血清淀粉样蛋白A调控CCR6/CCL20表达诱导Treg/Th17失衡在结节病发病机制中的研究

Sarcoidosis is a granulomatous disorder of unknown cause, affecting multiple organs. CD4+T cells play an important role in the formation of granuloma. We have found that the numbers of Treg cells and Th17 cells in both blood and BALF of active sarcoidosis patients were much higher, according to the healthy control. After treatment of glucocorticoid, the number declined, Which showed the imbalance of Treg/Th17 was an important cause of active sarcoidosis. Our research also showed that the expression of SAA,CCR6 and CCL20 was elevated in active sarcoidosis. Recently, some studies shown that serum amyloid A played a crucial role in the formation of granuloma. SAA could upregulate the expression of CCL20,while CCL20 could induce the migration of Treg cells and Th17 cells. Therefore, we hypothesze that, SAA regulates the expression of CCR6/CCL20, and induces Treg/Th17 imbalance, form the granuloma, leading to the active disease. The aim of this study is to test the hypothesis via in vitro and in vivo experiment. Furthermore, we aim to elucidate the mechanism of granuloma formation in sarcoidosis and provide theoretical basis for the new therapeutic targets.

结节病是一病因和发病机制未明的系统性肉芽肿性疾病。CD4+T细胞在结节病肉芽肿的发生、发展中起重要作用。我们研究发现，活动期结节病患者外周血、BALF Treg细胞、Th17细胞数量升高，治疗后恢复正常，提示Treg/Th17失衡是结节病活动的重要因素，且活动期SAA、CCR6、CCL20表达升高。近期文献报道血清淀粉样蛋白A（SAA）在结节病肉芽肿形成中发挥重要作用，SAA可上调CCL20表达，而CCL20可诱导Treg细胞、Th17细胞定向迁移。我们假设，SAA可通过调控CCR6/CCL20表达，影响Treg/Th17平衡，形成肉芽肿，导致疾病的活动。本课题将通过体内体外实验研究SAA对CCR6、CCL20表达的影响，对Th17、Treg细胞数量和功能的影响，在肉芽肿形成中的作用机制，从致病因素、趋化因子、信号通路角度深度了解结节病肉芽肿的发生机制，为寻求新的治疗靶点提供理论依据。

结节病是一种病因和发病机制未明的系统性肉芽肿性疾病。CD4+T细胞在结节病肉芽肿的发生、发展中起重要作用。近期文献报道血清淀粉样蛋白A（SAA）在结节病肉芽肿形成中发挥重要作用，SAA可上调CCL20表达，而CCL20可诱导Treg细胞、Th17细胞定向迁移。本研究从临床样本、体外细胞实验、体内动物实验三个层面，阐明Treg/Th17平衡对结节病活动性的影响，SAA在结节病肉芽肿形成中的作用及相关机制。结果显示，Treg 细胞、Th17 细胞数量及功能与结节病活动性密切相关，SAA在结节病模型肺组织、血清、BALF上清中均高表达，提示与肉芽肿形成密切相关。体外、体内实验均显示，SAA干预可促进Th17细胞增殖，释放炎症因子水平增加，同时促进Treg细胞高表达，SAA干预可使CCL20水平升高，CCR6+细胞表达水平升高，从而影响Treg细胞、Th17细胞水平及功能。CCL20单抗可部分抑制Th17细胞的增殖和炎症因子的释放。SAA可能通过PI3K/AKT、NF-κB信号通路影响Treg/Th17细胞，从而在结节病肉芽肿形成过程中发挥作用。