Gut-educated IgA plasma cells defend the meningeal venous sinuses

Fitzpatrick, Zachary; Frazer, Gordon L.; Ferro, A; Clare, Simon; Bouladoux, Nicolas; Ferdinand, John R.; Tuong, Zewen Kelvin; Negro-Demontel, María Luciana; Kumar, Nitin; Suchánek, Ondřej; Tajsic, Tamara; Harcourt, Katherine; Scott, Kirsten M.; Bashford-Rogers, Rachel; Helmy, Adel; Reich, Daniel S.; Belkaid, Yasmine; Lawley, Trevor D.; McGavern, Dorian B.; Clatworthy, Menna R.

doi:10.1038/s41586-020-2886-4

Cited by 199 publications

(225 citation statements)

References 41 publications

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Section: Figurementioning

confidence: 99%

“…In the latest issue of Nature Fitzpatrick et al 6 . report for the first time a critical role for humoral immunity in the meninges, which acts as a protective barrier against microbial invasion 6 . The authors discovered that both mouse and human meninges contain both B cells and mature plasma cells at steady state, which increased in abundance in aged animals.…”

Section: Figurementioning

confidence: 99%

“…Strikingly, the authors found that disruption of the intestinal barrier (where IgA plasma cells are classically enriched) increased the number of these cells in the meninges, suggesting a potential link between these two sites. Indeed, Fitzpatrick et al 6 . found that the IgA plasma cells in the meninges were dependent on the presence of resident gut commensals and that developing B cells and plasma cells are seemingly educated in the intestine prior to residing in the meninges.…”

Section: Figurementioning

confidence: 99%

“…Furthermore, C. albicans is a dimorphic fungus (can grow in yeast or hyphal form) and these generate differing downstream immunity and pathogenesis 9 . As the authors suggest that IgA plasma cells may originate in the intestine, 6 these findings raise the possibility that cross‐reactive or antigen‐specific IgA generated in the gut may recognize both commensal and invasive C. albicans (majority of which will be in yeast form) 9 . Yet, whether meningeal IgA is uniquely effective against invasive hyphal forms, possibly via boosting microglial responses, remains to be determined.…”

Section: Figurementioning

confidence: 99%

“…In this context, Fitzpatrick et al . demonstrated the presence of IgA + plasma cells in the meninges was lost in naive T‐cell deficient and germ‐free mice, suggesting that IgA + plasma cells present in the central nervous system are generated through T‐cell‐dependent mechanisms and dependent on intestinal commensal microbes 6 . Indeed, selective colonization of germ‐free mice with segmented filamentous bacteria, but not skin‐dwelling microbes, was sufficient to restore IgA + plasma cells within the meninges.…”

Section: Figurementioning

confidence: 99%

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B cells on the brain: meningeal IgA and a novel gut–brain firewall

2020

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Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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B cells on the brain: meningeal IgA and a novel gut–brain firewall

2020

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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

et al. 2022

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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.

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Therapeutic targeting of gut‐originating regulatory B cells in neuroinflammatory diseases

Neziraj,

Siewert,

Pössnecker

et al. 2023

Eur J Immunol

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Regulatory B cells (Bregs) are immunosuppressive cells that support immunological tolerance by the production of interleukin (IL)‐10, IL‐35, and transforming growth factor β (TGF‐β). Bregs arise from different developmental stages in response to inflammatory stimuli. In that regard, mounting evidence points towards a direct influence of gut microbiota on mucosal B cell development, activation, and regulation in health and disease. While an increasing number of diseases are associated with alterations in gut microbiome (dysbiosis), little is known about the role of microbiota on Breg development and induction in neuroinflammatory disorders. Notably, gut‐originating, IL‐10‐ and immunoglobulin A (IgA)‐producing regulatory plasma cells have recently been demonstrated to egress from the gut to suppress inflammation in the central nervous system (CNS) raising fundamental questions about the triggers and functions of mucosal‐originating Bregs in systemic inflammation. Advancing our understanding of regulatory B cells in neuroinflammatory diseases could lead to novel therapeutic approaches.Here, we summarize main aspects about regulatory B cell differentiation and functions and evidence about their involvement in neuroinflammatory diseases. Further, we highlight current data of gut‐originating regulatory B cells and their microbial interactions and discuss future microbiota‐/regulatory B cell‐targeted therapies in immune‐mediated diseases.This article is protected by copyright. All rights reserved

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Gut-educated IgA plasma cells defend the meningeal venous sinuses

Cited by 199 publications

References 41 publications

B cells on the brain: meningeal IgA and a novel gut–brain firewall

B cells on the brain: meningeal IgA and a novel gut–brain firewall

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

Therapeutic targeting of gut‐originating regulatory B cells in neuroinflammatory diseases

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