Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice
Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice
复制标题
DOI：
10.1038/nature02119
复制
发表时间：
2003-11-27
期刊：
影响因子：
64.8
通讯作者：
Sakaguchi, S
中科院分区：
文献类型：
--
作者：
Sakaguchi, N;Takahashi, T;Sakaguchi, S
风湿性关节炎（RA），其折磨约1%的世界人口，是一种病因不明的慢性全身性炎性疾病，主要影响多个关节的滑膜（1-3）。尽管CD 4 + T细胞似乎是RA的主要介质，但致关节炎性CD 4（+）T细胞如何产生和激活仍不清楚（1-3）。考虑到在胸腺中正常T细胞发育过程中，高度自身反应性T细胞克隆被删除，T细胞选择异常被怀疑是自身免疫性疾病的一个原因（4，5）。在这里，我们表明，编码ZAP-70的SH 2结构域的基因的自发点突变，ZAP-70是T细胞中的关键信号转导分子（6），导致小鼠的慢性自身免疫性关节炎，在许多方面与人类RA相似。从T细胞抗原受体通过异常ZAP-70的改变的信号转导改变了T细胞对胸腺选择的阈值，导致对否则阴性选择的自身免疫T细胞的阳性选择。由于T细胞库向高自身反应性的遗传决定的选择性转变，致关节炎T细胞的胸腺产生也可能对RA患者亚组的疾病发展至关重要。
Rheumatoid arthritis (RA), which afflicts about 1% of the world population, is a chronic systemic inflammatory disease of unknown aetiology that primarily affects the synovial membranes of multiple joints(1-3). Although CD4+ T cells seem to be the prime mediators of RA, it remains unclear how arthritogenic CD4(+) T cells are generated and activated(1-3). Given that highly self-reactive T-cell clones are deleted during normal T-cell development in the thymus, abnormality in T-cell selection has been suspected as one cause of autoimmune disease(4,5). Here we show that a spontaneous point mutation of the gene encoding an SH2 domain of ZAP-70, a key signal transduction molecule in T cells(6), causes chronic autoimmune arthritis in mice that resembles human RA in many aspects. Altered signal transduction from T-cell antigen receptor through the aberrant ZAP-70 changes the thresholds of T cells to thymic selection, leading to the positive selection of otherwise negatively selected autoimmune T cells. Thymic production of arthritogenic T cells due to a genetically determined selection shift of the T-cell repertoire towards high self-reactivity might also be crucial to the development of disease in a subset of patients with RA.