Spolski Rosanne, Kashyap Mohit, Robinson Constance, Yu Zuxi, Leonard Warren J
Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, Room 7B05, Bethesda, MD 20892-1674, USA.
Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):14028-33. doi: 10.1073/pnas.0804358105. Epub 2008 Sep 8.
IL-21 is a pleiotropic type I cytokine that shares the common cytokine receptor gamma chain and plays important roles for normal Ig production, terminal B cell differentiation to plasma cells, and Th17 differentiation. IL-21 is elevated in several autoimmune diseases, and blocking its action has attenuated disease in MRL/lpr mice and in collagen-induced arthritis. The diabetes-associated Idd3 locus is at the Il2/Il21 locus, and elevated IL-21 was observed in the nonobese diabetic (NOD) mouse and suggested to contribute to diabetes by augmenting T cell homeostatic proliferation. To determine the role of IL-21 in diabetes, Il21r-knockout (KO) mice were backcrossed to NOD mice. These mice were devoid of lymphocytic infiltration into the pancreas, and only 1 of 20 animals had an elevated glucose compared with 60% of NOD mice on a wild-type (WT) background. Although TCR and Treg-related responses were normal, these mice had reduced Th17 cells and significantly higher levels of mRNAs encoding members of the Reg (regenerating) gene family whose transgenic expression protects against diabetes. Our studies establish a critical role for IL-21 in the development of type I diabetes in the NOD mouse, with obvious potential implications for type I diabetes in humans.
白细胞介素-21（IL-21）是一种多效性的I型细胞因子，它共享常见的细胞因子受体γ链，在正常免疫球蛋白产生、B细胞终末分化为浆细胞以及辅助性T细胞17（Th17）分化过程中发挥重要作用。在几种自身免疫性疾病中，IL-21水平会升高，阻断其作用可减轻MRL/lpr小鼠和胶原诱导性关节炎的病情。与糖尿病相关的Idd3基因座位于Il2/Il21基因座处，在非肥胖糖尿病（NOD）小鼠中观察到IL-21水平升高，提示其通过增强T细胞稳态增殖促进糖尿病的发生。为了确定IL-21在糖尿病中的作用，将Il21r基因敲除（KO）小鼠与NOD小鼠进行回交。这些小鼠胰腺中没有淋巴细胞浸润，20只动物中只有1只血糖升高，而野生型（WT）背景的NOD小鼠中有60%血糖升高。尽管T细胞受体（TCR）和调节性T细胞（Treg）相关反应正常，但这些小鼠的Th17细胞减少，编码Reg（再生）基因家族成员的mRNA水平显著升高，该基因家族的转基因表达可预防糖尿病。我们的研究证实了IL-21在NOD小鼠I型糖尿病发病过程中的关键作用，对人类I型糖尿病具有明显的潜在意义。
