Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice
| Autor: | Takeshi Takahashi, Toshiko Sakihama, Noriko Sakaguchi, Sayuri Yamazaki, Takashi Nomura, Takaji Matsutani, Shimon Sakaguchi, Hiroshi Hata, Tomoyuki Tagami, Syuichi Nakatsuru, Izumi Negishi |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Male
T-Lymphocytes Mutation Missense Arthritis Apoptosis Mice Transgenic Thymus Gland Biology medicine.disease_cause Arthritis Rheumatoid src Homology Domains Mice medicine Animals Amino Acid Sequence Thymic T cell selection Autoimmune disease Mutation ZAP-70 Protein-Tyrosine Kinase Multidisciplinary Base Sequence Point mutation T lymphocyte Protein-Tyrosine Kinases medicine.disease Disease Models Animal Rheumatoid arthritis Chronic Disease Immunology Female Signal transduction Signal Transduction |
| Zdroj: | Nature. 426:454-460 |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|