Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice
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 arthritogen...
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Veröffentlicht in: | Nature 2003-11, Vol.426 (6965), p.454-460 |
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Zusammenfassung: | 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. |
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ISSN: | 0028-0836 1476-4687 |
DOI: | 10.1038/nature02119 |