Molecular mimicry: does it explain how EBV causes MS?
EBV & host genetic predispositions increase your risk of MS by 260x and the presence of antibody responses against three or more cross-reactive peptides by up to 1,366x.
When applying epidemiological principles, the association between Epstein-Barr virus (EBV) infection and the development of multiple sclerosis (MS) is likely to be causal, as I have previously discussed. This will lead to MS prevention studies to see whether or not an EBV vaccine to prevent infectious mononucleosis (IM) will reduce the incidence of MS.
The billion-dollar question is how EBV causes MS. Many immunologists think it is driven by molecular mimicry, i.e., an EBV protein fools the immune system into making a mistake, and instead of fighting the infection, it attacks itself.
Two controversial papers from Austria have been published in the last 12 months (see below). I have been asked to comment on them several times but have been reluctant up until now.
This group has investigated the link between EBV infection and the development of MS, focusing on how the immune system's response to EBV might trigger autoimmunity in the central nervous system (CNS).
The research highlights a specific mechanism involving molecular mimicry, where antibodies generated against the EBV protein, EBNA-1, mistakenly attack similar proteins found in the CNS. This cross-reactivity is particularly notable with antibodies against the EBNA-1 region EBNA381-452, which is significantly higher in MS patients than healthy controls.
Key findings that support the association between EBV and MS:
Higher antibodies against specific regions of EBNA-1, mainly those cross-reactive with CNS proteins, are observed in people with MS (pwMS).
PwMS patients display an accumulation of immune responses targeting both EBNA-1 and the cross-reacting CNS proteins (CNS-derived glial cell adhesion molecule or GlialCAM, α-crystallin B chain or CRYAB, myelin basic protein or MBP, and anoctamin 2 or ANO2). These include antibodies, B cells, and T cells specific to these targets.
Healthy individuals with high EBNA-1 antibody levels who did not develop MS often exhibited potent protective immune mechanisms. These primarily involve cytotoxic NKG2C+ and NKG2D+ NK cells capable of eliminating cells displaying cross-reactive CNS proteins. NK cells are part of the innate immune system and fight viruses.
PwMS were more likely to have genetic variants, such as the KLRC2 deletion variant, which weakens NKG2C+ NK cell responses.
Certain EBV variants encoding specific latent membrane protein 1 (LMP-1) peptides (GGDPHLPTL and GGDPPLPTL) were frequently found in pwMS and are associated with HLA-E upregulation and subsequent immune evasion.
Infection with specific cytomegalovirus (CMV) variants encoding particular UL40 peptides can contribute to protection from MS by boosting NKG2C+ NK cell responses. CMV is another herpes virus and has been shown to protect against MS in other studies.
EBV reactivation in GlialCAM370–389-specific immune cells was observed in pwMS. This reactivation potentially contributes to HLA-E upregulation, mediated by IL-27 secretion, further promoting immune evasion.
The authors report in the first paper that these defined virus and host genetic pre-dispositions are associated with an up to 260x increased risk of MS. In the second paper, the presence of high levels of anti-EBNA-specific antibody responses against three or more cross-reactive peptide regions are associated with a 1,366x increased risk for the development of MS. These findings need to be confirmed as they have the potential to allow the early identification of people at risk for MS and could be included in the extended MS endophenotype. The antibody assays and levels could be used to get a read-out early on MS prevention strategies, i.e. a successful MS preventive treatment should blunt these antibody responses or, better still, prevent them from occurring in the first place.
Early observations
It is remarkable how many of the study subjects who developed MS had IM (75%), and those who seroconverted asymptomatically had an episode of EBV reactivation to allow EBV viral detection and DNA sequencing. 100% of subjects had detectable EBV virus in their peripheral blood, which allowed DNA sequencing of EBV’s LMP gene.
These results are much higher than what is found in other studies. Most epidemiology studies only report an IM rate of about 20-30% in adult seronegative subjects who seroconvert with follow-up. It is reported that subjects who seroconvert asymptomatically uncommonly have detectable EBV reactivation in the peripheral blood over time. This has been our experience.
The 270 pwMS in this study were identified by linking an EBV seroconversion database of ~25,000 subjects with the Vienna Multiple Sclerosis Database (VMSD). Most people in the seroconversion database had IM (~81%). The remaining participants (~19%) were included due to an EBV seroconversion in the absence of reported symptoms of IM. However, they had several follow-up plasma samples from these subjects, during which the EBV seroconversion occurred.
Two hundred seventy subjects out of ~25,000 subjects give an MS incidence of about 1%, which is about what you would expect as the lifetime risk of MS in individuals with a history of IM. The incidence of MS in this study is over a 10-12-year period; therefore, it is much higher than expected. This cohort of subjects is very different from the general population.
I need some help from the immunologists and virologists regarding the methods, but a lack of negative controls is an issue. I suppose the investigators went for the jugular and focused on EBV’s EBNA-1. It would have been great to see other viruses and other sequences tested. There seem to be no specific differences between individual EBNA-1 or CNS-derived peptide-specific antibody levels that differentiate pwMS from healthy controls; the combination of levels is the differentiator. This, to me, makes it difficult to explain things on molecular mimicry. Surely, the latter would be black-and-white rather than grey? In autoantibody-mediated diseases, the pathogenic or disease-causing autoantibody is usually absent in healthy controls.
An increased risk of 1,366x is genuinely remarkable and needs replicating. I am sure several groups will be trying to do this. Groups in Harvard, San Francisco, New York and Sweden will have the samples to reproduce this work. If I were a betting man, I would give odds on these results being reproduced, but I am not.
A counterfactual
Suppose this combination of antibody assays was available to you. Would you want to test your immediate family members to see if they were at high risk of getting MS compared to the general population? And if yes, what would you do about it? In the future, I sincerely hope both these options become available, i.e. an accurate MS risk calculator and an intervention to reduce the risk.
Papers
Multiple sclerosis (MS) is a demyelinating disease of the CNS. Epstein-Barr virus (EBV) contributes to the MS pathogenesis because high levels of EBV EBNA386-405-specific antibodies cross react with the CNS-derived GlialCAM370-389. However, it is unclear why only some individuals with such high autoreactive antibody titers develop MS. Here, we show that autoreactive cells are eliminated by distinct immune responses, which are determined by genetic variations of the host, as well as of the infecting EBV and human cytomegalovirus (HCMV). We demonstrate that potent cytotoxic NKG2C+ and NKG2D+ natural killer (NK) cells and distinct EBV-specific T cell responses kill autoreactive GlialCAM370-389-specific cells. Furthermore, immune evasion of these autoreactive cells was induced by EBV-variant-specific upregulation of the immunomodulatory HLA-E. These defined virus and host genetic pre-dispositions are associated with an up to 260-fold increased risk of MS. Our findings thus allow the early identification of patients at risk for MS and suggest additional therapeutic options against MS.
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Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have problems, please tell your healthcare professional, who will be able to help you.
From your perspective ('I'me in a corner') re EBV it looks convincing. But there is 'something missing' A very similar presentation can be made for HHV6, another Herpes virus that 'lives' latent and occasionally activating almost exclusively in immune cells. It is inevitable that when there is immune reactivity these viruses are dragged into the events, and appear to be implicated. But are they?......really? There is something else going on 'that is missing' and we must be open to suprises. There must be a case for a serious symposium to thrash out these questions and look for the missing pieces?
The evidence on the role of EBV in the pathogenesis of MS is overwhelming. Yet studies on antivirals (e.g. tenofovir) in MS are interrupted due to lack of funding. As a doctor I don't like conspiracy theories but I'm starting to be disappointed by the willful blindness of part of the pharmaceutical system