A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice
A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice
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DOI：
10.1073/pnas.0807309106
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发表时间：
2009-02-03
影响因子：
11.1
通讯作者：
Roopenian, Derry C.
中科院分区：
文献类型：
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作者：
Bubier, Jason A.;Sproule, Thomas J.;Roopenian, Derry C.
白细胞介素21（IL-21）是由CD 4 T细胞产生的多效性细胞因子，其通过与由共同细胞因子受体γ链和IL-21受体（IL-21 R）组成的受体结合来影响T、B和NK细胞的分化和功能。IL-21是一种与产生IL-17的CD 4 T细胞（T（H）17）和滤泡CD 4 T辅助细胞（T-FH）相关的产物，其涉及自身免疫性疾病，包括BXSB-Yaa小鼠特征性的严重系统性红斑狼疮（SLE）样疾病。为了确定IL-21是否在这种疾病中起重要作用，我们比较了IL-21 R缺陷型和IL-21 R胜任型BXSB-Yaa小鼠的SLE多个参数。缺陷型小鼠没有表现出IL-21 R活性Yaa小鼠SLE的异常特征，包括高丙种球蛋白血症、自身抗体产生、边缘区B细胞和单核细胞增多症频率降低、肾脏疾病和过早发病。与这种自身免疫性疾病相关的IL-21产生不是T（H）17细胞的产物，并且不限于常规CXCR 5（+）T-FH，而是广泛地由ICOS+ CD 4（+）脾T细胞产生。因此，由异常的CD 4 T细胞群产生的IL-21对于这种致命疾病的发展至关重要，并且更普遍地，可以在人类SLE和相关的自身免疫性疾病中发挥重要作用。
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.