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

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-κB 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.

CD40 Mediates Downregulation of CD32B on Specific Memory B Cell Populations in Rheumatoid Arthritis

“…Alternatively, a recent study revealed that increased CD40L mRNA expression is associated with DNA demethylation in female patients with RA (31). Importantly, a significant correlation was noted between CD4 (34). Therefore, our studies suggest that following CD40 ligation, these therapies could paradoxically enhance the ability of B cells to survive by limiting the effects of Ab-Ag-mediated signaling through CD32B.…”

Interleukin‐21 promotes osteoclastogenesis in humans with rheumatoid arthritis and in mice with collagen‐induced arthritis

“…Regarding the role of IL-21 in inflammatory forms of arthritis such as RA, studies in both mice and humans suggest that IL-21 might be involved in disease progression (29)(30)(31). Young et al demonstrated that blockade of IL-21 with the IL-21R-Fc fusion protein ameliorated clinical disease activity in animal models of inflammatory arthritis, suggesting that IL-21 contributes to the pathologic process of RA (30).…”

“…Young et al demonstrated that blockade of IL-21 with the IL-21R-Fc fusion protein ameliorated clinical disease activity in animal models of inflammatory arthritis, suggesting that IL-21 contributes to the pathologic process of RA (30). Jang et al reported that IL-21 signaling is essential for the development of inflammatory arthritis in the autoimmune K/BxN mouse, a model of RA that is thought to arise mainly from autoantibody-mediated inflammatory responses (31). Those investigators demonstrated that IL-21R-deficient K/BxN mice were "completely refractory to the development of spontaneous arthritis."…”

“…Several studies have shown that IL-21 production is associated with the development of certain autoimmune diseases such as systemic lupus erythematosus (26)(27)(28), RA (29)(30)(31), and primary Sjögren's syndrome (32). Regarding the role of IL-21 in inflammatory forms of arthritis such as RA, studies in both mice and humans suggest that IL-21 might be involved in disease progression (29)(30)(31).…”

From IL-15 to IL-33: the never-ending list of new players in inflammation. Is it time to forget the humble aspirin and move ahead?

“…Not surprisingly, IL-21 blocking agents such as IL-21R-Fc fusion proteins have been shown a partial success in a model of SLE, the MRL-lpr mice [66], with a significant benefit in the mouse models of RA: the collagen-induced arthritis and the adjuvant induced arthritis [67,68]. This complex nature of IL-21…”