Recent reports continue to shed light on mechanisms of non-synonymous rs2476601 (R620W). PTPN22 encodes the protein tyrosine phosphotase which has an important regulatory role in multiple signaling pathways and functions to dephosphorylate specific tyrosine residues in target proteins. The R620W mutation changes the highly conserved amino acid arginine to tryptophan which disrupts the P1 proline-rich motif and could cause accelerated degradation of the tyrosine phosphotase protein [53], [54]. TCR signaling has been shown to be reduced in T cells containing the disease-susceptibility allele [17]. Protein degradation may lead to hyper-responsiveness of lymphocyte and dendritic cells, which could help explain increased risk for autoimmunity [54]. Additionally, the PTPN22 risk genotype (R620W) may also alter B cell signaling transduction either through decreases in B cell proliferation or a deficit in phosphorylation of key signaling proteins [20]. Recent murine studies provide important new insight regarding the role of PTPN22 (R620W) risk allele in regulation of signal transduction and maintenance of immune tolerance. Interestingly, when the analog mutation of (R620W) has been knocked into the murine ortholog of the gene, this mutation did not
