IL-17/Th17-巨噬细胞调控机制在结节病中作用研究

Sarcoidosis is a systematic disease most affects lung, it is a common-seen interstitial lung disease. The classical pathological characteristic of sarcoidosis is granulomata which consist of macrophages and lymphocytes. Immune response disorder is a key factor in the pathogenesis of sarcoidosis. We found that the elevation of IL-17 and enhancement of Th17 immune response play key roles in sarcoidosis. This project based on the hypothesis that “there is mutual regulation between IL-17/Th17 and macrophages in sarcoidosis”, try to elucidate the mechanisms of IL-17/Th17 response enhanced and macrophages phenotypic difference. Evaluating the level of IL-17/Th17 and the phenotypic of macrophages in lung tissue, peripheral blood and BALF in different stages and prognosis of sarcoidosis patients, culturing lymphocytes and monocytes in vitro, in order to reveal the differentiation mechanisms of Th17 and macrophage in sarcoidosis. Sarcoid-granulomata and sarcoid-fibrosis mouse models are used to investigate the differentiation mechanisms of Th17 and macrophage. By establishing a sarcoidosis mouse model on IL-17 knock-out mice, the mechanism of IL-17 in sarcoidosis by affecting the differentiation of macrophages are investigated.

结节病是一种以肺部受累最多见的多系统疾病，是常见的间质性肺疾病。结节病以形成巨噬细胞和淋巴细胞为主的肉芽肿结构为其典型病理特点。免疫反应异常是结节病发病机制的重要因素，我们的前期研究结果发现IL-17表达升高及Th17免疫反应增强在结节病发病中有重要作用。本项目基于“结节病中存在IL-17/Th17-巨噬细胞相互调控机制”的假设，试图阐明结节病中IL-17/Th17细胞水平异常及巨噬细胞表型差异的发生机制。通过评估不同分期及预后患者肺组织、外周血及肺泡灌洗液中IL-17/Th17表达水平及巨噬细胞表型差异与疾病病情及预后的关系，对淋巴细胞及单核细胞进行体外培养，来揭示结节病中Th17和巨噬细胞分化机制。利用结节病肉芽肿及肺纤维化小鼠动物模型进行Th17及巨噬细胞调控机制研究。通过对IL-17基因敲除小鼠构建结节病动物模型，阐明IL-17通过影响巨噬细胞分化参与结节病发病的机制。

结节病是一种以肺部受累最多见的多系统疾病，是常见的间质性肺疾病。结节病以形成巨噬细胞和淋巴细胞为主的肉芽肿结构为其典型病理特点。免疫反应异常是结节病发病机制的重要因素。本项目基于“结节病中存在IL-17/Th17-巨噬细胞相互调控机制”的假设，通过前瞻性队列研究收集结节病患者的临床资料、外周血及肺泡灌洗液（BALF），通过检测血清、肺泡灌洗液上清中IL-17分泌水平，检测外周血单个核细胞及BALF来源细胞的淋巴细胞亚群分布，评估IL-17/Th17水平与疾病不同分期及预后的关系。通过检测结节病肉芽肿及肺纤维化小鼠动物模型中不同疾病进程的肺组织中巨噬细胞特异的表面标志物表达水平，发现在肉芽肿阶段肺组织中以M1型巨噬细胞为主而肺纤维化小鼠肺内存在M2型巨噬细胞表达升高；同时通过抑制体内IL-17的表达能够有效抑制小鼠结节病的发生发展伴随有M2型巨噬细胞表达减低。我们的研究发现了IL-17/Th17表达与疾病活动性及不良预后相关，同时通过动物实验证实了M2型巨噬细胞参与疾病慢性进程及肺纤维化形成并可能受到IL-17的调控。