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The PTPN22gain-of-function+1858T(+) genotypes correlate with low IL-2 expression in thymomas and predispose to myasthenia gravis

Genes & Immunity volume 10, pages 667–672 (2009)Cite this article

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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Authors and Affiliations

  1. Institute of Pathology, University of Würzburg, Würzburg, Germany

    W-Y Chuang, P Ströbel, M Inoue, H K Müller-Hermelink & A Marx

  2. Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan

    W-Y Chuang & T-t Kuo

  3. Institute of Pathology, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany

    P Ströbel, D Belharazem & A Marx

  4. Department of Neurology, University of Würzburg, Würzburg, Germany

    P Rieckmann & K V Toyka

  5. Department of Neurology, University of Mainz, Mainz, Germany

    W Nix

  6. Department of Neurology, University of Regensburg, Regensburg, Germany

    B Schalke

  7. Department of Neurology, University of Bochum, Bochum, Germany

    R Gold

  8. Department of Neurology, Diakoniekrankenhaus, Rothenburg, Wümme, Germany

    R Kiefer

  9. Department of Transfusion Medicine and Hemotherapy, University of Würzburg, Würzburg, Germany

    E Klinker & A Opitz

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  1. W-Y Chuang
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Correspondence to A Marx.

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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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