PTPN22: the archetypal non-HLA autoimmunity gene

Abstract

PTPN22 encodes a tyrosine phosphatase that is expressed by haematopoietic cells and functions as a key regulator of immune homeostasis by inhibiting T-cell receptor signalling and by selectively promoting type I interferon responses after activation of myeloid-cell pattern-recognition receptors. A single nucleotide polymorphism of PTPN22, 1858C>T (rs2476601), disrupts an interaction motif in the protein, and is the most important non-HLA genetic risk factor for rheumatoid arthritis and the second most important for juvenile idiopathic arthritis. PTPN22 exemplifies a shared autoimmunity gene, affecting the pathogenesis of systemic lupus erythematosus, vasculitis and other autoimmune diseases. In this Review, we explore the role of PTPN22 in autoimmune connective tissue disease, with particular emphasis on candidate-gene and genome-wide association studies and clinical variability of disease. We also propose a number of PTPN22-dependent functional models of the pathogenesis of autoimmune diseases.

Figure 1

Variants of human PTPN22. PTPN22 encodes a tyrosine phosphatase with an N-terminal catalytic domain, an interdomain region and a C-terminal domain with four proline-rich regions. Several SNPs in the PTPN22 gene are associated with autoimmune disease. The autoimmune-protective 788G>A SNP (rs33996649) causes an Arg263Gln substitution in the PTPN22 catalytic domain (purple). The autoimmune-predisposing 1858C>T SNP (rs2476601) causes an Arg620Trp substitution in the first proline-rich motif (blue diamond). The autoimmune-predisposing −1123G>C SNP (rs2488457) is in the promoter region of the PTPN22 gene. Abbreviations: PTPN22, tyrosine-protein phosphatase nonreceptor type 22; SNP, single-nucleotide polymorphism.

Figure 2

PTPN22 regulation of cell signalling. PTPN22 has dual roles in the regulation of immune-cell signalling. a | In T cells, PTPN22 restricts signalling by inhibitory tyrosine dephosphorylation of key promoters of signalling downstream of the TCR: the SRC family tyrosine protein kinase Lck; the SYK family kinase ZAP-70 and the TCR-associated CD3ζ-chain. The catalytic activity of PTPN22 is essential for this role. b | In myeloid cells, PTPN22 acts as a selective promoter of the type I interferon response by promoting the Lys63-linked autoubiquitination of TRAF3 and phosphorylation of IRF3 and IRF7 downstream of pattern-recognition receptors. In contrast to lymphocytes, the catalytic activity of PTPN22 is not substantially involved in the promotion of TLR signalling in myeloid cells. Instead, myeloid cells rely on scaffolding properties within the C-terminal domain of the protein. Abbreviations: IRF3, interferon regulatory factor 3; IRF7, interferon regulatory factor 7; NFAT, nuclear factor of activated T cells; PTPN22, tyrosine-protein phosphatase nonreceptor type 22; TCR, T-cell receptor; TLR, Toll-like receptor; TRAF3, TNF-receptor-associated factor 3.

Figure 3

Models of PTPN22-regulated autoimmune disease. a | The PTPN22 ArgTrp620 promotes the expansion of pathogenic, autoimmune T cells. b | PTPN22 ArgTrp620 alters the B-cell repertoire, promoting autoantibody production. c | PTPN22 ArgTrp620 impairs type I interferon production by myeloid cells, which during homeostasis functions to antagonize the effect of proinflammatory cytokines, for example, to protect against arthritis in the synovium. Abbreviations: PTPN22, tyrosine-protein phosphatase nonreceptor type 22; T_REG cell, regulatory T cell.