Mechanisms of skin-derived sensitization for allergic lung priming

该提案旨在阐明先天免疫细胞如何影响皮肤中2型免疫应答期间高亲和力IgE和IgG1的形成，以及这如何导致过敏性哮喘的易感性。为此，我们将通过分析（I）皮肤炎症局部部位的引发，（II）引流淋巴结中的适应性免疫应答和（III）针对皮肤抗原的体液免疫转移至肺部，来遵循皮肤引发介导的哮喘发展的预期步骤。在实验上，我们将使用缺乏嗜碱性粒细胞、嗜酸性粒细胞或ILC2的转基因小鼠，在具有抗原特异性组织致敏的特应性皮炎适应模型中。在这种设置中，我们将确定在过敏性免疫引发发作期间所提及的细胞类型在局部皮肤炎症环境中的作用。我们将进一步确定它们在皮肤的2型免疫应答期间对耳引流颈淋巴结中的生发中心应答的数量和质量以及抗原特异性抗体形成的影响。最后，我们将分析肺，以揭示先天效应细胞对最初通过皮肤遇到的抗原致敏的相关性。在这项为期一年的提案中产生的数据将为器官的交叉启动提供机制上的见解，并将为未来在哮喘和过敏反应小鼠模型中的体内功能研究奠定基础。

This proposal aims to elucidate how innate immune cells influence the formation of high-affinity IgE and IgG1 during a type 2 immune response in the skin and how this contributes to predisposition to allergic asthma. To do so we will follow anticipated steps in skin priming-mediated asthma development by analysis of (I) priming at the local site of skin inflammation, (II) the adaptive immune response in the draining lymph node and (III) the transfer of humoral immunity directed against skin antigens to the lung. Experimentally we will use genetically modified mice that lack either basophils, eosinophils or ILC2s in an adapted model of atopic dermatitis with antigen-specific tissue sensitization. In this setup, we will determine the role of the mentioned cell types in the local skin inflammation environment during the onset of an allergic immune priming. We will further define their influence during a type 2 immune response of the skin on the quantity and quality of the germinal center response in the ear-draining cervical lymph nodes and the antigen-specific antibody formation. Finally, we will analyze the lung to uncover the relevance of innate effector cells for sensitization of the lung against antigen initially encountered via the skin. The data generated in this one-year proposal will provide mechanistic insights for cross priming of organs and will build the basis for future functional in vivo studies in mouse models of asthma and anaphylaxis.