Male sex chromosomal complement exacerbates the pathogenicity of Th17 cells in a chronic model of central nervous system autoimmunity.

Autor:	Doss PMIA; axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Pavillon CHUL, 2705 boulevard Laurier, Quebec City, QC G1V 4G2, Canada., Umair M; axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Pavillon CHUL, 2705 boulevard Laurier, Quebec City, QC G1V 4G2, Canada., Baillargeon J; axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Pavillon CHUL, 2705 boulevard Laurier, Quebec City, QC G1V 4G2, Canada., Fazazi R; axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Pavillon CHUL, 2705 boulevard Laurier, Quebec City, QC G1V 4G2, Canada., Fudge N; Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL A1B 3V6, Canada., Akbar I; axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Pavillon CHUL, 2705 boulevard Laurier, Quebec City, QC G1V 4G2, Canada., Yeola AP; axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Pavillon CHUL, 2705 boulevard Laurier, Quebec City, QC G1V 4G2, Canada., Williams JB; Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL A1B 3V6, Canada., Leclercq M; axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Pavillon CHUL, 2705 boulevard Laurier, Quebec City, QC G1V 4G2, Canada., Joly-Beauparlant C; axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Pavillon CHUL, 2705 boulevard Laurier, Quebec City, QC G1V 4G2, Canada., Beauchemin P; Department of Neurology, CHU de Québec-Université Laval, Quebec City, QC G1V 4G2, Canada; Faculty of Medicine, Université Laval, 1050 ave de la Médecine, Quebec City, QC, Canada., Ruda GF; Target Discovery Institute and NIHR, Oxford Biomedical Research Centre, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK., Alpaugh M; axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Pavillon CHUL, 2705 boulevard Laurier, Quebec City, QC G1V 4G2, Canada., Anderson AC; Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham & Women's Hospital, 60 Fenwood Road, Boston, MA 02115, USA., Brennan PE; Target Discovery Institute and NIHR, Oxford Biomedical Research Centre, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK; Alzheimer's Research UK, Oxford Drug Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK., Droit A; axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Pavillon CHUL, 2705 boulevard Laurier, Quebec City, QC G1V 4G2, Canada; Faculty of Medicine, Université Laval, 1050 ave de la Médecine, Quebec City, QC, Canada., Lassmann H; Division of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, Vienna 1090, Austria., Moore CS; Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL A1B 3V6, Canada; Department of Neurology, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL A1B 3V6, Canada., Rangachari M; axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Pavillon CHUL, 2705 boulevard Laurier, Quebec City, QC G1V 4G2, Canada; Faculty of Medicine, Université Laval, 1050 ave de la Médecine, Quebec City, QC, Canada. Electronic address: manu.rangachari@crchudequebec.ulaval.ca.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2021 Mar 09; Vol. 34 (10), pp. 108833.
DOI:	10.1016/j.celrep.2021.108833
Abstrakt:	Sex differences in multiple sclerosis (MS) incidence and severity have long been recognized. However, the underlying cellular and molecular mechanisms for why male sex is associated with more aggressive disease remain poorly defined. Using a T cell adoptive transfer model of chronic experimental autoimmune encephalomyelitis (EAE), we find that male Th17 cells induce disease of increased severity relative to female Th17 cells, irrespective of whether transferred to male or female recipients. Throughout the disease course, a greater frequency of male Th17 cells produce IFNγ, a hallmark of pathogenic Th17 responses. Intriguingly, XY chromosomal complement increases the pathogenicity of male Th17 cells. An X-linked immune regulator, Jarid1c, is downregulated in pathogenic male murine Th17 cells, and functional experiments reveal that it represses the severity of Th17-mediated EAE. Furthermore, Jarid1c expression is downregulated in CD4 + T cells from MS-affected individuals. Our data indicate that male sex chromosomal complement critically regulates Th17 cell pathogenicity. Competing Interests: Declaration of interests M.R. has received speaker honoraria from Boehringer-Ingelheim GmbH, EMD Serono Canada, F. Hoffmann-La Roche, and Biogen Canada and has a research contract with Remedy Pharmaceuticals. These interests are unrelated to the present work. (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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