CD103+DC在新生期肺炎链球菌感染实验性哮喘中的作用机制探讨

Asthma is the most common chronic airway disease in children and the pathogenesis remains unclear. Recent studies suggest that deficiency in Foxp3+Tr may play an important role in the pathogenesis of asthma. Our pilot studies suggest streptococcus pneumoniae (S.p) infection in neonatal mice inhibits Foxp3+Tr development and induce experimental asthma. More recent studies demonstrated CD103+DC can promote Foxp3+Tr development. Intestinal bacterial pathogens have been shown to inhibit CD103+DC expression and the development of Foxp3+Tr which leads to chronic intestinal inflammation. It is not known whether S.p infection in neonatal mice induced inhibition of Foxp3+Tr development is associated with a decreased expression and/or function of CD103+DC. Based on our pilot studies, we aim to study further the effects of neonatal S.p infection on the number and function of CD103+DC, to determine the association between CD103+DC and Foxp3+Tr development and their relation with airway inflammation and hyperresponsiveness of experimental asthma. Through the research we can determine the immune mechanisms of neonatal S.p infection inhibiting Foxp3+Tr development, inform strategies of early intervention to Foxp3+Tr cells development and provide new theoretical foundation for primary prevention and clinical treatment of asthma.

哮喘是常见慢性气道炎症性疾病，研究显示Foxp3+Tr发育抑制与哮喘发生相关。我们前期研究发现新生期S.p感染抑制Foxp3+Tr发育促进哮喘发生，但Foxp3+Tr发育抑制机制不清。最新研究发现CD103+DC能促进Foxp3+Tr发育，致病菌感染抑制肠道CD103+DC表达引起Foxp3+Tr发育抑制可致慢性炎症性肠病，新生期S.p感染抑制Foxp3+Tr发育是否与S.p感染抑制肺部CD103+DC表达及功能有关尚未见报道。本课题进一步研究新生期S.p感染对肺CD103+DC表达水平、功能的影响及其与Foxp3+Tr表达相关性，研究S.p感染鼠肺CD103+DC对初始CD4+T细胞分化为Foxp3+Tr的影响，探讨回输CD103+DC对新生期S.p感染实验性哮喘及Foxp3+Tr发育的影响，阐明新生期S.p感染抑制Foxp3+Tr发育促进哮喘发生机制，为防治哮喘提供新思路和理论基础。

我们前期研究发现新生期肺炎链球菌（S.p)感染促进哮喘发生，可能与感染后抑制Foxp3+Tr细胞发育有关，但具体机制尚不清楚。有研究肠道致病菌感染发现，抑制肠道CD103+DC表达及Foxp3+Tr发育可致慢性炎症性肠病。本课题组进一步研究了新生期S.p感染对肺CD103+DC表达水平、功能的影响及其与Foxp3+Tr表达相关性，以期阐明新生期S.p感染抑制Foxp3+Tr发育促进哮喘发生机制。体内研究发现，新生期肺炎链球菌感染抑制肺组织CD103+DC及Foxp3+Tr细胞发育，破坏CD103+DC及Foxp3+Tr表达相关性，同时诱导CD11b+DCs聚集增多而促进CD4+Th17表达，感染后DCs表面共刺激分子CD40/86及MHC-Ⅱ表达均增强。体外实验证实，新生期肺炎链球菌感染后CD103+DC与初始CD4+T细胞共培养上清液IL-10，IL-12，TGF-β水平显著降低，共培养细胞中t-bet、Foxp3-mRNA表达水平显著降低，Foxp3+Tr及Th1细胞水平明显减少，Th2、Th17细胞水平显著升高。通过研究证实，新生期肺炎链球菌感染抑制初始CD4+T细胞向Foxp3+Tr及Th1细胞分化发育，诱导初始CD4+T细胞向Th17及Th2分化，可能与感染抑制CD103+DC的分化及成熟有关，初步阐明新生期S.p感染抑制Foxp3+Tr发育促进哮喘发生的机制，为防治哮喘提供新思路和理论基础。