PTPN22 Deficiency Cooperates with the CD45 E613R Allele to Break Tolerance on a Non-Autoimmune Background

摘要: Pep and CD45 are tyrosine phosphatases whose targets include the Src-family kinases, critical mediators of Ag receptor signaling. A polymorphism in PTPN22, gene that encodes human orthologue Lyp, confers susceptibility to multiple autoimmune diseases context complex genetic backgrounds. However, functional significance R620W risk allele is not clear. We report misexpression wild-type or Pep/Lyp Jurkat cells, its binding partner Csk, unmasks as a hypomorph. It has been shown previously although Pep-deficient mice on B6 background have hyperresponsive memory T autoimmunity does develop. Mice containing point mutation juxtamembrane wedge domain (E613R) develop B cell-driven, lupus-like disease mixed 129/B6 background, but background. studied ability deficiency act modifier E613R nonautoimmune understand how loci might interact autoimmunity. In this study we double mutant well lymphadenopathy, polyclonal lymphocyte activation, accelerated cell formation. Following stimulation, peripheral cells phenocopy whereas respond like Pep−/− cells. These studies suggest susceptible microenvironment can drive break tolerance.