Abstract
Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) inhibits T-cell activation and interleukin-2 (IL-2) production. The PTPN22gain-of-function+1858T(+) genotypes predispose to multiple autoimmune diseases, including early-onset (non-thymomatous) myasthenia gravis (MG). The disease association and the requirement of IL-2/IL-2 receptor signaling for intrathymic, negative T-cell selection have suggested that these genotypes may weaken T-cell receptor (TCR) signaling and impair the deletion of autoreactive T cells. Evidence for this hypothesis is missing. Thymoma-associated MG, which depends on intratumorous generation and export of mature autoreactive CD4(+) T cells, is a model of autoimmunity because of central tolerance failure. Here, we analyzed the PTPN22 +1858C/T single nucleotide polymorphism in 426 German Caucasian individuals, including 125 thymoma patients (79 with MG), and investigated intratumorous IL-2 expression levels. Unlike two previous studies on French and Swedish patients, we found strong association of PTPN22 +1858T(+) genotypes not only with early-onset MG (P=0.00034) but also with thymoma-associated MG (P=0.0028). IL-2 expression in thymomas with PTPN22 +1858T(+) genotypes (P=0.028) was lower, implying weaker TCR signaling. We conclude that the PTPN22gain-of-function variant biases towards MG in a subgroup of thymoma patients possibly by impeding central tolerance induction.
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Acknowledgements
We thank C Siehndel, T Pohle, and J Maar for expert technical assistance; Pärt Peterson, University of Tartu, Estonia; Nick Willcox, University of Oxford; and Henri-Jean Garchon, University Paris-Descartes for critical comments. This study was supported by European Union Grants LSHB-CT-2003-503410 (Euro-Thymaide) and No. 2005105 (European Myasthenia Gravis Network) (to AM and PS); and by Grant 106430 of the Deutsche Krebshilfe (to HK M-H, PS, and AM).
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Chuang, WY., Ströbel, P., Belharazem, D. et al. The PTPN22gain-of-function+1858T(+) genotypes correlate with low IL-2 expression in thymomas and predispose to myasthenia gravis. Genes Immun 10, 667–672 (2009). https://doi.org/10.1038/gene.2009.64
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DOI: https://doi.org/10.1038/gene.2009.64
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