Abatacept is a recombinant fusion protein composed of the extracellular domain of cytotoxic T-lymphocyte antigen 4 and the Fc portion of immunoglobulin (Ig) G. The mechanism of action of abatacept in rheumatoid arthritis (RA) is believed to be competitive inhibition of T cell costimulation mediated by the binding of CD28 to CD80/CD86 on antigen-presenting cells, and recent studies have shown that abatacept induces reverse signaling in macrophages and osteoclast precursors in a T cell-independent manner. This study aimed to investigate the therapeutic effects of abatacept on circulating monocytes that contribute to RA pathogenesis. Purified circulating monocytes derived from RA patients and controls were cultured in the absence or presence of abatacept or CD28-Ig for 24 h. The recovered cells were subjected to flow cytometry to evaluate the expression levels of cell surface molecules, and cytokines and chemokines in the culture supernatant were measured by multiplex bead arrays. The expression of candidate molecules was further examined by immunoblotting using total cellular extracts of the cultured monocytes. Finally, the effects of abatacept on cytokine production in monocytes stimulated with the immune complex of anti-citrullinated peptide antibodies (ACPAs) were examined. CD64/FcγRI was identified as a monocyte-derived molecule that was downregulated by abatacept but not CD28-Ig. This effect was observed in both RA patients and controls. The abatacept-induced downregulation of CD64/FcγRI was abolished by treatment with anti-CD86 antibodies but not anti-CD80 antibodies. Abatacept suppressed the production of interleukin (IL)-1β, IL-6, C-C motif chemokine ligand 2, and tumor necrosis factor-α in cultured monocytes stimulated with the ACPA immune complex. The therapeutic effects of abatacept on RA are mediated, in part, by the downregulation of CD64/FcγRI on circulating monocytes via direct binding to CD86 and the suppression of immune complex-mediated inflammatory cytokine production.

中文翻译：

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阿巴西普下调循环单核细胞上的 Fcγ 受体 I：类风湿性关节炎患者的潜在治疗机制

阿巴西普是一种重组融合蛋白，由细胞毒性 T 淋巴细胞抗原 4 的细胞外结构域和免疫球蛋白 (Ig) G 的 Fc 部分组成。阿巴西普在类风湿性关节炎 (RA) 中的作用机制被认为是竞争性抑制 T 细胞由 CD28 与抗原呈递细胞上的 CD80/CD86 结合介导的共刺激，最近的研究表明，阿巴西普以不依赖 T 细胞的方式在巨噬细胞和破骨细胞前体中诱导反向信号传导。本研究旨在研究阿巴西普对促进 RA 发病机制的循环单核细胞的治疗作用。来自 RA 患者和对照的纯化循环单核细胞在不存在或存在阿巴西普或 CD28-Ig 的情况下培养 24 小时。将回收的细胞进行流式细胞仪检测以评估细胞表面分子的表达水平，并通过多重珠阵列测量培养上清液中的细胞因子和趋化因子。使用培养的单核细胞的总细胞提取物通过免疫印迹进一步检查候选分子的表达。最后，研究了阿巴西普对用抗瓜氨酸肽抗体 (ACPA) 的免疫复合物刺激的单核细胞中细胞因子产生的影响。CD64/FcγRI 被鉴定为单核细胞衍生的分子，被阿巴西普下调，但不被 CD28-Ig 下调。在 RA 患者和对照中都观察到了这种效果。通过用抗 CD86 抗体而不是抗 CD80 抗体处理消除了阿巴西普诱导的 CD64/FcγRI 下调。阿巴西普抑制用 ACPA 免疫复合物刺激的培养单核细胞中白细胞介素 (IL)-1β、IL-6、CC 基序趋化因子配体 2 和肿瘤坏死因子-α 的产生。阿巴西普对 RA 的治疗作用部分是通过直接结合 CD86 下调循环单核细胞上的 CD64/FcγRI 和抑制免疫复合物介导的炎性细胞因子产生来介导的。