@article{58956841e9824fc28ef8aa0708e0aa71,
title = "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.",
author = "Pr{\"o}bstel, {Anne Katrin} and Xiaoyuan Zhou and Ryan Baumann and Sven Wischnewski and Michael Kutza and Rojas, {Olga L.} and Katrin Sellrie and Antje Bischof and Kicheol Kim and Akshaya Ramesh and Ravi Dandekar and Greenfield, {Ariele L.} and Schubert, {Ryan D.} and Bisanz, {Jordan E.} and Stephanie Vistnes and Khashayar Khaleghi and James Landefeld and Gina Kirkish and Friederike Liesche-Starnecker and Valeria Ramaglia and Sneha Singh and Tran, {Edwina B.} and Patrick Barba and Kelsey Zorn and Johanna Oechtering and Karin Forsberg and Shiow, {Lawrence R.} and Henry, {Roland G.} and Jennifer Graves and Cree, {Bruce A.C.} and Hauser, {Stephen L.} and Jens Kuhle and Gelfand, {Jeffrey M.} and Andersen, {Peter M.} and J{\"u}rgen Schlegel and Turnbaugh, {Peter J.} and Seeberger, {Peter H.} and Gommerman, {Jennifer L.} and Wilson, {Michael R.} and Lucas Schirmer and Baranzini, {Sergio E.}",
note = "Funding Information: We thank all patients for their study participation; R. Gomez and the UCSF EPIC and ORIGINS Study Team for aids in patient recruitment; and E. Eggers, R. Loudermilk, S. Caillier, A. Santaniello, M. {\"O}zt{\"u}rk, H. Miller, V. Alonso, and A.-C. Lecourt for technical assistance. We also thank the UCSF Parnassus Flow Cytometry Core, which is supported by Diabetes Research Center (DRC) grants NIH P30 DK063720 and NIH S10 15100D021822-01, and S. Lynch and D. Fadrosh from the UCSF Microbiome Research Core. We would like to also thank D. Gveric for selecting and providing human brain samples from the UK MS Tissue Bank, funded by the MS Society of Great Britain and Northern Ireland. Further, we thank N. W. Palm and A. L. Kau for valuable aids in establishing the IgA-SEQ technique, E. Allen-Vercoe for providing the RePOOPulate template, M. Goulian for providing the E. coli MP1 strain, J. Gordon for providing the monoclonal anti–Bacteroides thetaiotaomicron antibody, K. Dornmair for providing the humanized 818C5 antibody, and Dorian B. McGavern for constructive comments on the manuscript. Last, we thank A. Hupalowska for assistance with schematic illustrations. Funding: This work was supported by Swiss National Science Foundation fellowships (P2SKP3_164938/1; P300PB_177927/1); National MS Society (NMSS) fellowship (Kathleen C. Moore Fellowship: FG-1708-28871); intramural funding from the University of Basel (A.-K.P.); student fellowships from the Medical Faculty Mannheim, University of Heidelberg (S.W.) and the Hertie Foundation (M.K.); NMSS Clinician Scientist Development Award (Kathleen C. Moore Fellowship: FAN-1507-05497) (A.L.G.); NMSS–American Brain Foundation (ABF) Clinician Scientist Development Award (FAN-1608-25607) (R.D.S.); a grant from the National Institute of Neurological Disorders and Stroke (R35NS111644) (S.L.H.); and grants from the Swedish Brain Foundation (2012-0262, 2012-0305, 2013-0279, and 2016-0303), the Swedish Science Council (2012-3167 and 2017-03100), the Knut and Alice Wallenberg Foundation (2012.0091 and 2014.0305), the Ulla-Carin Lindquist Foundation, the Neurof{\"o}rbundet Association, Ume{\aa} University Insamlingsstiftelsen (223-2808-12, 223-1881-13, and 2.1.12-1605-14), V{\"a}sterbotten County Council (grant 56103-7002829), Swedish Brain Power, and King Gustaf V and Queen Victoria{\textquoteright}s Freemason{\textquoteright}s Foundation (P.A.). P.H.S. thanks the Max-Planck Society for generous financial support. This study was also supported by MS Society of Canada operating grant (3194) and Foundation grant from the Canadian Institutes of Health Research (15992) (to. J.L.G.), Debbie and Andy Rachleff Foundation (M.R.W.), research grants from the Hertie Foundation (medMS MyLab, P1180016) and NMSS (FG-1902-33617) (L.S.), Distinguished Professor in Neurology at UCSF and Heidrich Friends and Family endowed chair in Neurology at UCSF (S.E.B.), and Valhalla Charitable Foundation (S.L.H. and S.E.B.). Publisher Copyright: Copyright {\textcopyright} 2020 The Authors, some rights reserved.",
year = "2020",
month = nov,
day = "20",
doi = "10.1126/SCIIMMUNOL.ABC7191",
language = "English (US)",
volume = "5",
journal = "Science immunology",
issn = "2470-9468",
publisher = "American Association for the Advancement of Science",
number = "53",
}