Abstract
Despite the development of several targeted therapies for rheumatoid arthritis (RA), there is still no reliable drug-specific predictor to assist rheumatologists in selecting the most effective targeted therapy for each patient. Recently, a gene signature caused by impaired induction of PTPN22 in anti-CD3 stimulated peripheral blood mononuclear cells (PBMC) was observed in healthy at-risk individuals. However, the downstream target genes of PTPN22 and the molecular mechanisms regulating its expression are still poorly understood. Here we report that the PTPN22 gene signature is also present in PBMC from patients with active RA and can be reversed after effective treatment. The expression of PTPN22 correlates with that of more than 1000 genes in Th cells of anti-CD3 stimulated PBMC of healthy donors and is inhibited by TNFα or CD28 signals, but not IL-6, through distinct mechanisms. In addition, the impaired induction of PTPN22 in PBMC of patients with active RA can be normalized in vitro by several targeted therapies. More importantly, the in vitro normalization of PTPN22 expression correlates with clinical response to the targeted therapies in a longitudinal RA cohort. Thus, in vitro normalization of PTPN22 expression by targeted therapies can potentially be used to predict clinical response.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 121-130 |
| Number of pages | 10 |
| Journal | Journal of Autoimmunity |
| Volume | 101 |
| DOIs | |
| State | Published - Jul 2019 |
Funding
This work was supported by Innovative Research Grant and K Supplement Award from Rheumatology Research Foundation ; Tobe and Stephen Malawista, MD Endowment in Academic Rheumatology; Flagship Program of Precision Medicine for Asia-Pacific Biomedical Valley, National Health Research Institutes, Taiwan ; National Institutes of Health (grant numbers AR070171 , AR074788 , AR072791 , AR064850 , AR070253 , AR049880 , HG008685 , AR057327 , HL119718 , AR071326 , AR069688 , AR066953 , AR072577 , and OT2OD026553 ). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. A patent application based on the results described in this manuscript has been submitted. YCL was an unpaid advisory board member of Eli Lilly and received a grant from Pfizer. There is no other conflict of interest.This work was supported by Innovative Research Grant and K Supplement Award from Rheumatology Research Foundation; Tobe and Stephen Malawista, MD Endowment in Academic Rheumatology; Flagship Program of Precision Medicine for Asia-Pacific Biomedical Valley, National Health Research Institutes, Taiwan; National Institutes of Health (grant numbers AR070171, AR074788, AR072791, AR064850, AR070253, AR049880, HG008685, AR057327, HL119718, AR071326, AR069688, AR066953, AR072577, and OT2OD026553). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank Michael Gurish for technical help and Adam Chicoine and the Human Immunology Center Flow Cytometry core for assistance with cell sorting. We also thank Alyssa Wohlfahrt for her assistance in the recruitment of subjects and general oversight of the CPIRA study. We thank the participants and staff of the Partners Biobank for their contributions.
Keywords
- CD28
- PTPN22
- Response prediction
- Rheumatoid arthritis
- TNFα
- Targeted therapy
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
