title: Soluble PD-1 aggravates progression of collagen-induced arthritis through Th1 and Th17 pathways.
abstract: BACKGROUND
  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 γ, tumor necrosis factor α, 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.
authors.affiliation: Jiangsu Institute of Clinical Immunology, First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
authors.forename: Cuiping
authors.initials: C
authors.lastname: Liu
authors.affiliation: Jiangsu Institute of Clinical Immunology, First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
authors.forename: Juean
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Jiangsu Province Key Laboratory of Stem Cell Research, Soochow University, Suzhou, 215006, China.
authors.forename: Li
authors.initials: L
authors.lastname: Gao
authors.affiliation: Jiangsu Province Key Laboratory of Stem Cell Research, Soochow University, Suzhou, 215006, China.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Wang
authors.affiliation: Jiangsu Province Key Laboratory of Stem Cell Research, Soochow University, Suzhou, 215006, China.
authors.forename: Xiaohan
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Rheumatology, Third Affiliated Hospital of Soochow University, Changzhou, 213003, China.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.affiliation: Jiangsu Institute of Clinical Immunology, First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Rheumatology, Third Affiliated Hospital of Soochow University, Changzhou, 213003, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Xu
authors.affiliation: Jiangsu Institute of Clinical Immunology, First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Jiangsu Institute of Clinical Immunology, First Affiliated Hospital of Soochow University, Suzhou, 215006, China. xueguangzh@126.com.|Jiangsu Province Key Laboratory of Stem Cell Research, Soochow University, Suzhou, 215006, China. xueguangzh@126.com.
authors.forename: Xueguang
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D055114:X-Ray Microtomography
chemical_list: C105992:PDCD1 protein, human; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor