Dataset Information

Gut microbiota-specific IgA⁺ B cells traffic to the CNS in active multiple sclerosis.

ABSTRACT: Changes in gut microbiota composition and a diverse role of B cells have recently been implicated in multiple sclerosis (MS), a central nervous system (CNS) autoimmune disease. Immunoglobulin A (IgA) is a key regulator at the mucosal interface. However, whether gut microbiota shape IgA responses and what role IgA⁺ cells have in neuroinflammation are unknown. Here, we identify IgA-bound taxa in MS and show that IgA-producing cells specific for MS-associated taxa traffic to the inflamed CNS, resulting in a strong, compartmentalized IgA enrichment in active MS and other neuroinflammatory diseases. Unlike previously characterized polyreactive anti-commensal IgA responses, CNS IgA cross-reacts with surface structures on specific bacterial strains but not with brain tissue. These findings establish gut microbiota-specific IgA⁺ cells as a systemic mediator in MS and suggest a critical role of mucosal B cells during active neuroinflammation with broad implications for IgA as an informative biomarker and IgA-producing cells as an immune subset to harness for therapeutic interventions.

SUBMITTER: Probstel AK

PROVIDER: S-EPMC8043673 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Gut microbiota-specific IgA<sup>+</sup> B cells traffic to the CNS in active multiple sclerosis.

Pröbstel Anne-Katrin AK Zhou Xiaoyuan X Baumann Ryan R Wischnewski Sven S Kutza Michael M Rojas Olga L OL Sellrie Katrin K Bischof Antje A Kim Kicheol K Ramesh Akshaya A Dandekar Ravi R Greenfield Ariele L AL Schubert Ryan D RD Bisanz Jordan E JE Vistnes Stephanie S Khaleghi Khashayar K Landefeld James J Kirkish Gina G Liesche-Starnecker Friederike F Ramaglia Valeria V Singh Sneha S Tran Edwina B EB Barba Patrick P Zorn Kelsey K Oechtering Johanna J Forsberg Karin K Shiow Lawrence R LR Henry Roland G RG Graves Jennifer J Cree Bruce A C BAC Hauser Stephen L SL Kuhle Jens J Gelfand Jeffrey M JM Andersen Peter M PM Schlegel Jürgen J Turnbaugh Peter J PJ Seeberger Peter H PH Gommerman Jennifer L JL Wilson Michael R MR Schirmer Lucas L Baranzini Sergio E SE

Science immunology 20201101 53

Changes in gut microbiota composition and a diverse role of B cells have recently been implicated in multiple sclerosis (MS), a central nervous system (CNS) autoimmune disease. Immunoglobulin A (IgA) is a key regulator at the mucosal interface. However, whether gut microbiota shape IgA responses and what role IgA<sup>+</sup> cells have in neuroinflammation are unknown. Here, we identify IgA-bound taxa in MS and show that IgA-producing cells specific for MS-associated taxa traffic to the inflamed ...[more]

PMID: 33219152

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Project description:The mechanism underlying the progression of relapsing-remitting multiple sclerosis to secondary progressive multiple sclerosis (SPMS), characterized by accumulating fixed disability, is yet to be fully understood. Although alterations in the gut microbiota have recently been highlighted in multiple sclerosis pathogenesis, the mechanism linking the altered gut environment with the remote CNS pathology remains unclear. Here, we analyse human CD4+ memory T cells expressing the gut-homing chemokine receptor CCR9 and found a reduced frequency of CCR9+ memory T cells in the peripheral blood of patients with SPMS relative to healthy controls. The reduction in the proportion of CCR9+ cells among CD4+ memory T cells (%CCR9) in SPMS did not correlate with age, disease duration or expanded disability status scale score, although %CCR9 decreased linearly with age in healthy controls. During the clinical relapse of both, relapsing-remitting multiple sclerosis and neuromyelitis optica, a high proportion of cells expressing the lymphocyte activating 3 gene (LAG3) was detected among CCR9+ memory T cells isolated from the CSF, similar to that observed for mouse regulatory intraepithelial lymphocytes. In healthy individuals, CCR9+ memory T cells expressed higher levels of CCR6, a CNS-homing chemokine receptor, and exhibited a regulatory profile characterized by both the expression of C-MAF and the production of IL-4 and IL-10. However, in CCR9+ memory T cells, the expression of RORγt was specifically upregulated, and the production of IL-17A and IFNγ was high in patients with SPMS, indicating a loss of regulatory function. The evaluation of other cytokines supported the finding that CCR9+ memory T cells acquire a more inflammatory profile in SPMS, reporting similar aspects to CCR9+ memory T cells of the elderly healthy controls. CCR9+ memory T cell frequency decreased in germ-free mice, whereas antibiotic treatment increased their number in specific pathogen-free conditions. Here, we also demonstrate that CCR9+ memory T cells preferentially infiltrate into the inflamed CNS resulting from the initial phase and that they express LAG3 in the late phase in the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. Antibiotic treatment reduced experimental autoimmune encephalomyelitis symptoms and was accompanied by an increase in CCR9+ memory T cells in the peripheral blood. Antibodies against mucosal vascular addressin cell adhesion molecule 1 (MADCAM1), which is capable of blocking cell migration to the gut, also ameliorated experimental autoimmune encephalomyelitis. Overall, we postulate that the alterations in CCR9+ memory T cells observed, caused by either the gut microbiota changes or ageing, may lead to the development of SPMS.

Dataset Information

Gut microbiota-specific IgA⁺ B cells traffic to the CNS in active multiple sclerosis.

Publications

Gut microbiota-specific IgA<sup>+</sup> B cells traffic to the CNS in active multiple sclerosis.

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OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

Gut microbiota-specific IgA+ B cells traffic to the CNS in active multiple sclerosis.

Publications

Gut microbiota-specific IgA<sup>+</sup> B cells traffic to the CNS in active multiple sclerosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Gut microbiota-specific IgA⁺ B cells traffic to the CNS in active multiple sclerosis.