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

• Published in: Nature 2003-11, Vol.426 (6965), p.454-460
• Main Authors: Sakaguchi, Shimon, Sakaguchi, Noriko, Takahashi, Takeshi, Hata, Hiroshi, Nomura, Takashi, Tagami, Tomoyuki, Yamazaki, Sayuri, Sakihama, Toshiko, Matsutani, Takaji, Negishi, Izumi, Nakatsuru, Syuichi
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Apoptosis; Arthritis, Rheumatoid - enzymology; Arthritis, Rheumatoid - genetics; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - pathology; Autoimmunity (experimental aspects and models); Base Sequence; Biological and medical sciences; Cellular biology; Chronic Disease; Disease Models, Animal; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Genetics; Humanities and Social Sciences; letter; Male; Mice; Mice, Transgenic; multidisciplinary; Mutation; Mutation, Missense - genetics; Protein-Tyrosine Kinases - chemistry; Protein-Tyrosine Kinases - genetics; Rheumatoid arthritis; Rodents; Science; Science (multidisciplinary); Signal Transduction; src Homology Domains; T-Lymphocytes - immunology; T-Lymphocytes - pathology; Thymus Gland - immunology; Thymus Gland - pathology; World population; ZAP-70 Protein-Tyrosine Kinase
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature02119

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.