Title

A molecular signature of preclinical rheumatoid arthritis triggered by dysregulated PTPN22

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Thompson Lab

Publication Date

2016-10-20

Document Type

Article

Disciplines

Biochemistry | Enzymes and Coenzymes | Musculoskeletal Diseases | Rheumatology

Abstract

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

10.1172/jci.insight.90045

Source

JCI Insight. 2016 Oct 20;1(17):e90045. Link to article on publisher's site

Journal/Book/Conference Title

JCI insight

Comments

Full list of authors omitted for brevity. For full list see article.

Related Resources

Link to Article in PubMed

PubMed ID

27777982

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