A defect in central tolerance in NOD mice
A defect in central tolerance in NOD mice
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DOI：
10.1038/ni726
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发表时间：
2001-11-01
影响因子：
30.5
通讯作者：
Sprent, J
中科院分区：
文献类型：
--
作者：
Kishimoto, H;Sprent, J
非肥胖糖尿病（NOD）小鼠发生自身免疫性疾病的易感性通常归因于外周耐受机制的缺陷。在这里，有证据表明NOD小鼠胸腺细胞的中枢耐受（负选择）存在缺陷。NOD小鼠的中枢耐受性受损在髓质中发现的半成熟胸腺细胞群中最为突出。这种缺陷在体内和体外都很明显，不依赖于IA β (g7)的表达，影响fas依赖性和非依赖性的凋亡途径；对于fas依赖性凋亡，NOD胸腺细胞耐受缺陷与T细胞受体介导的caspase 8同源FLICE （fas相关死亡结构域样白细胞介素I β -转换酶）抑制蛋白的上调相关。根据这些发现，NOD小鼠的发病可能反映了中枢和外周耐受性的缺陷。
The predisposition of nonobese diabetic (NOD) mice to develop autoimmune disease is usually attributed to defects in peripheral tolerance mechanisms. Here, evidence is presented that NOD mice display a defect in central tolerance (negative selection) of thymocytes. Impaired central tolerance in NOD mice was most prominent in a population of semi-mature thymocytes found in the medulla. The defect was apparent in vivo as well as in vitro, was independent of IA beta (g7) expression and affected both Fas-dependent and Fas-independent pathways of apoptosis; for Fas-dependent apoptosis, the defective tolerance of NOD thymocytes correlated with the strong T cell receptor-mediated up-regulation of caspase 8-homologous FLICE (Fas-associated death-domain-like interleukin I beta -converting enzyme)-inhibitory protein. In light of these findings, disease onset in NOD mice may reflect defects in central as well as peripheral tolerance.