy burden of microbial or parasitic infections in childhood [5]. This would explain the low rates of MS among individuals born in developing countries, even after migration to high-risk areas, and the positive correlations of MS risk with socioeconomic status, education, childhood infections at a late age and other markers of a low infection burden in childhood. However, this hypothesis does not explain the critical finding that individuals who are not infected with EBV infection, despite having par excellence a low burden of childhood infections, have an extremely low MS risk. The significance of this finding has long gone unappreciated, because the rarity of EBV negativity in adults reduced the power of individual studies, and the consistency and strength of the association became clear only in meta-analyses [2,6]. An additional concern was the possibility that EBV-negative individuals are coincidentally genetically resistant to both EBV infection and MS, but this explanation is virtually ruled out by the low MS risk in EBV-negative children – most of whom will be infected with EBV before adulthood and are thus genetically susceptible – compared with EBV-positive children [7,8]. The integration of these findings with the observation that mononucleosis, which is usually the expression of a primary EBV infection during adolescence or adulthood, is associated with a two- to threefold increase in the risk of MS [9,10], provides consistent and compelling evidence that EBV infection is a strong risk factor for MS – infection in childhood increases MS hazard by eight- to tenfold, whereas infection later in life increases the hazard by 20- to 30-fold.

To better understand the nature of the relation between EBV and MS, we [11–13] and others [14] have examined the temporal relation between antibody responses to EBV and MS onset in longitudinal studies. The most consistent finding is that plasma antibody titers against the EBV nuclear antigen-1 (EBNA-1) increase several years before the onset of neurological symptoms of MS. These antibodies in patients with mononucleosis appear only during convalescence and then persist at stable levels for several decades, and are thus a marker of previous EBV infection. Among individuals who will develop MS, a secondary (i.e., not due to primary EBV infection) increase in anti-EBNA-1 titers seems to occur at some point between 17 and 29 years of age [12]. Since anti-EBNA-1 titers correlate with cellular immunity to EBV, this increase may reflect a reactivation of T-cell immune responses to EBV [15]. Whether this reactivation is caused by re-infection with EBV itself or with other exogenous or endogenous factors remains unknown. It has been recently reported that a substantial proportion of healthy individuals carry more than one EBV strain [16], but it is uncertain whether these were acquired simultaneously or sequentially, and there are no data on antibody responses following reinfection with a different EBV strain.“...evidence from pathological and epidemiological studies suggests that prevention of EBV infection would result in a marked decline in MS incidence.”

Although the epidemiology of mononucleosis and MS are strikingly similar [17], some critical aspects of MS epidemiology are not easily explained by EBV infection [2]. Among these, the most notable is the decrease in MS risk among migrants from high to low MS risk areas [3]. Although migration in early childhood could conceivably afford some protection by anticipating age at EBV infection, no protection would be expected among individuals who migrate at later ages. By contrast, a decrease in MS risk seems to be associated with migration up to 15 years of age and, in one study, even with migration during adulthood [18]. Furthermore, the MS epidemics in the Faroe Islands cannot be explained by EBV, because almost certainly EBV was ubiquitous in the Faroe Islands, as it is in all other human populations investigated [4]. One possibility is that the EBV strains in areas of low MS incidence are less likely to cause MS. Alternatively, other infectious or non-infectious factors may modulate the results of EBV infection. Neither of these explanations, however, contradicts the strong association between EBV infection and MS risk.

The combined evidence from pathological and epidemiological studies suggest that prevention of EBV infection would result in a marked, probably tenfold, decline in MS incidence. Considering that mononucleosis itself is a major cause of morbidity, and that EBV may also increase risk of systemic lupus erythematosus [19] (and perhaps other autoimmune diseases), ongoing efforts to develop a vaccine that prevents infection are worthwhile [20]. Monitoring the long-term effects of the vaccine, however, would be important, because we cannot exclude the possibility that the effects on the immune system of persistent EBV infection still have some unknown beneficial effects and because a partially-effective vaccine could delay age at EBV infection and paradoxically increase incidence of both mononucleosis and MS. What about the treatment of MS? The results of three placebo-controlled trials of the antiviral alacyclovir or its precursor valacyclovir suggested overall a non-significant benefit in the treated patients [21–23], but these studies were too small to be conclusive and alacyclovir does not decrease the number of latently infected B cells. Currently, several new drugs for MS treatment are in the pipeline, but none are an antiviral nor have they been developed taking into account the presence and probable pathogenic role of EBV-infected B cells in the CNS [24]. Attempts to confirm the presence of EBV-infected B cells in the brains of most MS patients and the relation between these cells and MS pathology are ongoing in different laboratories. Meanwhile, perhaps pharmaceutical companies should start warming to the idea that MS could, after all, be a rare complication of EBV infection and that this may be important in drug development.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.