RGD Reference Report - 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.

General

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.
RGD ID:	6892964
Pubmed:	PMID:19342640 (View Abstract at PubMed)
DOI:	DOI:10.4049/jimmunol.0804350 (Journal Full-text)
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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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
rheumatoid arthritis		ISO	RDG:1312688	6892964; 6892964		RGD
rheumatoid arthritis		IMP		6892964		RGD

Objects Annotated

Genes (Rattus norvegicus)

Il21r (interleukin 21 receptor)

Genes (Mus musculus)

Il21r (interleukin 21 receptor)

Genes (Homo sapiens)

IL21R (interleukin 21 receptor)

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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.