Sakaguchi Noriko, Takahashi Takeshi, Hata Hiroshi, Nomura Takashi, Tagami Tomoyuki, Yamazaki Sayuri, Sakihama Toshiko, Matsutani Takaji, Negishi Izumi, Nakatsuru Syuichi, Sakaguchi Shimon
Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
Nature. 2003 Nov 27;426(6965):454-60. doi: 10.1038/nature02119.
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. Although CD4(+) T cells seem to be the prime mediators of RA, it remains unclear how arthritogenic CD4(+) T cells are generated and activated. 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. 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, 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.
类风湿性关节炎（RA）影响着全球约1%的人口，是一种病因不明的慢性全身性炎症性疾病，主要影响多个关节的滑膜。虽然CD4(+) T细胞似乎是RA的主要介质，但尚不清楚致关节炎的CD4(+) T细胞是如何产生和激活的。鉴于高度自身反应性的T细胞克隆在胸腺中正常T细胞发育过程中会被清除，T细胞选择异常被怀疑是自身免疫性疾病的一个原因。在此，我们表明，T细胞中关键信号转导分子ZAP-70编码SH2结构域的基因发生自发点突变，会在小鼠中引发慢性自身免疫性关节炎，在许多方面类似于人类RA。通过异常的ZAP-70从T细胞抗原受体改变的信号转导改变了T细胞对胸腺选择的阈值，导致原本被阴性选择的自身免疫性T细胞被阳性选择。由于T细胞库因基因决定的选择转变而向高自身反应性发展，胸腺产生致关节炎T细胞可能对一部分RA患者疾病的发展也至关重要。
