Dataset Information

PTPN22.6, a dominant negative isoform of PTPN22 and potential biomarker of rheumatoid arthritis.

ABSTRACT: PTPN22 is a tyrosine phosphatase and functions as a damper of TCR signals. A C-to-T single nucleotide polymorphism (SNP) located at position 1858 of human PTPN22 cDNA and converting an arginine (R620) to tryptophan (W620) confers the highest risk of rheumatoid arthritis among non-HLA genetic variations that are known to be associated with this disease. The effect of the R-to-W conversion on the phosphatase activity of PTPN22 protein and the impact of the minor T allele of the C1858T SNP on the activation of T cells has remained controversial. In addition, how the overall activity of PTPN22 is regulated and how the R-to-W conversion contributes to rheumatoid arthritis is still poorly understood. Here we report the identification of an alternative splice form of human PTPN22, namely PTPN22.6. It lacks the nearly entire phosphatase domain and can function as a dominant negative isoform of the full length PTPN22. Although conversion of R620 to W620 in the context of PTPN22.1 attenuated T cell activation, expression of the tryptophan variant of PTPN22.6 reciprocally led to hyperactivation of human T cells. More importantly, the level of PTPN22.6 in peripheral blood correlates with disease activity of rheumatoid arthritis. Our data depict a model that can reconcile the conflicting observations on the functional impact of the C1858T SNP and also suggest that PTPN22.6 is a novel biomarker of rheumatoid arthritis.

SUBMITTER: Chang HH

PROVIDER: S-EPMC3299735 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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PTPN22.6, a dominant negative isoform of PTPN22 and potential biomarker of rheumatoid arthritis.

Chang Hui-Hsin HH Tai Tzong-Shyuan TS Lu Bing B Iannaccone Christine C Cernadas Manuela M Weinblatt Michael M Shadick Nancy N Miaw Shi-Chuen SC Ho I-Cheng IC

PloS one 20120312 3

PTPN22 is a tyrosine phosphatase and functions as a damper of TCR signals. A C-to-T single nucleotide polymorphism (SNP) located at position 1858 of human PTPN22 cDNA and converting an arginine (R620) to tryptophan (W620) confers the highest risk of rheumatoid arthritis among non-HLA genetic variations that are known to be associated with this disease. The effect of the R-to-W conversion on the phosphatase activity of PTPN22 protein and the impact of the minor T allele of the C1858T SNP on the a ...[more]

PMID: 22427951

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Project description:BackgroundChemerin has a potential role in perpetuating inflammation in autoimmune diseases. Nevertheless, to date, there is no conclusive information on whether high chemerin levels increase the severity of rheumatoid arthritis (RA). Therefore, this study evaluated whether serum chemerin is a biomarker of disease activity in RA patients.MethodsStudy design: cross-sectional. The assessment included clinical and laboratory characteristics, body mass index (BMI) and fat mass. The severity of the disease activity was identified according to the DAS28-CRP index as follows: A) RA with a DAS28-CRP≤2.9 (remission/mild activity) and B) RA with a DAS28-CRP>2.9 (moderate/severe activity). Serum chemerin concentrations were measured by ELISA, and ≥103 ng/mL was considered a high level. Logistic regression analysis was applied to determine whether high chemerin levels were associated with disease activity in RA after adjusting for confounders. Multiple regression analysis was performed to identify variables associated with chemerin levels.ResultsOf 210 RA patients, 89 (42%) subjects had moderate/severe disease activity and had higher serum chemerin levels than patients with low disease activity or remission (86 ± 34 vs 73± 27; p = 0.003). Serum chemerin correlated with the number of swollen joints (r = 0.15; p = 0.03), DAS28-CRP (r = 0.22; p = 0.002), and C-reactive protein levels (r = 0.14; p = 0.04), but no correlation was observed with BMI and fat mass. In the adjusted logistic regression analysis, high chemerin levels (≥103 ng/mL) were associated with an increased risk of moderate/severe disease activity (OR: 2.76, 95% CI 1.35-5.62; p = 0.005). In the multiple regression analysis, after adjusting for potential confounders, serum chemerin levels were associated with higher DAS28-CRP (p = 0.002).ConclusionsHigher chemerin levels increased the risk of moderate and severe disease activity in RA. These results support the role of chemerin as a marker of inflammation in RA. Follow-up studies will identify if maintaining low chemerin levels can be used as a therapeutic target.

Dataset Information

PTPN22.6, a dominant negative isoform of PTPN22 and potential biomarker of rheumatoid arthritis.

Publications

PTPN22.6, a dominant negative isoform of PTPN22 and potential biomarker of rheumatoid arthritis.

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