1. Male sex chromosomal complement exacerbates the pathogenicity of Th17 cells in a chronic model of central nervous system autoimmunity.
- Author
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Doss PMIA, Umair M, Baillargeon J, Fazazi R, Fudge N, Akbar I, Yeola AP, Williams JB, Leclercq M, Joly-Beauparlant C, Beauchemin P, Ruda GF, Alpaugh M, Anderson AC, Brennan PE, Droit A, Lassmann H, Moore CS, and Rangachari M
- Subjects
- Animals, Autoimmunity, CD4-Positive T-Lymphocytes cytology, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, Disease Models, Animal, Down-Regulation, Encephalomyelitis, Autoimmune, Experimental immunology, Encephalomyelitis, Autoimmune, Experimental metabolism, Female, Histone Demethylases genetics, Histone Demethylases metabolism, Humans, Interferon-gamma metabolism, Male, Mice, Mice, Inbred NOD, Mice, Transgenic, Middle Aged, Multiple Sclerosis immunology, Multiple Sclerosis pathology, Nuclear Receptor Subfamily 1, Group F, Member 3 metabolism, Severity of Illness Index, Th17 Cells cytology, Th17 Cells metabolism, Encephalomyelitis, Autoimmune, Experimental pathology, Sex Chromosomes genetics, Th17 Cells immunology
- Abstract
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.)- Published
- 2021
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