Anti-commensal IgG Drives Intestinal Inflammation and Type 17 Immunity in Ulcerative Colitis.

Autor:	Castro-Dopico T; Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge CB2 0QH, UK., Dennison TW; Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge CB2 0QH, UK., Ferdinand JR; Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge CB2 0QH, UK., Mathews RJ; Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge CB2 0QH, UK., Fleming A; Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge CB2 0QH, UK., Clift D; Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, UK., Stewart BJ; Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge CB2 0QH, UK., Jing C; Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge CB2 0QH, UK., Strongili K; Division of Gastroenterology, Cambridge Universities NHS Foundation Trust, Cambridge CB2 0QQ, UK., Labzin LI; Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, UK., Monk EJM; Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge CB2 0QH, UK., Saeb-Parsy K; University of Cambridge Department of Surgery, Cambridge CB2 0QQ, UK., Bryant CE; Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, UK., Clare S; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK., Parkes M; Division of Gastroenterology, Cambridge Universities NHS Foundation Trust, Cambridge CB2 0QQ, UK., Clatworthy MR; Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge CB2 0QH, UK; Cellular Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinton CB10 1SA, UK. Electronic address: mrc38@cam.ac.uk.
Jazyk:	angličtina
Zdroj:	Immunity [Immunity] 2019 Apr 16; Vol. 50 (4), pp. 1099-1114.e10. Date of Electronic Publication: 2019 Mar 12.
DOI:	10.1016/j.immuni.2019.02.006
Abstrakt:	Inflammatory bowel disease is a chronic, relapsing condition with two subtypes, Crohn's disease (CD) and ulcerative colitis (UC). Genome-wide association studies (GWASs) in UC implicate a FCGR2A variant that alters the binding affinity of the antibody receptor it encodes, FcγRIIA, for immunoglobulin G (IgG). Here, we aimed to understand the mechanisms whereby changes in FcγRIIA affinity would affect inflammation in an IgA-dominated organ. We found a profound induction of anti-commensal IgG and a concomitant increase in activating FcγR signaling in the colonic mucosa of UC patients. Commensal-IgG immune complexes engaged gut-resident FcγR-expressing macrophages, inducing NLRP3- and reactive-oxygen-species-dependent production of interleukin-1β (IL-1β) and neutrophil-recruiting chemokines. These responses were modulated by the FCGR2A genotype. In vivo manipulation of macrophage FcγR signal strength in a mouse model of UC determined the magnitude of intestinal inflammation and IL-1β-dependent type 17 immunity. The identification of an important contribution of IgG-FcγR-dependent inflammation to UC has therapeutic implications. (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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