A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice

作者：Bubier Jason A; Sproule Thomas J; Foreman Oded; Spolski Rosanne; Shaffer Daniel J; Morse Herbert C III; Leonard Warren J; Roopenian Derry C^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2009, 106(5): 1518-1523.

DOI：10.1073/pnas.0807309106

• autoimmune disease
• autoantibodies
• B cells
• T cells

Interleukin 21 (IL-21) is a pleiotropic cytokine produced by CD4 T cells that affects the differentiation and function of T, B, and NK cells by binding to a receptor consisting of the common cytokine receptor gamma chain and the IL-21 receptor (IL-21R). IL-21, a product associated with IL-17-producing CD4 T cells (T(H)17) and follicular CD4 T helper cells (T-FH), has been implicated in autoimmune disorders including the severe systemic lupus erythematosus (SLE)-like disease characteristic of BXSB-Yaa mice. To determine whether IL-21 plays a significant role in this disease, we compared IL-21R-deficient and -competent BXSB-Yaa mice for multiple parameters of SLE. The deficient mice showed none of the abnormalities characteristic of SLE in IL-21R-competent Yaa mice, including hypergammaglobulinemia, autoantibody production, reduced frequencies of marginal zone B cells and monocytosis, renal disease, and premature morbidity. IL-21 production associated with this autoimmune disease was not a product of T(H)17 cells and was not limited to conventional CXCR5( ) T-FH but instead was produced broadly by ICOS CD4( ) splenic T cells. IL-21 arising from an abnormal population of CD4 T cells is thus central to the development of this lethal disease, and, more generally, could play an important role in human SLE and related autoimmune disorders.

• 出版日期2009-2-3