EBV as the “gluten of MS” hypothesis provides a rationale for trialing antiviral therapies

Abstract

Infection with the Epstein-Barr virus (EBV) has long been established as an environmental factor associated with multiple sclerosis (MS) risk ( Thacker et al., 2006 Thacker EL Mirzaei F Ascherio A. Infectious mononucleosis and risk for multiple sclerosis: a meta-analysis. Ann. Neurol. 2006; 59: 499-503https://doi.org/10.1002/ana.20820 Crossref PubMed Scopus (362) Google Scholar , Munger et al., 2011 Munger KL Levin LI O’Reilly EJ Falk KI Ascherio A Anti-Epstein-Barr virus antibodies as serological markers of multiple sclerosis: a prospective study among United States military personnel. Mult. Scler. 2011; 17: 1185-1193https://doi.org/10.1177/1352458511408991 Crossref PubMed Scopus (140) Google Scholar , Levin et al., 2010 Levin LI Munger KL O’Reilly EJ Falk KI Ascherio A Primary infection with the Epstein-Barr virus and risk of multiple sclerosis. Ann. Neurol. 2010; 67: 824-830 PubMed Google Scholar , Ascherio and Munger, 2007 Ascherio A Munger KL. Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann. Neurol. 2007; 61: 288-299https://doi.org/10.1002/ana.21117 Crossref PubMed Scopus (756) Google Scholar ). More recent epidemiological evidence has cemented its role as the likely causal agent for the development of MS ( Bjornevik et al., 2022 Bjornevik K Cortese M Healy BC et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022; 375: 296-301https://doi.org/10.1126/science.abj8222 Crossref PubMed Scopus (142) Google Scholar ). However, the current evidence linking EBV to MS does not distinguish between EBV as merely a trigger for development of disease vs. an actual contributor to disease pathogenesis after diagnosis. The mechanisms by which EBV infection leads to MS remain elusive, and an extensive list of hypotheses has been proposed to date ( Bar-Or et al., 2020 Bar-Or A Pender MP Khanna R et al. Epstein-Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies. Trends Mol. Med. 2020; 26: 296-310https://doi.org/10.1016/j.molmed.2019.11.003 Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar ). A non-exhaustive summary of suggested models includes (1) the hit-and-run hypothesis, where the initial EBV infection created a milieu for autoimmunity but EBV itself is no longer driving the disease, (2) the two-hit hypothesis which requires a second exposure to an unknown environmental factor timed synchronously to interact with EBV, (3) the direct infection of central nervous system (CNS) antigen-specific B cells where EBV latent proteins modify B cells to become autoreactive, (4) cross-reactivity where EBV antigens associated with MS (e.g. EBNA-1) are erroneously mistaken by the immune system as self and (5) bystander damage where a vigorous response to EBV creates toxic mediators which preferentially cause oligodendrocyte cell death. To date, no single hypothesis has been sufficient to explain MS.