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

Pröbstel A, Zhou X, Baumann R, Wischnewski S, Kutza M, Rosa L, Sellrie K, Bischof A, Kim K, Ramesh A, Dandekar R, Greenfield A, Schubert R, Bisanz J, Vistnes S, Khaleghi K, Landefeld J, Kirkish G, Liesche-Starnecker F, Ramaglia V, Singh S, Tran E, Barba P, Zorn K, Oechtering J, Forsberg K, Shiow L, Henry R, Graves J, Cree B, Hauser S, Kuhle J, Gelfand J, Andersen P, Schlegel J, Turnbaugh P, Seeberger P, Gommerman J, Wilson M, Schirmer L, Sergio P, Baranzini E (2020) Science Immunology Vol. 5, Issue 53, eabc7191 DOI: 10.1126/sciimmunol.abc7191 

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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.

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.


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