过敏原-IgE-FcεRI活化树突状细胞在特应性皮炎中的作用及机制研究

Allergen and its specific IgE are closely related with atopic dermatitis (AD). Exposure to allergens could aggravate AD inflammation, but the exact mechanism is unclear. The IgE Fc receptor (FcεRI) is an important receptor that bridges allergens, specific IgE and immune effector cells together. FcεRI expressed on mast cells and basophils mediates immediate hypersensitivity that is inconsistent with the delayed inflammatory properties of AD lesions. We found that the number of dendritic cells (DCs) in AD lesions increased as well as the expression of FcεRI. Dust mite antigen could activate DCs in AD patients and induced the secretion of TNF-α and IL-1β. In consideration of our preliminary data, we put forward the hypothesis that FcεRI expressed in DC mediates the recognition of allergens and their specific IgE, which in turn activates DC and promotes the inflammation of AD. In this study, we propose to use dust mites as model antigen to study the following questions in human MoDC and human FcεRI transgenic mice：①The mechanism of dust mite-IgE-FcεRI on DC activation and T cell polarization; ② The role of FcεRI via DCs in mediating skin immune response. Through the above study, it is expected to reveal the mechanism of allergen-specific IgE in promoting AD skin inflammation and establish a new strategy for the prevention and treatment of AD.

过敏原及其特异性IgE与特应性皮炎(AD)密切相关，接触过敏原会导致AD症状加重，但确切的机制不清。IgE Fc受体(FcεRI)是连接过敏原、特异性IgE和免疫效应细胞的重要受体，表达于肥大细胞和嗜碱性粒细胞的FcεRI介导速发型应答，与AD皮损的迟发型炎症性质不符。我们发现AD皮损中树突状细胞(DC)数量增多，其表面FcεRI增加，尘螨抗原可以活化AD患者DC，诱导TNF-α和IL-1β分泌，因而提出假说认为，表达于DC的FcεRI介导了对过敏原-特异性IgE的识别，进而活化DC并促进AD的皮肤炎症。本课题拟以尘螨为模式抗原，从人MoDC和人FcεRI转基因小鼠两个层面，分析尘螨-IgE-FcεRI对DC活化、介导T细胞极化的作用及分子机制，研究FcεRI通过DC在介导皮肤免疫应答中的作用及机制。本研究有望揭示过敏原-特异性IgE促进AD皮肤炎症的机制，建立AD预防和治疗的新策略。

特应性皮炎（atopic dermatitis, AD）是一种常见的慢性、复发性、炎症性皮肤病。过敏原及其特异性IgE在AD中的作用一直被广泛关注。约70％的AD患者血清总IgE水平升高，约60%的AD 患者可检出尘螨特异性IgE，其滴度与疾病严重程度呈正相关。因此我们提出假说认为，皮肤炎症是诱导IgE产生的重要途径，表达于DC的FcεRI介导了对过敏原-特异性IgE的识别，进而活化DC并促进AD的皮肤炎症。本课题研究内容包括以下三个部分：1、NP+BSA和IgE-NP为模式抗原，研究了过敏原-IgE-FcεRI对DC活化、介导T细胞极化的作用及分子机制；2、通过对B细胞受体库的分析，探讨AD和银屑病中IgE的起源；3、过敏原在诱导经皮耐受小鼠模型中的作用机制。研究发现：1、AD皮损中树突状细胞(DC)数量增多，其表面FcεRI增加，尘螨抗原可以活化AD患者DC，诱导TNF-α和IL-1β分泌，并激活T细胞向Th2方向极化；2、IGHE来自AD和银屑病的比例高于正常对照，与血清总IgE水平呈正相关。IGHE可变区突变值低于IGHG和IGHA，但高于IGHM和IGHD，表明IgE的自然和适应性混合来源。在尘螨特异性IgE水平高的AD和银屑病患者中，IgE的VH使用存在弱偏倚。3、完整皮肤可以对过敏原产生免疫耐受，朗格汉斯细胞是产生经皮耐受所必须的。在小鼠模型中，朗格汉斯细胞通过langerin介导皮肤对卵清蛋白的免疫耐受。本研究有望揭示过敏原-特异性IgE促进AD皮肤炎症的机制，建立AD预防和治疗的新策略。