MBD2通过调节Th2/Th17细胞群分化及功能参与哮喘的致病机制研究

We found that there is a new subset of CD4+ T cells in asthma patient's peripheral blood, which can secret IL-4 and IL-17, called "Th2/Th17 cells". The numbers of this "Th2/Th17 cells" is closely related to severity of asthma and may be mediated the asthmatic airway mixed inflammation.The clarification of this cells'fuction and regulatory mechanism may become a potential therapeutic targets for severe and or refractory asthma.MBD2 is an important member of MBDs(methy-CpG-binding domain proteins) family.Previous study showed that the expression of MBD2 was significantly increased in asthma patient's CD4+T cells,which was from peripheral blood samples；the result in vitro differentiational experiment showed that Th17 and Th17 relevant IL-17 were dramatically decreased in MBD2(-/-)na?ve CD4+ T cells.These data indicated that MBD2 might play a critical role in asthma and CD4+T cell differentiation and function. Based on our previous results, we plan to study the role of MBD2 in asthma through large scale clinical blood samples analysis and MBD2(-/-) asthma animal model.In addition, we will investigate the molecular mechanism about MBD2 on regulating subsets of CD4+T cells' differentiation and asthma development,which can provide theoretical foundation for the treatment of asthma.

我们发现哮喘患者外周血CD4+T细胞群中存在着一类能同时分泌IL-4及IL-17的细胞亚群，称之为"Th2/Th17型细胞"，其数量与哮喘严重性密切相关，可能介导哮喘气道混合性炎症。阐明该类细胞的作用及调控机制，可能成为重症和/或难治性哮喘重要的潜在治疗靶点。MBD2是甲基化CpG域结合蛋白MBDs家族重要成员。初步研究发现：重症哮喘患者外周血CD4+T细胞存在MBD2表达升高；体外分化研究表明：MBD2-/-型小鼠脾初始 CD4+T细胞定向分化成Th17及IL-17的产生均明显下降，上述结果提示MBD2与哮喘以及CD4+T细胞分化与功能存在密切关系。本项目拟在前期研究基础上，通过哮喘患者血样分析，构建MBD2-/-哮喘小鼠模型，研究MBD2在哮喘发病中的作用；同时分析MBD2参与CD4+T细胞各亚群分化调节以及哮喘发病的可能分子机制，为以MBD2为靶分子的哮喘治疗研究奠定理论基础。

由于重症哮喘致死率高，医疗耗资多，治疗处于瓶颈阶段，阐明其发病机制可能为重症哮喘找出潜在治疗靶点。但目前国内外没有成熟的重症哮喘动物模型。在哮喘发病机制探讨中，免疫学的调节异常的研究占据着重要地位。同时，哮喘发病机制涉及遗传易感因子与环境因素的相互作用，MBD2 是甲基化 CpG 域结合蛋白 MBDs 家族重要成员。我们首先构建重症 小鼠模型，证实MBD2对CD4+ T 细胞分化的影响，并明确了HIF-1α与IRF4在该调控中的作用。通过体外实验研究探索出了MBD2、HIF-1α与IRF4对CD4+ T 细胞分化及功能的影响，并探清了相关分子机制。同时探讨了Th2-Th17双表型细胞对哮喘表型的影响及与MBD2之间的关系，初步探讨了新型免疫学表型和哮喘表型之间的联系。特别是，项目通过MBD2-/-小鼠构建在体实验明确MBD2对各个靶基因及CD4+ T 细胞分化与功能的影响，为以 MBD2 为靶分子的哮喘治疗研究奠定理论基础。