The PTPN22 gain-of-function 1858T() genotypes correlate with low IL-2 expression in thymomas and predispose to myasthenia gravis

Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) inhibits T-cell activation and interleukin-2 (IL-2) production. The PTPN22 gain-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 (P0.00034) but also with thymoma-associated MG (P0.0028). IL-2 expression in thymomas with PTPN22 1858T() genotypes (P0.028) was lower, implying weaker TCR signaling. We conclude that the PTPN22 gain-of-function variant biases towards MG in a subgroup of thymoma patients possibly by impeding central tolerance induction.