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This article is part of the supplement: Proceedings of the 8th Global Arthritis Research Network (GARN) Meeting and 1st Bio-Rheumatology International Congress (BRIC)

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Autoimmune arthritis caused by altered thymic T-cell selection due to a mutation of the ZAP-70 gene

Yoshinaga Ito1* and Shimon Sakaguchi12

  • * Corresponding author: Yoshinaga Ito

Author affiliations

1 Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan

2 Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan

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Citation and License

Arthritis Research & Therapy 2012, 14(Suppl 1):O10  doi:10.1186/ar3565

The electronic version of this article is the complete one and can be found online at:

Published:9 February 2012

© 2012 Ito and Sakaguchi; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Oral presentation

SKG mouse is a murine model of autoimmune arthritis. A spontaneous point mutation of the gene encoding an SH2 domain of the ζ-associated protein of 70 kDa gene (ZAP-70), a key signal transduction molecule in T cells, causes chronic autoimmune arthritis in SKG 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.

Based on the finding that the skg-mutation of ZAP-70 causes autoimmune arthritis, we then examined how attenuated TCR signaling affects the spectrum of autoimmune diseases. In a set of mice with the mutation, the amount of ZAP-70 protein as well as its tyrosine phosphorylation upon TCR stimulation decreased from +/+, skg/+, skg/skg, to skg/− mice in a stepwise manner. The reduction resulted in graded alterations of thymic positive and negative selection of self-reactive T cells and Foxp3+ natural regulatory T cells (Tregs) and their respective functions. Consequently, skg/− mice spontaneously developed autoimmune arthritis even in a microbially clean environment, whereas skg/skg mice required stimulation through innate immunity for disease manifestation. After Treg depletion, organ-specific autoimmune diseases, especially autoimmune gastritis, predominantly developed in +/+, at a lesser incidence in skg/+, but not in skg/skg BALB/c mice, which suffered from other autoimmune diseases, especially autoimmune arthritis. In correlation with this change, gastritis-mediating TCR transgenic T cells were positively selected in +/+, less in skg/+, but not in skg/skg BALB/c mice. Similarly, on the genetic background of diabetes-prone NOD mice, diabetes spontaneously developed in +/+, at a lesser incidence in skg/+, but not in skg/skg mice, which instead succumbed to arthritis. Thus, the graded attenuation of TCR signaling alters the repertoire and the function of autoimmune T cells and natural Tregs in a progressive manner. It also changes the dependency of disease development on environmental stimuli. These findings collectively provide a model of how genetic anomaly of T cell signaling contributes to the development of autoimmune disease.