Lymphoid tyrosine phosphatase and autoimmunity: human genetics rediscovers tyrosine phosphatases

Abstract

A relatively large number of protein tyrosine phosphatases (PTPs) are known to regulate signaling through the T cell receptor (TCR). Recent human genetics studies have shown that several of these PTPs are encoded by major autoimmunity genes. Here, we will focus on the lymphoid tyrosine phosphatase (LYP), a critical negative modulator of TCR signaling encoded by the PTPN22 gene. The functional analysis of autoimmune-associated PTPN22 genetic variants suggests that genetic variability of TCR signal transduction contributes to the pathogenesis of autoimmunity in humans.

Association Study of the PTPN22 Gene Polymorphisms with Systemic Lupus Erythematosus in Lorestan Province of Iran

“…The existence of an allele of PTPN22 (+1858C > T), participating in the R620W mutation, and the existence of a single nucleotide variant (-1123G > C) of this gene, located on its promoter, were demonstrated in SLE and other autoimmune diseases (16). The PTPN22 C1858T allele corresponding to R620W amino acid substitution (arginine to tryptophan) was associated with several autoimmune diseases including SLE.…”

The PTPN22 1858T allele but not variants in the proximal promoter region ofIL-21gene is associated with the susceptibility to type 1 diabetes and the presence of autoantibodies in a Brazilian cohort

“…Another important non-HLA gene, the protein tyrosine phosphatase non-receptor 22 (PTPN22), regulates T cell receptor signalling. The PTPN22 C1858T variant, which corresponds to the lymphoid protein tyrosine phosphatase-LYP-Arg620Trp variant associated with pathogenic T cell responses [6][7][8][9], has emerged recently as an important risk factor for type 1 diabetes and other autoimmune diseases [10,11].…”

Genetic evidence of PTPN22 effects on chronic lymphocytic leukemia

“…3 The risk allele has been shown to inhibit antigen-receptor signaling more strongly than the wild-type protein, 4 suggesting that it could compromise autoantigen-induced negative selection of autoreactive lymphocytes. Therefore, the finding by Hebbring et al that the PTPN22 R620W autoimmunity risk allele is present at a higher frequency in northern/western European CLL patients than in matched controls suggests that both…”