Soluble PD-1 aggravates progression of collagen-induced arthritis through Th1 and Th17 pathways

Abstract

IntroductionThe 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).MethodsExpression 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.ResultsHigh 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.ConclusionssPD-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.

Soluble B and T Lymphocyte Attenuator Correlates to Disease Severity in Sepsis and High Levels Are Associated with an Increased Risk of Mortality

“…Unfortunately we had incomplete data on lymphocyte count and could therefore not evaluate if sPD-1 levels correlated to lymphocyte levels. It has been demonstrated that sPD-1 can block the inhibitory effect of membrane-bound PD-1 on T-cell activation in vitro [38]. The observed decrease of plasma soluble PD-1 in the sepsis cohort could be explained by sPD-1 consumption upon immune activation as a result of ligation to PD-L1 and–L2, resulting in a loss of T cell inhibition in the acute phase of infection.…”

Contribution of Soluble Forms of Programmed Death 1 and Programmed Death Ligand 2 to Disease Severity and Progression in Systemic Sclerosis

“…In some experiments, mice with topo I-induced SSC received intraperitoneal injections of recombinant chimeric PD-1-Fc or PD-L2-Fc (0.15 mg/mouse; R&D Systems) every other day (34,35). In the mouse studies, 5 mice per group were examined.…”

Smoking promotes exacerbated inflammatory features in dendritic cells of Chilean rheumatoid arthritis patients

“…are the phenotypes of auto-reactive CD4 + T-cells involved in autoimmunity, including rheumatoid arthritis (RA) and its mouse model, the collagen-induced-arthritis (CIA) 8,9 . Indeed, due to that functional phenotype of DCs represent a key point of decision to promote tolerance or inflammation in response to specific antigens, the use of tolerogenic DCs loaded with auto-antigens as therapy for the treatment of RA is currently under clinical trials 10,11 .…”