title: Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice.
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.
authors.affiliation: Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Sakaguchi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hata
authors.forename: Takashi
authors.initials: T
authors.lastname: Nomura
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Tagami
authors.forename: Sayuri
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Toshiko
authors.initials: T
authors.lastname: Sakihama
authors.forename: Takaji
authors.initials: T
authors.lastname: Matsutani
authors.forename: Izumi
authors.initials: I
authors.lastname: Negishi
authors.forename: Syuichi
authors.initials: S
authors.lastname: Nakatsuru
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D001483:Base Sequence; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D013950:Thymus Gland / Q000276:immunology / Q000473:pathology*; D051746:ZAP-70 Protein-Tyrosine Kinase; D018909:src Homology Domains
chemical_list: D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse