过敏性气道炎症中嗜碱性粒细胞诱发Th2免疫应答与HO-1干预调节

Asthma is an allergic airway disease characterized by a Th2-dominant immune response. Recent studies revealed that basophils were capable of enhancing the differentiation of Th2 by antigen presenting and releasing a large amount of IL-4, thus become a critical factor in initiating Th2-dominant immune response. The results also showed that heme oxygenase-1 (HO-1) expressed by basophils exerted immune regulation. Our previous study demonstrated that basophils were able to express major histocompatibility complex (MHC) class II and costimulatory molecules, such as CD40. The number of the basophils in CD40KO mice was not able to increase significantly after antigen stimulation compared to that in wild-type Balb/C mice. Activation of CD40 using anti-CD40 agonist antibody significantly promoted Th2 priming in vitro. Meanwhile, we found that HO-1 could inhibit the basophils from expressing of CD40 and reduce Th2 differentiation stimulated by the basophils. Based on the above results, in this study, we are going to investigate the involment of CD40 signaling pathway in the establishment of Th2 immune response by mediating the activation and function of the basophils, as well as regulating Th2 differentiation. Moreover, the involvement of HO-1 in inhibiting the establishment of Th2 immune response will also be studied in vivo and in vitro.

Th2免疫应答是过敏性疾病发病的免疫学基础。最新研究表明嗜碱性粒细胞（Ba）通过专职抗原递呈功能、分泌IL-4促进Th2分化，被认为是启动Th2免疫应答的关键因素；此外Ba可表达血红素加氧酶-1（HO-1)，起免疫调节作用。我们前期研究显示：Ba表达CD40；但CD40基因剔除小鼠，经抗原刺激后Ba数量变化不明显，且其骨髓细胞分化为Ba的比例显著下降；而抗CD40抗体增强CD40信号通路则明显提高Ba诱导产生Th2细胞。同时发现HO-1能下调Ba表达CD40、以及抑制Ba对Th2细胞的分化作用。基于上述发现，我们假设：CD40信号通路参与Ba活化与功能，并调节与Th2的相互作用；而HO-1可能直接或通过CD40信号通路调节Ba的活化和功能。因此本课题在前期工作基础上，拟通过体内外研究，探讨在过敏性气道炎症中Ba始动Th2免疫应答和CD40信号通路的作用及其机制，以及HO-1干预的调节效应。

Th2免疫应答是过敏性疾病发病的免疫学基础。最新研究表明嗜碱性粒细胞（Ba）具有专职抗原递呈功能、分泌IL-4促进Th2分化，被认为是启动Th2免疫应答的关键因素；此外Ba可表达血红素加氧酶-1（HO-1），起免疫调节作用。本研究明确了嗜碱性粒细胞在启动过敏性气道炎症中的重要作用，且OX40-OX40L信号通路和CD40-CD40L信号通路介导嗜碱性粒细胞促进Th2免疫应答，诱发过敏性气道炎症，阻断该通路，有望作为临床过敏性哮喘治疗的靶点；其次，研究发现上调HO-1则抑制嗜碱性粒细胞成熟、共刺激分子CD40、CD80、MHC II和活化标志物CD200R表达和DQ-OVA摄取，并促进嗜碱性粒细胞凋亡，从而抑制其诱发的Th2免疫应答及过敏性气道炎症。本研究为阐明嗜酸性粒细胞为主的哮喘炎症的免疫学发病机制提供理论基础，并为临床治疗哮喘提供潜在的靶点。