A molecular signature of preclinical rheumatoid arthritis triggered by dysregulated PTPN22
Hui-Hsin Chang, … , V. Michael Holers, I-Cheng Ho
Hui-Hsin Chang, … , V. Michael Holers, I-Cheng Ho
Published October 20, 2016
Citation Information: JCI Insight. 2016;1(17):e90045. https://doi.org/10.1172/jci.insight.90045.
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Research Article

A molecular signature of preclinical rheumatoid arthritis triggered by dysregulated PTPN22

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.

Authors

Hui-Hsin Chang, Guang-Yaw Liu, Nishant Dwivedi, Bo Sun, Yuko Okamoto, Jennifer D. Kinslow, Kevin D. Deane, M. Kristen Demoruelle, Jill M. Norris, Paul R. Thompson, Jeffrey A. Sparks, Deepak A. Rao, Elizabeth W. Karlson, Hui-Chih Hung, V. Michael Holers, I-Cheng Ho

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Figure 1

Hypercitrullination in PBMCs of healthy first-degree relatives of rheumatoid arthritis patients recruited at Brigham and Women’s Hospital.

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Hypercitrullination in PBMCs of healthy first-degree relatives of rheuma...
PBMCs obtained from healthy first-degree relatives (FDRs) (A), healthy donors carrying (CT) or not carrying (CC) the C1858T SNP (A and B), patients with osteoarthritis (OA) (B), treated rheumatoid arthritis (tRA) patients (B), and early/untreated rheumatoid arthritis (eRA) patients (C) were directly analyzed by Western blots for the level of citrullinated histone H3 (cit-H3) or total histone H3 (H3). The identity of each donor within each group is denoted with Arabic numerals. The level of cit-H3 was quantified with densitometry and normalized against that of H3. The normalized density of CT #4 in A was arbitrarily set as 1. The normalized density of cit-H3 from all donors is shown in D. The normalized cit-H3 levels of FDR of anti-citrullinated protein antibody (ACPA+) or ACPA– probands are shown in E. Statistical analysis was performed with 1-way ANOVA followed by multiple comparison tests (D) or with 2-tailed Student’s t test (E). The CC group was used as the control group. ***P < 0.001; ****P < 0.0001. The bars shown in D and E represent mean ± SD.