Why Is <scp>MS</scp> a More Frequent Complication of <scp>EBV</scp> Infection in Females?

Multiple sclerosis (MS) is a T helper (Th) cell-mediated disease that targets central nervous system (CNS) white matter. This disease affects three times more females than males. For many years, the etiology of MS was not well understood and the exact nature of the autoimmune reaction was speculative. It has now become clear that MS is a rare complication of Epstein-Barr Virus (EBV) infection and that the virus induces an EBV nuclear antigen (EBNA-1)-specific T and B cell response that is cross-reactive against a number of CNS antigens including Glial cell-associated membrane protein (GlialCAM), Anoctamin-2 (Ano-2), myelin basic protein (MBP), and alpha-B-crystallin (CRYAB). Recent studies have clarified the involvement of the major human leukocyte antigen (HLA) MS risk haplotype, HLA-DR15, in sustaining autoreactive T cell responses and its interaction with EBV. Here, we overview this literature through the lens that MS is a disease that affects females more than males. We describe how EBV seroprevalence and the incidence of infectious mononucleosis are greater in females during the early teen years, a period of increased MS susceptibility. We overview how females with MS develop greater levels of EBNA-1-cross-reactive autoantibodies and show greater myelin-specific T helper 1 (Th1) cells in peripheral blood. Finally, we provide evidence that EBV-infected B cells may achieve a greater state of latency in females and discuss how this may perpetuate CNS autoimmunity. At the same time, our literature search identified many missed opportunities to learn about sex differences in MS. Our hope is that this review will motivate researchers in the future to disaggregate data by sex to accelerate discoveries in this disease.