title: Mucosal CXCR4+ IgG plasma cells contribute to the pathogenesis of human ulcerative colitis through FcγR-mediated CD14 macrophage activation.
abstract: 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 (FcγR) 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(+)CD27(low), CCR10(low)CXCR4(high)) compared with IgA plasma cells (CD19(+/-)CD27(high), CCR10(high)CXCR4(-/low)). In vitro IgG-IC stimulation activated intestinal CD14 macrophages that were increased in number in the inflamed mucosa of UC patients via FcγRI and FcγRII, 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-FcγR signalling.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Michihide
authors.initials: M
authors.lastname: Uo
authors.forename: Tadakazu
authors.initials: T
authors.lastname: Hisamatsu
authors.forename: Jun
authors.initials: J
authors.lastname: Miyoshi
authors.forename: Daiki
authors.initials: D
authors.lastname: Kaito
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Yoneno
authors.forename: Mina T
authors.initials: MT
authors.lastname: Kitazume
authors.forename: Maiko
authors.initials: M
authors.lastname: Mori
authors.forename: Akira
authors.initials: A
authors.lastname: Sugita
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Koganei
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Matsuoka
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanai
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hibi
mesh_terms: D003093:Colitis, Ulcerative / Q000209:etiology* / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000502:physiology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000502:physiology; D007413:Intestinal Mucosa / Q000276:immunology / Q000502:physiology; D018950:Lipopolysaccharide Receptors / Q000276:immunology / Q000502:physiology; D008262:Macrophage Activation / Q000276:immunology* / Q000502:physiology; D010950:Plasma Cells / Q000276:immunology / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000276:immunology / Q000502:physiology*; D017452:Receptors, IgG / Q000276:immunology / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology / Q000502:physiology; D059467:Transcriptome / Q000502:physiology
chemical_list: C527276:CXCR4 protein, human; D016207:Cytokines; D007074:Immunoglobulin G; D018950:Lipopolysaccharide Receptors; D019718:Receptors, CXCR4; D017452:Receptors, IgG