Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge CB2 0QH, UK.
Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
Immunity. 2019 Apr 16;50(4):1099-1114.e10. doi: 10.1016/j.immuni.2019.02.006. Epub 2019 Mar 12.
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.
炎症性肠病是一种慢性、复发性疾病，有两种亚型，克罗恩病（CD）和溃疡性结肠炎（UC）。UC 的全基因组关联研究（GWAS）表明，一种 FCGR2A 变体改变了它编码的抗体受体 FcγRIIA 对免疫球蛋白 G（IgG）的结合亲和力。在这里，我们旨在了解 FcγRIIA 亲和力的变化将如何影响 IgA 占主导地位的器官中的炎症。我们发现在 UC 患者的结肠黏膜中，抗共生 IgG 的显著诱导和激活 FcγR 信号的同时增加。共生 IgG 免疫复合物与肠道驻留的 FcγR 表达巨噬细胞结合，诱导 NLRP3 和活性氧物质依赖的白细胞介素 1β（IL-1β）和中性粒细胞募集趋化因子的产生。这些反应受 FCGR2A 基因型的调节。在 UC 小鼠模型中对巨噬细胞 FcγR 信号强度的体内操作决定了肠道炎症和依赖于 IL-1β 的 17 型免疫的程度。FcγR 依赖性 IgG 炎症对 UC 的重要贡献的鉴定具有治疗意义。
