Research ArticleNEUROIMMUNOLOGY

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

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Science Immunology  20 Nov 2020:
Vol. 5, Issue 53, eabc7191
DOI: 10.1126/sciimmunol.abc7191

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Regulatory IgA response

Multiple sclerosis (MS) is associated with production of oligoclonal IgG antibodies within the central nervous system (CNS), but less is known about the status of IgA-producing cells. Pröbstel et al. detected clonally expanded IgA+ cells in cerebrospinal fluid and tissue adjacent to areas of active MS-associated demyelination. Recombinant IgA antibodies assembled from the cloned antibody genes bound to surface antigens found on multiple bacterial phyla but did not cross-react with brain tissue. Recruitment of gut-associated IgA+ B cells and plasma cells to the CNS is a potential biomarker of disease activity in MS. The arrival of these cells in the CNS may reflect recruitment of a homeostatic set of regulatory cells from the gut that have the capacity to dampen excessive inflammation.

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.

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