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PTPN22: its role in SLE and autoimmunity.

ABSTRACT: A functional variant of protein tyrosine phosphatase nonreceptor 22 (PTPN22) has recently been shown to be associated with multiple autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis, type 1 diabetes, and autoimmune thyroid disease. In this review, we discuss the structure and function of this gene and its disease-associated polymorphisms. In addition, we review the studies investigating the association between this gene and SLE, along with other autoimmune diseases.

SUBMITTER: Chung SA

PROVIDER: S-EPMC2875134 | biostudies-literature | 2007 Dec

REPOSITORIES: biostudies-literature

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PTPN22: its role in SLE and autoimmunity.

Chung Sharon A SA Criswell Lindsey A LA

Autoimmunity 20071201 8

A functional variant of protein tyrosine phosphatase nonreceptor 22 (PTPN22) has recently been shown to be associated with multiple autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis, type 1 diabetes, and autoimmune thyroid disease. In this review, we discuss the structure and function of this gene and its disease-associated polymorphisms. In addition, we review the studies investigating the association between this gene and SLE, along with other autoimmune d ...[more]

PMID: 18075792

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Project description:BACKGROUND:Cancer immunotherapy has evolved from interferon-alpha (IFN?) and interleukin-2 in the 1980s to CTLA-4 and PD-1/PD-L1 checkpoint inhibitors (CPIs), the latter highlighting the importance of enhancing T-cell functions. While the search for novel immunomodulatory pathways continues, combination therapies augmenting multiple pathways can also increase efficacy. The association of autoimmune-related adverse events with clinical efficacy following CPI treatment has been inferred and suggests that breaking tolerance thresholds associated with autoimmunity may affect host immune responses for effective cancer immunotherapy. RESULTS:Here, we show that loss of autoimmune associated PTPN22, a key desensitization node for multiple signaling pathways, including IFN? receptor (IFNAR) and T-cell receptor, can augment tumor responses. Implantation of syngeneic tumors in Ptpn22-/- mice led to expansion and activation of peripheral and intratumoral T cells and, in turn, spontaneous tumor regression as well as enhanced responses in combination with anti-PD-L1 treatment. Using genetically modified mice expressing a catalytically inactive PTPN22 or the autoimmunity-associated human single-nucleotide polymorphism variant, augmentation of antitumor immunity was dependent on PTPN22 phosphatase activity and partially on its adaptor functions. Further, antitumor responses were dependent on both CD4+ and?CD8+T cells and, in part, IFNAR function. Finally, we demonstrate that the autoimmune susceptibility Ptpn22(C1858T) variant is associated with lower risk of developing non-melanoma skin cancers, improved overall survival and increased risk for development of hyperthyroidism or hypothyroidism following atezolizumab (anti-PD-L1) treatment. CONCLUSIONS:Together, these data suggest that inhibition of PTPN22 phosphatase activity may provide an effective therapeutic option for cancer immunotherapy and that exploring genetic variants that shift immune tolerance thresholds may serve as a paradigm for finding new cancer immunotherapy targets.

Project description:Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a negative regulator of T-cell activation associated with several autoimmune diseases, including systemic lupus erythematosus (SLE). Missense rs2476601 is associated with SLE in individuals with European ancestry. Since the rs2476601 risk allele frequency differs dramatically across ethnicities, we assessed robustness of PTPN22 association with SLE and its clinical sub-phenotypes across four ethnically diverse populations. Ten SNPs were genotyped in 8220 SLE cases and 7369 controls from in European-Americans (EA), African-Americans (AA), Asians (AS), and Hispanics (HS). We performed imputation-based association followed by conditional analysis to identify independent associations. Significantly associated SNPs were tested for association with SLE clinical sub-phenotypes, including autoantibody profiles. Multiple testing was accounted for by using false discovery rate. We successfully imputed and tested allelic association for 107 SNPs within the PTPN22 region and detected evidence of ethnic-specific associations from EA and HS. In EA, the strongest association was at rs2476601 (P = 4.7 × 10(-9), OR = 1.40 (95% CI = 1.25-1.56)). Independent association with rs1217414 was also observed in EA, and both SNPs are correlated with increased European ancestry. For HS imputed intronic SNP, rs3765598, predicted to be a cis-eQTL, was associated (P = 0.007, OR = 0.79 and 95% CI = 0.67-0.94). No significant associations were observed in AA or AS. Case-only analysis using lupus-related clinical criteria revealed differences between EA SLE patients positive for moderate to high titers of IgG anti-cardiolipin (aCL IgG >20) versus negative aCL IgG at rs2476601 (P = 0.012, OR = 1.65). Association was reinforced when these cases were compared to controls (P = 2.7 × 10(-5), OR = 2.11). Our results validate that rs2476601 is the most significantly associated SNP in individuals with European ancestry. Additionally, rs1217414 and rs3765598 may be associated with SLE. Further studies are required to confirm the involvement of rs2476601 with aCL IgG.

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PTPN22: its role in SLE and autoimmunity.

Publications

PTPN22: its role in SLE and autoimmunity.

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