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

N Sakaguchi, T Takahashi, H Hata, T Nomura… - Nature, 2003 - nature.com
N Sakaguchi, T Takahashi, H Hata, T Nomura, T Tagami, S Yamazaki, T Sakihama…
Nature, 2003nature.com
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 …
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.
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