Mechanisms of skin-derived sensitization for allergic lung priming

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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.