Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, 230032, China.
Acta Pharmacol Sin. 2022 Feb;43(2):387-400. doi: 10.1038/s41401-021-00665-w. Epub 2021 Apr 16.
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by synovitis and the destruction of small joints. Emerging evidence shows that immunoglobulin D (IgD) stimulation induces T-cell activation, which may contribute to diseases pathogenesis in RA. In this study, we investigated the downstream signaling pathways by which IgD activated T cells as well as the possible role of IgD in the T-B interaction. Peripheral blood mononuclear cells were isolated from peripheral blood of healthy controls and RA patients. We demonstrated that IgD activated T cells through IgD receptor (IgDR)-lymphocyte-specific protein tyrosine kinase (Lck)-zeta-associated protein 70 (ZAP70)/phosphatidylinositol 3-kinase (PI3K)/nuclear factor kappa-B (NF-κB) signaling pathways; IgD-induced CD4 T cells promoted the proliferation of CD19 B cells in RA patients. A novel fusion protein IgD-Fc-Ig (composed of human IgD-Fc domain and IgG Fc domain, which specifically blocked the IgD-IgDR binding) inhibited the coexpression of IgDR and phosphorylated Lck (p-Lck) and the expression levels of p-Lck, p-ZAP70, p-PI3K on CD4 T cells, and decreased NF-κB nuclear translocation in Jurkat cells. Meanwhile, IgD-Fc-Ig downregulated the expression levels of CD40L on CD4 T cells as well as CD40, CD86 on CD19 B cells in RA patients and healthy controls. It also decreased the expression levels of CD40L on CD4 T cells and CD40 on CD19 B cells from spleens of collagen-induced arthritis (CIA) mice and reduced IL-17A level in mouse serum. Moreover, administration of IgD-Fc-Ig (1.625-13 mg/kg, iv, twice a week for 4 weeks) in CIA mice dose-dependently decreased the protein expression levels of CD40, CD40L, and IgD in spleens. IgD-Fc-Ig restrains T-cell activation through inhibiting IgD-IgDR-Lck-ZAP70-PI3K-NF-κB signaling, thus inhibiting B-cell activation. Our data provide experimental evidences for application of IgD-Fc-Ig as a highly selective T cell-targeting treatment for RA.
类风湿关节炎（RA）是一种慢性系统性自身免疫性疾病，其特征为滑膜炎和小关节破坏。新出现的证据表明，免疫球蛋白 D（IgD）刺激诱导 T 细胞活化，这可能有助于 RA 的发病机制。在这项研究中，我们研究了 IgD 激活 T 细胞的下游信号通路，以及 IgD 在 T-B 相互作用中的可能作用。我们从健康对照者和 RA 患者的外周血中分离出外周血单核细胞。我们证明 IgD 通过 IgD 受体（IgDR）-淋巴细胞特异性蛋白酪氨酸激酶（Lck）-zeta 相关蛋白 70（ZAP70）/磷酸肌醇 3-激酶（PI3K）/核因子 kappa-B（NF-κB）信号通路激活 T 细胞；IgD 诱导的 CD4 T 细胞促进 RA 患者 CD19 B 细胞的增殖。一种新型融合蛋白 IgD-Fc-Ig（由人 IgD-Fc 结构域和 IgG Fc 结构域组成，特异性阻断 IgD-IgDR 结合）抑制 CD4 T 细胞上 IgDR 和磷酸化 Lck（p-Lck）的共表达以及 p-Lck、p-ZAP70、p-PI3K 的表达水平，并减少 Jurkat 细胞中 NF-κB 的核转位。同时，IgD-Fc-Ig 下调 RA 患者和健康对照者 CD4 T 细胞上 CD40L 的表达水平以及 CD19 B 细胞上 CD40、CD86 的表达水平。它还降低了胶原诱导关节炎（CIA）小鼠脾脏中 CD4 T 细胞上 CD40L 和 CD19 B 细胞上 CD40 的表达水平，并降低了小鼠血清中的 IL-17A 水平。此外，在 CIA 小鼠中，IgD-Fc-Ig（1.625-13mg/kg，iv，每周两次，共 4 周）给药剂量依赖性地降低了脾脏中 CD40、CD40L 和 IgD 的蛋白表达水平。IgD-Fc-Ig 通过抑制 IgD-IgDR-Lck-ZAP70-PI3K-NF-κB 信号通路抑制 T 细胞活化，从而抑制 B 细胞活化。我们的数据为 IgD-Fc-Ig 作为一种高度选择性的 T 细胞靶向治疗 RA 提供了实验证据。
