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 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.


CONCLUSIONS
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.
Wengner
Antje M
AM
Max Delbrück Center of Molecular Medicine, Berlin, Germany.
Höpken
Uta E
UE
Petrow
Peter K
PK
Hartmann
Sven
S
Schurigt
Uta
U
Bräuer
Rolf
R
Lipp
Martin
M
D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology*; D005260:Female; D006801:Humans; D008221:Lymphoid Tissue / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D054400:Receptors, CCR7 / Q000276:immunology*; D054380:Receptors, CXCR5 / Q000276:immunology*
C513179:CXCR5 protein, mouse; C515371:Ccr7 protein, mouse; D054400:Receptors, CCR7; D054380:Receptors, CXCR5