CXCR5‐ and CCR7‐dependent lymphoid neogenesis in a murine model of chronic antigen‐induced arthritis

Objective Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease with unknown etiology and only partially defined pathogenesis. The aim of this study was to establish a murine model of chronic arthritis in which the development of tertiary lymphoid tissue, a hallmark of human RA, is...

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Published in:Arthritis and rheumatism 2007-10, Vol.56 (10), p.3271-3283
Main Authors: Wengner, Antje M., Höpken, Uta E., Petrow, Peter K., Hartmann, Sven, Schurigt, Uta, Bräuer, Rolf, Lipp, Martin
Format: Article
Language:English
Subjects:
Animals
Arthritis, Experimental - immunology
Biological and medical sciences
Diseases of the osteoarticular system
Female
Humans
Inflammatory joint diseases
Lymphoid Tissue - immunology
Medical sciences
Mice
Mice, Inbred C57BL
Miscellaneous. Osteoarticular involvement in other diseases
Receptors, CCR7 - immunology
Receptors, CXCR5 - immunology
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Summary:Objective Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease with unknown etiology and only partially defined pathogenesis. The aim of this study was to establish a murine model of chronic arthritis in which the development of tertiary lymphoid tissue, a hallmark of human RA, is locally induced, and to characterize the roles of the homeostatic chemokine receptors CXCR5 and CCR7 in this process. Methods We developed a modified model of chronic antigen‐induced arthritis (AIA) in mice with a strong bias toward inflammation. Disease pathology was assessed up to 9 months in wild‐type, CXCR5‐deficient, and CCR7‐deficient mice by determination of knee joint swelling and cellular and humoral immune responses, as well as by histologic analysis of arthritic knee joints. Results In this novel model of AIA, mice developed organized ectopic lymphoid follicles with topologically segregated B cell and T cell areas, high endothelial venules, and germinal center formation within the chronically inflamed synovial tissue. Analysis of the initiation and progression of AIA in wild‐type, CXCR5−/−, and CCR7−/− mice revealed a reduction of acute inflammatory parameters in both knockout strains as well as significantly reduced joint destruction in CXCR5−/− mice. Most importantly, the development and organization of tertiary lymphoid tissue were significantly impaired in CXCR5‐deficient and CCR7‐deficient mice. Conclusion Our results suggest that an inflammatory microenvironment efficiently triggers lymphoid neogenesis in autoimmune diseases such as RA. Moreover, the generation of autoreactive tertiary lymphoid tissues, which is entirely dependent on homeostatic chemokines, may in turn maintain local aberrant chronic immune responses.
ISSN:0004-3591
1529-0131
DOI:10.1002/art.22939