Mucosal CXCR4+ IgG plasma cells contribute to the pathogenesis of human ulcerative colitis through Fc[GAMMA]R-mediated CD14 macrophage activation

Background Chronic inflammation characterised by IgG-producing plasma cell infiltration of colonic mucosa is a histological hallmark of ulcerative colitis (UC); however, whether its function is pathogenic or protective remains unclear. Objective To explore the contribution of intestinal IgG plasma cells to UC pathogenesis. Methods We isolated lamina propria mononuclear cells (LPMCs) from intestinal mucosa of UC patients and analysed the characteristics of intestinal plasma cells (expression profiles of differentiation molecules and chemokine receptors). We investigated the involvement of IgG-immune complex (IC)-Fc gamma receptor (Fc[GAMMA]R) signalling in intestinal inflammation by examining the cytokine production by LPMCs in response to IgG-IC stimulation. Results IgG plasma cells that were markedly increased in number in the inflamed mucosa of UC patients showed a distinct expression profile (CD19+ CD27low , CCR10low CXCR4high ) compared with IgA plasma cells (CD19+/- CD27high , CCR10high CXCR4-/low ). In vitro IgG-IC stimulation activated intestinal CD14 macrophages that were increased in number in the inflamed mucosa of UC patients via Fc[GAMMA]RI and Fc[GAMMA]RII, and induced the extensive production of pro-inflammatory cytokines such as tumour necrosis factor (TNF) and interleukin-1β (IL-1β), comparable to the effect of commensal bacteria stimulation. Co-stimulation with IgG-IC and commensal bacteria increased TNF and IL-1β production more than stimulation with the latter alone. Furthermore, IgG-IC notably up-regulated the expression of TL1A, whereas commensal bacteria specifically induced IL-23. Conclusions Collectively, these results demonstrate a novel aspect of UC pathogenesis in which unique IgG plasma cells infiltrate the inflamed mucosa via CXCR4, and critically influence UC pathogenesis by exacerbating mucosal inflammation through the activation of 'pathogenic' intestinal CD14 macrophages via IgG-IC-Fc[GAMMA]R signalling.