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

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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.

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Correspondence to Yoshinaga Ito.

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Keywords

  • Signal Transduction Molecule
  • Autoimmune Arthritis
  • Thymic Selection
  • Treg Depletion
  • Autoimmune Gastritis