Rheumatoid arthritis (RA) is a T lymphocyte-mediated autoimmune disease, although its immune mechanism has not been fully studied. In this study, healthy controls (HC), osteoarthritis patients (OA), and RA patients were enrolled, and mice were evenly divided into control, collagen-induced arthritis (CIA), PD-1 Fc/CIA (PD-1 Fc membrane fusion protein administered to CIA mice), OX40 Fc/CIA (OX40 Fc membrane fusion protein administered to CIA mice), and PD-1 Fc + OX40 Fc/CIA groups. The expressions of programmed death-1 (PD-1) and OX40 in CD4⁺ T lymphocytes and the levels of sPD-1, immunoglobulin, and proinflammatory factors in patients and mice were measured. The results showed that the expression levels of PD-1 and OX40 in CD4⁺ T lymphocytes separated from the peripheral blood and synovial fluid of RA patients and the spleen of CIA mice were observably elevated. The levels of soluble PD-1, interleukin (IL)-2, IL-4, IL-5, IL-17, and interferon-γ (IFN-γ) in RA patients obviously increased. In animal experiments, PD-1 Fc not only increased the serum levels of immunoglobulin G (IgG), IgG1, and IgG2a in CIA mice, but also increased the levels of IL-4, IL-2, IL-5, IL-17, and IFN-γ in mouse spleen cells and joint tissues, which, however, were reversed by OX40 Fc. In conclusion, OX40 inhibition could reverse the progression of RA caused by PD-1 blocking, and PD-1 might be a potential target for RA. Clinical Trials.gov ID: HGH2018012203

中文翻译：

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类风湿性关节炎共刺激分子PD-1和OX40的免疫功能及机制

类风湿性关节炎（RA）是一种 T 淋巴细胞介导的自身免疫性疾病，但其免疫机制尚未得到充分研究。本研究纳入健康对照（HC）、骨关节炎患者（OA）和RA患者，将小鼠平均分为对照、胶原诱导性关节炎（CIA）、PD-1 Fc/CIA（PD-1 Fc膜融合蛋白给予 CIA 小鼠）、OX40 Fc/CIA（给予 CIA 小鼠的 OX40 Fc 膜融合蛋白）和 PD-1 Fc + OX40 Fc/CIA 组。测定CD4 ⁺ T淋巴细胞中程序性死亡-1（PD-1）和OX40的表达，以及患者和小鼠体内sPD-1、免疫球蛋白和促炎因子的水平。结果显示CD4 ⁺中PD-1和OX40的表达水平从 RA 患者的外周血和滑液以及 CIA 小鼠的脾脏中分离的 T 淋巴细胞明显升高。RA患者可溶性PD-1、白细胞介素(IL)-2、IL-4、IL-5、IL-17和干扰素-γ(IFN-γ)水平明显升高。在动物实验中，PD-1 Fc不仅提高了CIA小鼠血清中免疫球蛋白G（IgG）、IgG1和IgG2a的水平，还提高了IL-4、IL-2、IL-5、IL-17的水平和小鼠脾细胞和关节组织中的 IFN-γ，然而，它们被 OX40 Fc 逆转。总之，OX40抑制可以逆转由PD-1阻断引起的RA的进展，PD-1可能是RA的潜在靶点。Clinical Trials.gov ID：HGH2018012203