Epstein–Barr virus infection, B-cell dysfunction and other risk factors converge in gut-associated lymphoid tissue to drive the immunopathogenesis of multiple sclerosis: a hypothesis

Multiple sclerosis is associated with Epstein–Barr virus (EBV) infection, B-cell dysfunction, gut dysbiosis, and environmental and genetic risk factors, including female sex. A disease model incorporating all these factors remains elusive. Here, we hypothesise that EBV-infected memory B cells (MBCs) migrate to gut-associated lymphoid tissue (GALT) through EBV-induced expression of LPAM-1, where they are subsequently activated by gut microbes and/or their products resulting in EBV reactivation and compartmentalised anti-EBV immune responses. These responses involve marginal zone (MZ) B cells that activate CD4⁺ T-cell responses, via HLA-DRB1, which promote downstream B-cell differentiation towards CD11c⁺/T-bet⁺ MBCs, as well as conventional MBCs. Intrinsic expression of low-affinity B-cell receptors (BCRs) by MZ B cells and CD11c⁺/T-bet⁺ MBCs promotes polyreactive BCR/antibody responses against EBV proteins (e.g. EBNA-1) that cross-react with central nervous system (CNS) autoantigens (e.g. GlialCAM). EBV protein/autoantigen-specific CD11c⁺/T-bet⁺ MBCs migrate to the meningeal immune system and CNS, facilitated by their expression of CXCR3, and induce cytotoxic CD8⁺ T-cell responses against CNS autoantigens amplified by BAFF, released from EBV-infected MBCs. An increased abundance of circulating IgA⁺ MBCs, observed in MS patients, might also reflect GALT-derived immune responses, including disease-enhancing IgA antibody responses against EBV and gut microbiota-specific regulatory IgA⁺ plasma cells. Female sex increases MZ B-cell and CD11c⁺/T-bet⁺ MBC activity while environmental risk factors affect gut dysbiosis. Thus, EBV infection, B-cell dysfunction and other risk factors converge in GALT to generate aberrant B-cell responses that drive pathogenic T-cell responses in the CNS.