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, Eunkyeong; Cho, Sin-Hye; Park, Hyunjoo; Paik, Doo-Jin; Kim, Jung Mogg; Youn, Jeehee
- Issue Date
- Apr-2009
- Publisher
- AMER ASSOC IMMUNOLOGISTS
- Citation
- JOURNAL OF IMMUNOLOGY, v.182, no.8, pp.4649 - 4656
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF IMMUNOLOGY
- Volume
- 182
- Number
- 8
- Start Page
- 4649
- End Page
- 4656
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/177033
- DOI
- 10.4049/jimmunol.0804350
- ISSN
- 0022-1767
- Abstract
- 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-kappa B 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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