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


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2003-11

AUTHORS

Noriko Sakaguchi, Takeshi Takahashi, Hiroshi Hata, Takashi Nomura, Tomoyuki Tagami, Sayuri Yamazaki, Toshiko Sakihama, Takaji Matsutani, Izumi Negishi, Syuichi Nakatsuru, Shimon Sakaguchi

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. More... »

PAGES

454

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nature02119

DOI

http://dx.doi.org/10.1038/nature02119

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1030665392

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/14647385


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