title: The PTPN22gain-of-function+1858T(+) genotypes correlate with low IL-2 expression in thymomas and predispose to myasthenia gravis.
abstract: 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 (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 PTPN22(gain-of-function) variant biases towards MG in a subgroup of thymoma patients possibly by impeding central tolerance induction.
authors.affiliation: Institute of Pathology, University of Würzburg, Würzburg, Germany.
authors.forename: W-Y
authors.initials: WY
authors.lastname: Chuang
authors.forename: P
authors.initials: P
authors.lastname: Ströbel
authors.forename: D
authors.initials: D
authors.lastname: Belharazem
authors.forename: P
authors.initials: P
authors.lastname: Rieckmann
authors.forename: K V
authors.initials: KV
authors.lastname: Toyka
authors.forename: W
authors.initials: W
authors.lastname: Nix
authors.forename: B
authors.initials: B
authors.lastname: Schalke
authors.forename: R
authors.initials: R
authors.lastname: Gold
authors.forename: R
authors.initials: R
authors.lastname: Kiefer
authors.forename: E
authors.initials: E
authors.lastname: Klinker
authors.forename: A
authors.initials: A
authors.lastname: Opitz
authors.forename: M
authors.initials: M
authors.lastname: Inoue
authors.forename: T-t
authors.initials: TT
authors.lastname: Kuo
authors.forename: H K
authors.initials: HK
authors.lastname: Müller-Hermelink
authors.forename: A
authors.initials: A
authors.lastname: Marx
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D060908:CTLA-4 Antigen; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis / Q000150:complications / Q000235:genetics / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics* / Q000276:immunology*; D013945:Thymoma / Q000150:complications / Q000235:genetics / Q000276:immunology*; D013953:Thymus Neoplasms / Q000150:complications / Q000235:genetics / Q000276:immunology*; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D007376:Interleukin-2; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22