Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immunopharmacology of Education Ministry of China, Hefei 230032, China.
Int Immunopharmacol. 2011 Dec;11(12):2167-75. doi: 10.1016/j.intimp.2011.09.014. Epub 2011 Oct 11.
The transmembrane activator and calcium modulator and cyclophilin ligand interactor-immunoglobulin (TACI-Ig), a recombinant fusion protein that modulates B and T cells activation by binding and neutralizing B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), has been shown to have a therapeutic effects on autoimmune disorders. The objective of this study was to investigate immunoregulatory efficacy of TACI-Ig on helper T (Th) cells in mesenteric lymph node (MLN) of adjuvant-induced arthritis (AA) in rats. The levels of BLyS, APRIL, interferon (IFN)-γ, interleukin (IL)-4, transforming growth factor beta (TGF)-β1, and IL-17 were measured by enzyme-linked immunosorbent assay. The localization and expression of TACI, B-cell maturation antigen (BCMA) and B cell activating factor-receptor (BAFF-R) were investigated by immunohistochemistry and western blotting analysis in MLN. Administration of TACI-Ig significantly reduced histological changes, along with decreased Th1 and Th17-cell cytokines and increased CD4(+)CD25(+)FOXP3(+) regulatory T cell (Treg) and Th2-cell cytokines in MLN of AA rats. The levels of BLyS and APRIL were decreased in MLN homogenate of AA rats after treatment with TACI-Ig. TACI-Ig inhibited TACI and BCMA expression, and increased BAFF-R expression in MLN with AA rats. Taken together, BLyS/APRIL-receptors signaling are important not only for B cell function but for T cell-mediated immune responses. TACI-Ig might exert its anti-inflammatory and immunoregulatory effects through inducing immune balance of Th1/Th2 and Treg/Th17 in peripheral MLN. The mechanisms of TACI-Ig on BLyS/APRIL-receptors-dependent signaling in MLN lymphocytes may play key roles in the pathogenesis of autoimmune disorders.
跨膜激活剂和钙调节剂及亲环素配体相互作用蛋白-免疫球蛋白（TACI-Ig）是一种重组融合蛋白，通过结合和中和 B 淋巴细胞刺激物（BLyS）和增殖诱导配体（APRIL）来调节 B 和 T 细胞的激活，已被证明对自身免疫性疾病具有治疗作用。本研究旨在探讨 TACI-Ig 对佐剂诱导关节炎（AA）大鼠肠系膜淋巴结（MLN）辅助性 T（Th）细胞的免疫调节作用。通过酶联免疫吸附试验测定 BLyS、APRIL、干扰素（IFN）-γ、白细胞介素（IL）-4、转化生长因子β（TGF）-β1 和 IL-17 的水平。通过免疫组织化学和 Western blot 分析检测 MLN 中 TACI、B 细胞成熟抗原（BCMA）和 B 细胞激活因子受体（BAFF-R）的定位和表达。TACI-Ig 治疗可显著减轻 AA 大鼠 MLN 的组织学变化，降低 Th1 和 Th17 细胞细胞因子水平，增加 CD4+CD25+FOXP3+调节性 T 细胞（Treg）和 Th2 细胞细胞因子水平。TACI-Ig 治疗可降低 AA 大鼠 MLN 匀浆中 BLyS 和 APRIL 的水平。TACI-Ig 抑制 AA 大鼠 MLN 中 TACI 和 BCMA 的表达，增加 BAFF-R 的表达。综上所述，BLyS/APRIL 受体信号不仅对 B 细胞功能，而且对 T 细胞介导的免疫反应都很重要。TACI-Ig 可能通过诱导外周 MLN 中 Th1/Th2 和 Treg/Th17 的免疫平衡发挥其抗炎和免疫调节作用。TACI-Ig 在 MLN 淋巴细胞中 BLyS/APRIL 受体依赖性信号转导中的作用机制可能在自身免疫性疾病的发病机制中起关键作用。
