Ectopic lymphoid tissue alters the chemokine gradient, increases lymphocyte retention and exacerbates murine ileitis.

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 (TNFARE) 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 TNFARE 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.

• Authors: Eóin N McNamee, Joanne C Masterson, Paul Jedlicka, Colm B Collins, Ifor R Williams, Jesús Rivera-Nieves
• Journal: Gut (Gut) Vol. 62 Issue 1 Pg. 53-62 (Jan 2013) ISSN: 1468-3288 [Electronic] England
• PMID: 22267601 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Ccl19 protein, mouse
• Ccr7 protein, mouse
• Chemokine CCL19
• Chemokine CCL21
• Receptors, CCR7

Topics

• Animals
• Biomarkers (metabolism)
• Chemokine CCL19 (metabolism)
• Chemokine CCL21 (metabolism)
• Chemotaxis, Leukocyte
• Choristoma (immunology, pathology)
• Crohn Disease (immunology, pathology)
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Flow Cytometry
• Fluorescent Antibody Technique
• Humans
• Ileitis (immunology, pathology)
• Lymphoid Tissue
• Mice
• Mice, Mutant Strains
• Real-Time Polymerase Chain Reaction
• Receptors, CCR7 (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• T-Lymphocyte Subsets (metabolism)