Due to the complex multigenic nature of rheumatoid arthritis (RA) identification of RA susceptibility and severity genes appears to be more challenging than originally anticipated. Among many recently reported RA susceptibility genes, a missense single nucleotide polymorphism in the protein tyrosine phosphatase PTPN22 appears to be involved in susceptibility to multiple autoimmune diseases including diabetes, systemic lupus erythematosus and Graves disease. Whether this polymorphism is also associated with severity of the phenotype in diseased individuals is not known. PTPN22 encodes a hematapoetic phosphatase also known as Lyp that functions as a negative regulator of T-cell activation via interaction with the c-Src tyrosine kinase Csk and phosphorylation of regulatory tyrosines or other Src family kinases, such as Lck and Zap70. The R620W polymorphism results in substitution of conserved arginine with tryptophan in the proximal SHH-3 binding domain of PTPN22, which is necessary for interaction with Csk. In vitro experiments show that the W620 variant of PTPN22 binds less efficiently to Csk, suggesting T cells expressing this allele may be hyper-responsive and more prone to autoimmunity.