Schuster Cornelia, Gerold Kay D, Schober Kilian, Probst Lilli, Boerner Kevin, Kim Mi-Jeong, Ruckdeschel Anna, Serwold Thomas, Kissler Stephan
Joslin Diabetes Center, Harvard Medical School, 1 Joslin Place, Boston, MA, 02215, USA.
Rudolf Virchow Center/DFG Research Center for Experimental Biomedicine, University of Wurzburg, Josef-Schneider Strasse 2, 97080 Wurzburg, Germany.
Immunity. 2015 May 19;42(5):942-52. doi: 10.1016/j.immuni.2015.04.011. Epub 2015 May 12.
CLEC16A variation has been associated with multiple immune-mediated diseases, including type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, celiac disease, Crohn's disease, Addison's disease, primary biliary cirrhosis, rheumatoid arthritis, juvenile idiopathic arthritis, and alopecia areata. Despite strong genetic evidence implicating CLEC16A in autoimmunity, this gene's broad association with disease remains unexplained. We generated Clec16a knock-down (KD) mice in the nonobese diabetic (NOD) model for type 1 diabetes and found that Clec16a silencing protected against autoimmunity. Disease protection was attributable to T cell hyporeactivity, which was secondary to changes in thymic epithelial cell (TEC) stimuli that drive thymocyte selection. Our data indicate that T cell selection and reactivity were impacted by Clec16a variation in thymic epithelium owing to Clec16a's role in TEC autophagy. These findings provide a functional link between human CLEC16A variation and the immune dysregulation that underlies the risk of autoimmunity.
CLEC16A基因变异与多种免疫介导疾病相关，包括1型糖尿病、多发性硬化症、系统性红斑狼疮、乳糜泻、克罗恩病、艾迪生病、原发性胆汁性肝硬化、类风湿性关节炎、青少年特发性关节炎和斑秃。尽管有强有力的遗传学证据表明CLEC16A与自身免疫有关，但该基因与疾病的广泛关联仍无法解释。我们在1型糖尿病的非肥胖糖尿病（NOD）模型中构建了Clec16a基因敲低（KD）小鼠，发现Clec16a基因沉默可预防自身免疫。疾病预防归因于T细胞反应性降低，这是驱动胸腺细胞选择的胸腺上皮细胞（TEC）刺激变化的继发结果。我们的数据表明，由于Clec16a在TEC自噬中的作用，胸腺上皮细胞中的Clec16a变异影响了T细胞选择和反应性。这些发现为人CLEC16A基因变异与自身免疫风险背后的免疫失调之间提供了功能联系。
