Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice.
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.
Sakaguchi
Noriko
N
Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
Takahashi
Takeshi
T
Hata
Hiroshi
H
Nomura
Takashi
T
Tagami
Tomoyuki
T
Yamazaki
Sayuri
S
Sakihama
Toshiko
T
Matsutani
Takaji
T
Negishi
Izumi
I
Nakatsuru
Syuichi
S
Sakaguchi
Shimon
S
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
D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse