A molecular signature of preclinical rheumatoid arthritis triggered by dysregulated PTPN22
Department of Biochemistry and Molecular Pharmacology; Thompson Lab
Biochemistry | Enzymes and Coenzymes | Musculoskeletal Diseases | Rheumatology
A unique feature of rheumatoid arthritis (RA) is the presence of anti-citrullinated protein antibodies (ACPA). Several risk factors for RA are known to increase the expression or activity of peptidyl arginine deiminases (PADs), which catalyze citrullination and, when dysregulated, can result in hypercitrullination. However, the consequence of hypercitrullination is unknown and the function of each PAD has yet to be defined. Th cells of RA patients are hypoglycolytic and hyperproliferative due to impaired expression of PFKFB3 and ATM, respectively. Here, we report that these features are also observed in peripheral blood mononuclear cells (PBMCs) from healthy at-risk individuals (ARIs). PBMCs of ARIs are also hypercitrullinated and produce more IL-2 and Th17 cytokines but fewer Th2 cytokines. These abnormal features are due to impaired induction of PTPN22, a phosphatase that also suppresses citrullination independently of its phosphatase activity. Attenuated phosphatase activity of PTPN22 results in aberrant expression of IL-2, ATM, and PFKFB3, whereas diminished nonphosphatase activity of PTPN22 leads to hypercitrullination mediated by PADs. PAD2- or PAD4-mediated hypercitrullination reduces the expression of Th2 cytokines. By contrast, only PAD2-mediated hypercitrullination can increase the expression of Th17 cytokines. Taken together, our data depict a molecular signature of preclinical RA that is triggered by impaired induction of PTPN22.
DOI of Published Version
JCI Insight. 2016 Oct 20;1(17):e90045. Link to article on publisher's site
Chang H, Thompson PR, Ho I. (2016). A molecular signature of preclinical rheumatoid arthritis triggered by dysregulated PTPN22. Open Access Articles. https://doi.org/10.1172/jci.insight.90045. Retrieved from https://escholarship.umassmed.edu/oapubs/2957