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

Abstract

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.

Proteomics reveal biomarkers for diagnosis, disease activity and long-term disability outcomes in multiple sclerosis

“…Furthermore, CD27 and CD70 play a role in a costimulatory process that allows B cells to maintain activation of pathogenic T cells 66 . Moreover, the network shows the importance of MZB1, which may be involved in MS pathology through activating autoproliferative CD4 + T cells and pathogenic B cells in CSF and is thought to potentially trigger B cell response against Epstein-Barr virus (EBV) proteins 67 . Among the intermediate proteins, we identified a group of proteins that were not included in our initial protein panels (CCR1, CCR5, ITGAL, LCP2, SDCBP), whereof the proteins ITGAL, LCP2, and SDCBP can be detected in blood by mass spectrometry 68 .…”

Proteomics profiling reveals biomarkers for predicting diagnosis, disease activity and long-term disability outcome in multiple sclerosis

“…Furthermore, CD27 and CD70 play a role in a costimulatory process that allows B cells to maintain activation of pathogenic T cells 56 . Moreover, the network shows the importance of MZB1, which may be involved in MS pathology through activating autoproliferative CD4 + T cells and pathogenic B cells in CSF and is thought to potentially trigger B cell response against Epstein-Barr virus (EBV) proteins 57 . Among the intermediate proteins, we identified a group of proteins that were not included in our initial protein panels (CCR1, CCR5, ITGAL, LCP2, SDCBP), whereof the proteins ITGAL, LCP2, and SDCBP can be detected in blood by mass spectrometry 58 .…”

The adaptation model of immunity: A new insight into aetiology and treatment of multiple sclerosis

“…The SNS model proposes that breakage of immunological tolerance to the CNS, perhaps due to cross-reactivity of the immune response to viral infections such as EBV and those to myelin basic protein (MBP), 1 causes MS; thus, immune suppressive drugs are recommended to alleviate inflammation. Although some studies suggest that EBV is associated with MS by mimicking neuronal self-antigen, 29,30 this could be only guilt by association as over 95% of adults are exposed to EBV, yet the vast majority do not get MS. 31 In fact, while 95% of the world's population are infected with EBV, incidence of MS accounts for only 0.035% worldwide. 32,33 A study that failed to show any correlation between EBV and MS 34 has been ignored because these observations cannot be explained by the SNS model.…”