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A positive feedback loop of IL-21 signaling provoked by homeostatic CD4+CD25- T cell expansion is essential for the development of arthritis in autoimmune K/BxN mice.

Authors: Jang, E  Cho, SH  Park, H  Paik, DJ  Kim, JM  Youn, J 
Citation: Jang E, etal., J Immunol. 2009 Apr 15;182(8):4649-56.
Pubmed: (View Article at PubMed) PMID:19342640
DOI: Full-text: DOI:10.4049/jimmunol.0804350

Rheumatoid arthritis is a joint-specific autoimmune inflammatory disease of unknown etiology. The K/BxN mouse is a model of rheumatoid arthritis that is thought to be mainly due to autoantibody-mediated inflammatory responses. We showed previously that homeostatic proliferation of autoreactive CD4(+) T cells is required for disease initiation in the K/BxN mice. In this study, we show that the homeostatically proliferating CD4(+)CD25(-) T cells produce IL-21. We generated IL-21R-deficient (IL-21R(-/-)) K/BxN mice and found that these mice were completely refractory to the development of spontaneous arthritis. They contained fewer CD4(+) T cells with a reduced proportion of homeostatically proliferating cells, fewer follicular Th cells, and, surprisingly, more Th17 cells than their control counterparts. They also failed to develop IgG1(+) memory B cells and autoantigen-specific IgG1 Ab-secreting cells. IL-21 induced expression of receptor activator of NF-kappaB ligand (RANKL) a regulator of osteoclastogenesis, and few RANKL-expressing infiltrates were found in the synovia of IL-21R(-/-) K/BxN mice. Thus, our results demonstrate that IL-21 forms a positive feedback autocrine loop involving homeostatically activated CD4(+) cells and that it plays an essential role in the development of autoimmune arthritis by mechanisms dependent on follicular Th cell development, autoreactive B cell maturation, and RANKL induction but independent of Th17 cell function. Consistent with this, in vivo administration of soluble the IL-21R-Fc fusion protein delayed the onset and progression of arthritis. Our findings suggest that effective targeting of IL-21-mediated processes may be useful in treating autoimmune arthritis.


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CRRD Object Information
CRRD ID: 6892964
Created: 2012-08-21
Species: All species
Last Modified: 2012-08-21
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.