Immunological Mechanisms Underlying Mucosal IgE Responses

Background / rationale: Type 2 inflammation is driving several chronic diseases in the airway. On one hand allergic rhinitis (AR) and allergic asthma (AA) are driven by allergen expose, while on the other hand eosinophilic Type 2 inflammation with late onset eosinophilic asthma (LOA) and chronic rhinosinusitis with nasal polyps (CRSwNP) are of non-allergic ethiology. For late onset type2 asthma, many risk factors have been defined, but clear insights into disease ethiology are currently lacking. Given the quintessential role of IgE in disease ethiology of both diseases, understanding the molecular immunological mechanisms underlying mucosal IgE responses is essential to understand disease ethiology. Hypothesis: Distinct mechanisms drive local IgE production in AA and LOA Overall objectives: Elucidate the potential drivers of and immunological pathways leading to local IgE production in AA and LOA, and understand how dupilumab acts on these mechanisms. Methods: A unique combination of state-of-the-art methods will be applied, including single-cell RNA sequencing and receptor profiling, proteomics, determination of the microbial composition, recombinant antibody screening and disease modelling in cell cultures. Expected results: The investigators expect for the first time to discern the drivers of local IgE production in LOA and uncover the immunological pathways leading to local IgE production in AA and LOA. Moreover, the investigators will obtain insights into the role of Dupilumab in modulation mechanisms. Impact: If successful, these insights will answer a long standing, unresolved question in type 2 disease and might aid in the development of novel directed therapeutics for AA and LOA.