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Why Is MS a More Frequent Complication of EBV Infection in Females?
Shannon E Dunn1,2,3, Nuria Alvarez-Sanchez4, Lawrence Steinman5
1Sunnybrook Research Institute, Toronto, Ontario, Canada.
Abstract:
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.
Insights
Multiple sclerosis (MS) is linked to Epstein-Barr Virus (EBV) infection, with females experiencing higher rates. EBV triggers immune responses cross-reactive to CNS antigens, potentially explaining sex differences in MS pathogenesis.
Area of Science:
- Neuroimmunology
- Sex Differences in Disease
- Viral Immunology
Background:
- Multiple sclerosis (MS) is a T helper cell-mediated autoimmune disease targeting CNS white matter.
- MS affects females three times more often than males, with unclear etiology.
- Epstein-Barr Virus (EBV) infection is a known trigger for MS, inducing cross-reactive immune responses.
Purpose of the Study:
- To review the literature on MS pathogenesis, focusing on sex differences.
- To explore the role of EBV in MS, particularly in relation to female susceptibility.
- To highlight the need for sex-disaggregated data in MS research.
Main Methods:
- Literature review of studies on MS, EBV, and sex differences.
- Analysis of EBV seroprevalence and infectious mononucleosis incidence in females.
- Examination of autoantibody and T cell responses in females with MS.
Main Results:
- Females exhibit higher EBV seroprevalence and infectious mononucleosis rates during peak MS susceptibility years.
- Females with MS show increased EBNA-1 cross-reactive autoantibodies and myelin-specific T helper 1 cells.
- EBV-infected B cells may establish greater latency in females, potentially perpetuating CNS autoimmunity.
Conclusions:
- Sex differences in EBV infection and immune responses contribute to MS pathogenesis.
- Understanding these sex-based mechanisms is crucial for developing targeted MS therapies.
- Future MS research must disaggregate data by sex to accelerate discoveries.
