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Ectopic lymphoid tissue alters the chemokine gradient, increases lymphocyte retention and exacerbates murine ileitis
  1. Eóin N McNamee1,
  2. Joanne C Masterson1,2,
  3. Paul Jedlicka3,
  4. Colm B Collins1,
  5. Ifor R Williams4,
  6. Jesús Rivera-Nieves5
  1. 1Mucosal Inflammation Program, School of Medicine, Aurora, Colorado, USA
  2. 2Gastrointestinal Eosinophilic Disease Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital Colorado, Aurora, Colorado, USA
  3. 3Department of Pathology, University of Colorado, Denver, Colorado, USA
  4. 4Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA
  5. 5Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California at San Diego, San Diego, California, USA
  1. Correspondence to Dr Jesús Rivera-Nieves, Inflammatory Bowel Disease Center, Division of Gastroenterology, 9500 Gilman Drive Bldg UC303, San Diego, CA 92093-0063, USA; jriveran{at}ucsd.edu

Abstract

Background The earliest endoscopically-evident lesion in Crohn's disease is the aphthous ulcer, which develops over ectopic lymphoid tissues (ie, inducible lymphoid follicles (ILF), tertiary lymphoid tissue (TLT)) in the chronically inflamed intestine. ILF/TLT are induced within effector sites by homeostatic lymphoid chemokines, but their role in the development of intestinal ILF/TLT and in the pathogenesis of Crohn's disease is poorly understood.

Design Using a mouse model of Crohn's-like ileitis (TNF∆ARE) which develops florid induction of ILF/TLT within its terminal ileum, the contribution of the CCR7/CCL19/CCL21 chemokine axis during the development of TLT and its role in disease pathogenesis were assessed.

Results Both CCL19 and CCL21 were increased within the inflamed ileum of TNF∆ARE mice, which resulted in CCR7 internalisation and impaired T cell chemotaxis. ILF/TLT were a major source of CCL19 and CCL21 and increased local synthesis, augmented recruitment/retention of effector, naïve and central memory T cell subsets within the inflamed ileum. Immunoblockade of CCR7 resulted in further effector T cell retention and exacerbation of ileitis.

Conclusions Induction of ILF/TLT in the chronically inflamed intestine alters the homeostatic CCL19-CCL21 lymphoid-chemokine gradient and increases recruitment/retention of effector CCR7+ T cell subsets within the terminal ileum, contributing to the perpetuation of chronic inflammation. Thus, blockade of CCR7 or its ligands might result in deleterious consequences for subjects with chronic inflammatory diseases.

  • Tertiary lymphoid tissue
  • CCR7
  • CCL19
  • CCL21
  • Crohn's disease
  • chemokines
  • T-cell receptor
  • T lymphocytes
  • IBD basic research
  • adhesion molecules
  • gastrointestinal tract
  • mucosal immunity
  • interleukins
  • intestinal T cells
  • chemokines
  • IBD models
  • mucosa associated lymphoid tissue
  • immunology
  • mucosal immunology
  • gut immunology
  • T lymphocytes
  • selectins
  • mucosal defense

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Footnotes

  • Funding This work was supported by National Institutes of Health (USPHS DK080212) and Crohn's and Colitis Foundation of America Grants (CCFA # 2826) to JR-N; NIH/NCRR Colorado CTSI: UL1 RR025780 and Crohn's and Colitis Foundation of America Grants (CCFA # 3332) to ENM.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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