Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice |
| |
Authors: | Sakaguchi Noriko Takahashi Takeshi Hata Hiroshi Nomura Takashi Tagami Tomoyuki Yamazaki Sayuri Sakihama Toshiko Matsutani Takaji Negishi Izumi Nakatsuru Syuichi Sakaguchi Shimon |
| |
Affiliation: | Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan. |
| |
Abstract: | 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. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|