Dataset Information

Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10.

ABSTRACT: Plasma cells (PC) are found in the CNS of multiple sclerosis (MS) patients, yet their source and role in MS remains unclear. We find that some PC in the CNS of mice with experimental autoimmune encephalomyelitis (EAE) originate in the gut and produce immunoglobulin A (IgA). Moreover, we show that IgA⁺ PC are dramatically reduced in the gut during EAE, and likewise, a reduction in IgA-bound fecal bacteria is seen in MS patients during disease relapse. Removal of plasmablast (PB) plus PC resulted in exacerbated EAE that was normalized by the introduction of gut-derived IgA⁺ PC. Furthermore, mice with an over-abundance of IgA⁺ PB and/or PC were specifically resistant to the effector stage of EAE, and expression of interleukin (IL)-10 by PB plus PC was necessary and sufficient to confer resistance. Our data show that IgA⁺ PB and/or PC mobilized from the gut play an unexpected role in suppressing neuroinflammation.

SUBMITTER: Rojas OL

PROVIDER: S-EPMC6903689 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Publications

Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10.

Rojas Olga L OL Pröbstel Anne-Katrin AK Porfilio Elisa A EA Wang Angela A AA Charabati Marc M Sun Tian T Lee Dennis S W DSW Galicia Georgina G Ramaglia Valeria V Ward Lesley A LA Leung Leslie Y T LYT Najafi Ghazal G Khaleghi Khashayar K Garcillán Beatriz B Li Angela A Besla Rickvinder R Naouar Ikbel I Cao Eric Y EY Chiaranunt Pailin P Burrows Kyle K Robinson Hannah G HG Allanach Jessica R JR Yam Jennifer J Luck Helen H Campbell Daniel J DJ Allman David D Brooks David G DG Tomura Michio M Baumann Ryan R Zamvil Scott S SS Bar-Or Amit A Horwitz Marc S MS Winer Daniel A DA Mortha Arthur A Mackay Fabienne F Prat Alexandre A Osborne Lisa C LC Robbins Clinton C Baranzini Sergio E SE Gommerman Jennifer L JL

Cell 20190103 3

Plasma cells (PC) are found in the CNS of multiple sclerosis (MS) patients, yet their source and role in MS remains unclear. We find that some PC in the CNS of mice with experimental autoimmune encephalomyelitis (EAE) originate in the gut and produce immunoglobulin A (IgA). Moreover, we show that IgA<sup>+</sup> PC are dramatically reduced in the gut during EAE, and likewise, a reduction in IgA-bound fecal bacteria is seen in MS patients during disease relapse. Removal of plasmablast (PB) plus P ...[more]

PMID: 30612739

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Project description:Immunoglobulin A (IgA) most predominant antibody isotype at mucosal surfaces and is regulated by both T cell-dependent (TD) and independent (TI) mechanisms. In the TD pathway, T follicular helper (TFH) cells provide help to B cells to generate high-affinity antibodies. T follicular regulatory (TFR) cells fine-tune antibody responses, but precisely how these cellsregulate microbiota-directed IgA at mucosal sites has been unclear. Here, we used a TFR-deficient mouse model (Foxp3Cre Bcl6fl/fl; Bcl6FC) in which the gut microbiota develops in the absence of TFR cells, while the broader regulatory T cell compartment remains intact. While Bcl6FC mice showed similar levels of IgA-coated commensal bacteria to wild-type mice in the naïve state, following oral immunization, Bcl6FC mice exhibited a durable increase in IgA-coated commensal bacteria in feces and small intestine, without changes in overall community composition or epithelial barrier permeability. IgA-seq analysis of Bcl6FC mice revealed an increased diversity of IgA-coated taxa, both in naïve and orally immunized mice. IgA coating index analysis, a measure of IgA affinity, identified higher IgA binding to multiple taxa in Bcl6C mice compared to control mice. Consistent with these findings, sera from immunized Bcl6FC mice showed increased IgA binding to Alloprevotella and Klebsiella species but not to E. coli or Group A/B Streptococcus compared to control mice. B cell receptor repertoire sequencing demonstrated divergent patterns of somatic hypermutation (SMH) for IgA and IgG, where TFR cells repressed IgA SMH but enhanced IgG somatic hypermutation. Mechanistically, suppression of commensal-directed IgA required TFR-derived IL-10 but was independent of CTLA-4. IL-10 directly inhibited TGF-β-driven IgA class switching of B cells in vitro. Together, our data identify TFR cells as critical gatekeepers of mucosal IgA responses, constraining commensal-specific IgA responses through a novel IL-10-dependent pathway. Our findings haveimportant implications for regulation of the microbiome by TFR cells and IgA.

Dataset Information

Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10.

Publications

Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10.

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