Intravenous Immunoglobulin Attenuates Experimental Autoimmune Arthritis by Inducing Reciprocal Regulation of Th17 and Treg Cells in an Interleukin-10-Dependent Manner
Intravenous Immunoglobulin Attenuates Experimental Autoimmune Arthritis by Inducing Reciprocal Regulation of Th17 and Treg Cells in an Interleukin-10-Dependent Manner
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DOI：
10.1002/art.38627
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发表时间：
2014-07-01
影响因子：
13.3
通讯作者：
Cho, Mi-La
中科院分区：
文献类型：
--
作者：
Lee, Seon-Yeong;Jung, Young-Ok;Cho, Mi-La
目标。静脉注射免疫球蛋白(IVIG)被用作各种自身免疫性疾病的治疗剂。本研究的目的是观察IVIG对胶原性关节炎(CIA)的治疗作用，并找出其作用机制。给CIA小鼠静脉注射丙种球蛋白，测定其体内效应。用流式细胞仪分析Th17和Treg细胞频率，用酶联免疫吸附试验检测培养上清液中细胞因子水平。共聚焦显微镜观察脾组织中T细胞和B细胞亚群的变化。与未治疗的小鼠相比，接受IVIG治疗的小鼠的关节炎严重程度评分和关节炎发生率较低。组织病理学分析显示，静脉注射免疫球蛋白的小鼠关节损伤较轻。在IVIG治疗的小鼠中，促炎细胞因子、特异性II型胶原抗体和破骨细胞标志物的表达显著减少。IVIG诱导FoxP3表达增加，并抑制Th17细胞的发育。IVIG组小鼠脾内FoxP3+Treg细胞数增加，Th17细胞数减少。IVIG可增加FoxP3+滤泡辅助T细胞的数量，抑制生发中心B细胞的后续成熟。此外，IVIG还可上调IL-10和Fc-γ受体IIB的表达。在IL-10基因敲除小鼠中，IVIG对关节炎的治疗作用消失。这些结果表明IVIG可能通过调节CD4+T细胞分化而发挥治疗作用。IVIG的疗效依赖于IL-10。
Objective. Intravenous immunoglobulin (IVIG) is used as a therapeutic agent in various autoimmune diseases. The aims of this study were to investigate the therapeutic effects of IVIG on collagen-induced arthritis (CIA) and identify the mechanism responsible for any therapeutic effects.Methods. IVIG was administered to mice with CIA, and the in vivo effects were determined. Th17 and Treg cell frequencies were analyzed by flow cytometry, and cytokine levels in the supernatant were measured by enzyme-linked immunosorbent assay. Subpopulations of T cells and B cells in the spleen were assessed by confocal microscopy.Results. The arthritis severity score and incidence of arthritis were lower in mice treated with IVIG compared with untreated mice. Histopathologic analysis showed less joint damage in mice treated with IVIG. The expression of proinflammatory cytokines, specific type II collagen antibodies, and osteoclast markers was significantly reduced in mice treated with IVIG. Administration of IVIG induced increased FoxP3 expression and inhibited Th17 cell development. The number of FoxP3+ Treg cells was increased, and the number of Th17 cells was decreased in the spleens of mice treated with IVIG. The number of FoxP3+ follicular helper T cells was increased, and subsequent maturation of germinal center B cells was inhibited by IVIG. In addition, IVIG up-regulated interleukin-10 (IL-10) and Fc gamma receptor IIB expression. The treatment effects of IVIG on arthritis were lost in IL-10-knockout mice.Conclusion. These results showed that IVIG has therapeutic effects by modulating CD4+ T cell differentiation. The therapeutic effects of IVIG are dependent on IL-10.