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

Abstract

Summary 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.

Distinct microbial and immune niches of the human colon

“…Together, our simultaneous analyses of microbiome and neighbouring immune cells highlight the significance of environmental signals in shaping and maintaining regional adaptive immune cell composition and function in the intestine at steady-state. Dysregulation of T helper cells 52 and plasma cells 53,54,55 has been implicated in susceptibility to inflammatory bowel disease. Observations of the linked compartmentalisation of these immune cells and microbial species along the colon at steady-state may provide a platform for understanding the mechanisms underpinning the tropism of different intestinal diseases to specific regions of the gut, such as Crohn’s disease and ulcerative colitis.…”

Becalming Type 17 Inflammation in Ulcerative Colitis

“…Genome-wide association studies in ulcerative colitis point to a role for FcgRIIA, a receptor for IgG. Castro-Dopico et al (2019) find a profound induction of anti-commensal IgG in the colonic mucosa of UC patients and outline a pathway whereby FcgR activation by IgG triggers IL-1b production, type 17 immunity, and the exacerbation of inflammation.…”

“…Intestinal epithelial cell (IEC) endoplasmic reticulum (ER) stress induces activation of peritoneal B1b cells, leading to a protective polyreactive IgA response that is enhanced in patients with defective IEC autophagy and ER stress (Grootjans et al, 2019), thus linking an important genetic susceptibility pathway with a protective IgA response. In this issue of Immunity, Castro-Dopico et al (2019) examine the contribution of the IBD-susceptibility gene FCGR2A (Fc fragment of IgG receptor II-a), a single nucleotide polymorphism (SNP), which alters the binding affinity of the antibody receptor it encodes, FcgRIIA. An SNP in FCGR2A results in an amino-acid substitution (histidine to arginine at position 131) that decreases receptor affinity for IgG and leads to reduced activation of target cells.…”

Intestinal epithelial cells: at the interface of the microbiota and mucosal immunity

“…Very recently, an important role was identified for commensal‐specific IgG that results from epithelial disruption in the gut. Responsiveness to these IgGs in intestinal macrophages via activating Fc γ Rs drives intestinal inflammation and colitis . Although the effects of these IgGs on microbiota composition have not yet been characterized, future studies may define functions for both intestinal IgA and IgG in modulating commensal microbial communities.…”