The PTPN22 C1858T polymorphism is associated with skewing of cytokine profiles toward high interferon-α activity and low tumor necrosis factor α levels in patients with lupus

The pathogenesis of SLE is likely driven by a combination of genetic risk factors and environmental events which lead to an irreversible break in immunologic self-tolerance. IFN-α is a pleiotropic type I interferon with the potential to break self-tolerance by activating antigen presenting cells after uptake of self material (1). Serum IFN-α levels are frequently elevated in SLE patients (2). Additionally, a number of patients treated with recombinant human IFN-α for malignancy and chronic viral hepatitis have developed de novo SLE, which typically resolves after the IFN-α is discontinued (3). These data suggest a potential role for IFN-α in SLE susceptibility. In previous work, we have demonstrated that abnormally high serum IFN-α is common in SLE families in both healthy and SLE-affected members, as compared to unrelated individuals (4). These data implicate high serum IFN-α as a heritable SLE risk factor, however the causative genes underlying this risk factor are not known. The C1858T polymorphism in PTPN22 (rs2476601) has been associated with risk of SLE, as well as multiple other autoimmune diseases including autoimmune thyroid disease, juvenile idiopathic arthritis, rheumatoid arthritis, and type I diabetes (5). One genetic association study found the risk allele of PTPN22 was associated with SLE only in those SLE patients with concomitant autoimmune thyroid disease (AITD) (6). We have recently shown that AITD is associated with high serum IFN-α activity (7), and AITD is a frequent complication of recombinant IFN-α therapy for chronic viral hepatitis (8). IFN-α has also been implicated in the pathogenesis of many of the other diseases associated with the PTPN22 risk allele, including juvenile idiopathic arthritis (9) and type I diabetes (10). Interestingly, the PTPN22 risk allele is not associated with multiple sclerosis (5). Multiple sclerosis is commonly treated with IFN-β, a type I IFN which signals through the same receptor as IFN-α. The mechanism by which the risk variant of PTPN22 predisposes to autoimmunity is unknown. The polymorphism results in an arginine to tryptophan coding change in the Lyp protein, and work in lymphocytes suggests that the mutation results in decreased T- and B-cell responsiveness, as well as alterations in cytokine production in lymphocytes in vitro (11). While work has thus far focused on lymphocytes, the Lyp protein could presumably alter function in myeloid and dendritic cells. IFN-α has not previously been studied in the context of the PTPN22 risk allele, and any relationship between the risk allele and in vivo serum cytokine profiles is unknown. Given the clustering of high serum IFN-α activity in certain SLE families (4), and the overlapping association of PTPN22 with SLE and a number of other autoimmune diseases in which IFN-α is thought to be important in pathogenesis, we set out to examine serum IFN-α activity in SLE patients as it relates to PTPN22 genotype. We hypothesized that PTPN22 may be associated with high serum IFN-α, which could potentially explain its association with SLE as well as other autoimmune diseases.