过敏性哮喘中新型DC亚群(CD11c+FcεRI+CD49b+)调控Th2应答功能和机制的研究

Asthma is a Th2 response-mediated chronic airway inflammation. However, the DC subset initiating and maintaining Th2 cell polarization and its mechanisms remains controversial. We previously found a novel monocyte-derived DC subset(CD11c+FcεRI+CD49b+) in Schistosoma japonica infection mice which is competent to promote Th2 polarization. Interestingly, this CD11c+FcεRI+CD49b+DC is highly induced in asthmatic patient and mice compared to normal control, but whether this DC subset present in asthmatic disease is able to promote Th2 cell differentiation remains unknown. It has been demonstrated that both IL-3 and TSLP could promote the differentiation of FcεRI positive cells, and the expression of IL-3 and TSLP and their receptors were significantly up-regulated in asthma. Therefore, we hypothesize that : in asthmatic disease, over-expressed IL-3 or TSLP promotes monocyte to differentiate into CD11c+FcεRI+CD49b+DC which hence initiates Th2 immune response. In this study, experimental procedures including DC-T co-culture, conditional cell depletion, adoptive transfer and antibody blocking will be applied to investigate the role of CD11c+FcεRI+CD49b+DC in Th2 response and airway inflammation, and to investigate if IL-3-IL-3R and TSLP-TSLPR contribute to the induction of this Th2-promoting DC subset, thus providing scientific basis for novel therapeutic targets in treatment of asthma including FcεRI-positive DC, IL-3 or TSLP.

过敏性哮喘是Th2应答介导的气道慢性炎症反应。然而，启动和维持Th2应答的DC亚群和机制尚不明确。前期发现，在同为Th2应答介导的日本血吸虫感染模型中，单核细胞来源的新型DC亚群(CD11c+FcεRI+CD49b+)具有促Th2分化能力。此外，哮喘患者外周血和小鼠哮喘模型中均发现较高比例的CD11c+FcεRI+CD49b+DC，但是其临床意义和分化机制尚不清楚。研究证实，IL-3和TSLP具有促进FcεRI阳性细胞分化的功能，且在哮喘疾病中IL-3和TSLP及其受体表达水平显著增加。据此，本研究拟利用哮喘病人外周血和小鼠哮喘模型，通过DC与T细胞共培养、条件性细胞清除等手段研究该新型DC亚群在哮喘疾病Th2应答建立和维持中的作用，以及IL-3或TSLP在该DC亚群分化中的作用和机制，为将来设计针对FcεRI阳性DC、IL-3或TSLP为药靶的新型抗哮喘治疗提供理论基础。

哮喘是最常见的慢性肺部疾病之一。随着环境污染的加重及人们生存环境的改变，哮喘的发病率和病死率在全世界范围内仍然呈惊人地速度逐年增加。临床上对哮喘的诊断主要依赖于临床症状、病史以及肺功能的检测，血清IgE水平、外周血嗜酸性粒细胞比例等指标特异性较低；治疗上主要依赖于糖皮质激素、β2-肾上腺素受体激动剂（SABAs and LABAs）等药物，只对部分患者有效，且有明显副作用。因此，哮喘仍是人类的生命健康的重大威胁。目前得到公认的是，哮喘主要由Th2型免疫应答介导的免疫病理反应，且Th2应答水平的高低与哮喘严重程度呈正相关。但是，哮喘发病中启动和维持Th2应答的DC亚群和机制尚不清楚。 本课题研究发现，在哮喘患者外周血和小鼠哮喘模型中存在较高比例的新型DC亚群（CD11c+FcεRI+CD49b+DC）。通过检测分析过敏性哮喘患者外周血中CD11c+FcεRI+CD49b+DC、Th2细胞比例以及IgE水平，我们发现CD11c+FcεRI+CD49b+DC与Th2应答水平、气道炎症反应程度呈正相关，而与过敏原类型无直接相关性。与此同时，CD11c+FcεRI+CD49b+DC来源于炎症性单核细胞。哮喘患者外周血中TSLP和IL-3浓度显著高于健康对照。且TSLP和IL-3均能诱导人单核细胞分化为CD11c+FcεRI+CD49b+DC。体外共培养实验证实，CD11c+FcεRI+CD49b+DC能诱导初始CD4+T细胞分化为Th2细胞，产生细胞因子IL-4；传统的DC（CD11c+FcεRI-）仅能诱导CD4+T细胞分化为产生IFN-r的Th1细胞。这为过敏性哮喘的诊断、病情评估提供了潜在的监测指标，也为临床上以CD11c+FcεRI+CD49b+DC为哮喘的治疗靶点提供了理论参考。

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