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- Title
The PTPN22<sup>gain-of-function</sup>+1858T(+) genotypes correlate with low IL-2 expression in thymomas and predispose to myasthenia gravis.
- Authors
Chuang, W.-Y.; Ströbel, P.; Belharazem, D.; Rieckmann, P.; Toyka, K. V.; Nix, W.; Schalke, B.; Gold, R.; Kiefer, R.; Klinker, E.; Opitz, A.; Inoue, M.; Kuo, T.-t.; Müller-Hermelink, H. K.; Marx, A.
- 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.
- Publication
Genes & Immunity, 2009, Vol 10, Issue 8, p667
- ISSN
1466-4879
- Publication type
Academic Journal
- DOI
10.1038/gene.2009.64