Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice

Noriko Sakaguchi, Takeshi Takahashi, Hiroshi Hata, Takashi Nomura, Tomoyuki Tagami, Sayuri Yamazaki, Toshiko Sakihama, Takaji Matsutani, Izumi Negishi, Syuichi Nakatsuru and Shimon Sakaguchi ()
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Noriko Sakaguchi: Kyoto University
Takeshi Takahashi: Kyoto University
Hiroshi Hata: Kyoto University
Takashi Nomura: Kyoto University
Tomoyuki Tagami: Kyoto University
Sayuri Yamazaki: Kyoto University
Toshiko Sakihama: Kyoto University
Takaji Matsutani: Shionogi Institute for Medical Science
Izumi Negishi: Gunma University Hospital
Syuichi Nakatsuru: Kyoto University
Shimon Sakaguchi: Kyoto University

Nature, 2003, vol. 426, issue 6965, 454-460

Abstract: 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 joints1,2,3. Although CD4+ T cells seem to be the prime mediators of RA, it remains unclear how arthritogenic CD4+ T cells are generated and activated1,2,3. 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 disease4,5. 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 cells6, 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.

Date: 2003
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DOI: 10.1038/nature02119

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