Journal
ARTHRITIS RESEARCH & THERAPY
Volume 17, Issue -, Pages -Publisher
BIOMED CENTRAL LTD
DOI: 10.1186/s13075-015-0859-z
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Funding
- National Program on Key Basic Research Project (973 Program) [2013CB530501]
- National Natural Science Foundation of China [31320103918, 30930085, 31170834]
- Science and Technology Project of Suzhou [SYS201331]
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Introduction: The programmed cell death 1 (PD-1) protein is a critical regulator of T-cell activation and is also an important therapeutic target for autoimmune diseases. Little is known about the regulation and functional properties of the soluble PD-1 (sPD-1) variant. The aim of this study was to examine the role of sPD-1 in the regulation of human and murine rheumatoid arthritis (RA). Methods: Expression of cytokines and sPD-1 in sera, synovial fluid, and peripheral blood (PB) mononuclear cells of patients with RA were analyzed by enzyme-linked immunosorbent assay and quantitative polymerase chain reaction. PD-1 function was assessed in PB T cells after stimulation of the cells with anti-CD3 and PD-L1-Fc to crosslink PD-1. Recombinant PD-1-Fc was injected intraperitoneally into DBA/1 mice with collagen-induced arthritis (CIA) to analyze the function of sPD-1 in vivo. Results: High concentrations of sPD-1 were found in sera and synovial fluid of patients with RA. The levels of serum sPD-1 were significantly correlated with titers of rheumatoid factor (RF) (r = 0.306, p = 0.005) and 28-joint Disease Activity Score (r = 0.545, p < 0.001). Further characterization of sPD-1 revealed that it functionally blocked the inhibitory effect of membrane-bound PD-1 on T-cell activation. Interferon., tumor necrosis factor a, and interleukin 17A were identified as inducers of sPD-1 in vitro. Moreover, PD-1-Fc enhanced proinflammatory cytokine expression, generation of Th1 cells and Th17 cells, and joint pathology in a CIA model. Conclusions: sPD-1 regulates peripheral T-cell responses in both human and murine RA. Thus, sPD-1 may represent an additional biomarker or target in immunomodulatory therapy for RA.
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