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Mucosal CXCR4+ IgG plasma cells contribute to the pathogenesis of human ulcerative colitis through FcγR-mediated CD14 macrophage activation
  1. Michihide Uo1,2,
  2. Tadakazu Hisamatsu1,
  3. Jun Miyoshi1,
  4. Daiki Kaito1,
  5. Kazuaki Yoneno1,
  6. Mina T Kitazume1,
  7. Maiko Mori1,2,
  8. Akira Sugita3,
  9. Kazutaka Koganei3,
  10. Katsuyoshi Matsuoka1,
  11. Takanori Kanai1,
  12. Toshifumi Hibi1
  1. 1Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
  2. 2Pharmacology, Exploratory Research Laboratories, Research Center, Ajinomoto Pharmaceuticals Co. Ltd, Kawasaki, Japan
  3. 3Department of Surgery, Yokohama Municipal Citizen's Hospital, Yokohama, Japan
  1. Correspondence to Dr Toshifumi Hibi and Dr. Tadakazu Hisamatsu, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; thibi{at}sc.itc.keio.ac.jp, hisamachi{at}a7.keio.jp

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+CD27low, CCR10lowCXCR4high) compared with IgA plasma cells (CD19+/−CD27high, CCR10highCXCR4−/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.

  • Ulcerative Colitis
  • IBD Basic Research
  • Inflammation
  • B Cell
  • Macrophages

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