The PTPN22 allelic variant associated with autoimmunity impairs B cell signaling (49.28)

Abstract

Abstract PTPN22 is a gene encoding the protein tyrosine phosphatase (PTPase) Lyp. A single-nucleotide polymorphism (SNP) changing residue 1858 from cytosine to thymidine (1858C/T), encoding the variant Lyp620W, is associated with multiple autoimmune disorders. Studies have demonstrated that Lyp has an inhibitory effect on T cell receptor signaling, and that Lyp620W expression results in a dominant gain of inhibitory function. However, the presence of autoantibodies in all of the diseases associated with the 1858T variant, and recent evidence that Ca2+ flux is altered in B cells of 1858T carriers, strongly suggest that Lyp620W may play a role in B cell signaling and homeostasis. In this study we examined the B cell activation profiles following BCR ligation of healthy subjects who express Lyp620W. We found that B cells from these subjects display impaired B cell signal transduction, characterized by impaired proliferation and a decrease in phosphorylation of key signaling proteins including Syk and PLCγ2. Inhibition of Lyp PTPase activity reversed the signaling defect in B cells expressing Lyp620W, resulting in enhanced BCR activation to the level of LypR620 controls. These findings demonstrate that Lyp620W alters BCR signaling and implicates B cells in the mechanism by which the PTPN22 1858T allelic variant contributes to autoimmunity. This work was supported by funds from the Juvenile Diabetes Research Foundation.