PTPN22 splice forms: a new role in rheumatoid arthritis

The protein tyrosine phosphatase non-receptor type 22 (PTPN22), also called lymphoid tyrosine phosphatase (LYP), is expressed exclusively in hematopoietic cells and is a critical gatekeeper of T and B cell receptor (TCR and BCR) signaling. In the TCR signaling pathway, LYP acts downstream of receptor binding to inhibit the activity of key signaling effectors, thereby attenuating T cell activation. Specifically, LYP has been implicated in the dephosphorylation of the positive regulatory tyrosine residue in target Src-family protein tyrosine kinases, including FynT (Y417) and Lck (Y394). Recent studies have shown that LYP is also involved in the modulation of B cell populations and in their tolerance checkpoints through BCR signaling, but its precise mechanisms have not yet been established [1,2].PTPN22 has been identified as a shared susceptibility gene for a variety of human autoimmune diseases, including type 1 diabetes, rheumatoid arthritis (RA), autoimmune thyroid disease, systemic lupus erythematosus (SLE) and inflammatory bowel disease [3]. Genetic variation in PTPN22 has been investigated in autoimmune diseases, but until recently the role of PTPN22 modulation at the mRNA or protein level had not been considered. Alternative splicing can result in the expression of different LYP isoforms and, in a recent study published in Genome Medicine, Ronninger et al. [4] reported the first evidence of altered expression of PTPN22 splice forms in RA.Two missense single nucleotide polymorphisms (SNPs) in PTPN22 have been linked with autoimmunity: the R620W (C1858T, rs2476601) variant in exon 14, which seems to produce a gain of function, resulting in stronger negative regulation of T and B cell activation; and the R263Q (G788A; rs33996649) change in exon 10, which alters an amino acid in the catalytic domain of the enzyme, resulting in reduced phosphatase activity [3]. These variants have been consistently associated with susceptibility to RA, mainly in European population