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.

Autor: Leffler J; Telethon Kids Institute University of Western Australia Perth WA Australia., Trend S; Telethon Kids Institute University of Western Australia Perth WA Australia.; Perron Institute for Neurological and Translational Science University of Western Australia Perth WA Australia., Hart PH; Telethon Kids Institute University of Western Australia Perth WA Australia., French MA; School of Biomedical Sciences University of Western Australia Perth WA Australia.; Immunology Division PathWest Laboratory Medicine Perth WA Australia.
Jazyk: angličtina
Zdroj: Clinical & translational immunology [Clin Transl Immunology] 2022 Oct 31; Vol. 11 (11), pp. e1418. Date of Electronic Publication: 2022 Oct 31 (Print Publication: 2022).
DOI: 10.1002/cti2.1418
Abstrakt: 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.
Competing Interests: The authors declare no conflict of interest.
(© 2022 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje