MBL抑制Th17分化缓解矽肺病变及其免疫调节机制

我们最近发现，矽肺病人血浆MBL浓度降低，其水平与肺功能正相关、与Th17频率负相关；在体外MBL可抑制CD4+ T细胞向Th17分化；染矽尘后MBL–/– 小鼠较WT小鼠急性肺泡炎重、IL-17a表达和Th17频率高。据此提出本项目，拟就MBL抑制Th17分化而缓解矽肺病变及其免疫调节机制进行以下研究：①临床：MBL与Th17及矽肺病变的关系；②体外：细胞表型与调节机制；③动物：MBL–/– 和WT小鼠矽肺模型MBL与Th17及病变的关系、MBL补充治疗/基因治疗的影响。创新点和意义在于：①提出MBL通过调控Th17分化参与免疫调节的新观点，将丰富天然免疫指导获得性免疫应答的基础理论；②从免疫调节紊乱新角度阐述MBL失衡有关疾病发病机制，为其治疗研究提供新的科学依据。③揭示MBL失衡—Th17紊乱—矽肺病变的关系，为靶向MBL调控Th17分化以治疗矽肺提供理论和实验依据。

We recently found that the serum levels of mannan-binding lectin (MBL) in silicosis patients were significantly lower than those in healthy individuals, which was positively correlated with pulmonary functions but negatively correlated with the frequencies of T helper cell 17 (Th17) in the patients; MBL inhibited the differentiation of CD4+ T cells into Th17 cells in an in vitro Th17-inducing culture system; after exposure to silica particles, the pulmonary pathological changes in MBL–/– mice were more serious than thoses in wild type (WT) mice, and the expression of IL-17a and the frequencies of Th17 cells in MBL–/– mice were higher than thoses in WT mice. On the basis of these findings, we propose the present grant. The effects of MBL on the differentiation processe of Th17 cells, including their phenotype changes and the mechanisms underlining these effects such as the relative signal pathways of calreticulin and Th17 cell differentiation and the roles of cytokines and microRNAs, will be studied. The levels of MBL and the frequencies of Th17 cells in blood or lymphoid tissues will be examined, and the association among the MBL levels or MBL genotypes, Th17 cells’ frequencies, disease severity and pulmonary pathological changes will be analyzed in silicosis patients or in silicosis mouse models. The frequencies of Th17 cells and the disease pathology in MBL–/– mice with silicosis will be also examined after MBL reconstitution or MBL gene therapy. The innovation points and the significance of this project lie in: first, the viewpoint that MBL has a hand in acquired immune responses through regulating the differentiation of Th17 cells will be put forward, which will enrich the basic theory that innate immune system instructs acquired immune responses, and provide new theoretical bases and targets for treatment of diseases resulted from MBL imbalance and Th17 function disorder. Second, the pathogenesis mechanisms of MBL unbalance (deficiency or hyperfunction) will be expounded from a new viewpoint of immunoregulation disorder, which may supply new bases and strategies for treatment of this kind of diseases. Third, the relationship among MBL unbalance, Th17 disorder and silicosis disease severity will be revealed, which may help to elucidate the pathogenesis of silicosis and to develop novel strategies for silicosis therapies.