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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 joints1,2,3. Although CD4+ T cells seem to be the prime mediators of RA, it remains unclear how arthritogenic CD4+ T cells are generated and activated1,2,3. 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 disease4,5. 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 cells6, 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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Acknowledgements

We thank H. von Boemer for transgenic mice; M. Singh (GBF, Germany) for a gift of recombinant HSP-70 through the support of the UNDP/World Bank/WHO Special Program for Research and Training on Tropical Diseases; F. Melchers, R. Zinkernagel, K. Yamamoto, R. Suzuki and Z. Fehervari for discussion; A. Kosugi and T. Nakayama for reagents; and E. Moriizumi for immunohistochemistry and histology. This work was supported by grants-in-aid from the Ministry of Education, Science, Sports and Culture, the Ministry of Human Welfare, Japan Science and Technology Corporation, and the Organization for Pharmaceutical Safety and Research of Japan. Authors' contributions. The SKG strain was established by S.S. and N.S. The experiments in Figs 1, 2a–d, 3f–h, 4, Supplementary Figs 1, 4 and 6 were conducted by N.S. and S.S.; those in Fig. 2b–d by Ta.T., N.S., H.H., To.T., S.Y., T. S., S.N. and S.S.; those in Figs 2e, f, 3a–c, e and Supplementary Fig. 2 by Ta.T.; that in Fig. 3d by To.T.; that in Supplementary Fig. 3 by T.N., and that in Supplementary Fig. 5 by T.M. ZAP-70-deficient mice were provided by I.N.

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Correspondence to Shimon Sakaguchi.

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The authors declare that they have no competing financial interests.

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Supplementary Figure 1 (JPG 79 kb)

Supplementary Figure 2 (JPG 48 kb)

Supplementary Figure 3 (JPG 68 kb)

Supplementary Figure 4 (JPG 51 kb)

Supplementary Figure 5 (JPG 41 kb)

Supplementary Figure 6 (JPG 27 kb)

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Figure 1: Arthritis in SKG mice.
Figure 2: Genetic study of SKG arthritis.
Figure 3: T-cell abnormalities in SKG mice.
Figure 4: Altered thymic T-cell selection in SKG mice.

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