Basophil-driven mechanisms in skin-mediated sensitization for allergic lung responses.

• Applicant: Dr. Daniel Radtke
• Subject Area: Clinical Immunology and Allergology ; Immunology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 504087612

Allergen-sensitization via the skin is associated with a dysfunctional barrier that allows for priming of an inflammatory type 2 immune response as observed e.g. in atopic dermatitis (AD) patients. AD is a pruritic skin disease and the most common form of human skin atopy. TSLP-induced (MC903) AD serves as a murine model and is driven by basophil-dependent barrier damage and type 2 immunity. This implies an involvement of basophils in allergen-sensitization via the skin. Sensitization of distant organs likely contributes to the higher asthma rate described as a co-morbidity in AD patients.Using basophil-deficient mice (Mcpt8cre) in the AD model, we provide preliminary data that basophils enhance serum IgG1 and IgE titers to skin-encountered antigen. We further find IgE antibodies to skin-encountered antigen bound by basophils of the lung. These basophils can be activated by in vitro challenge with the same antigen, indicating relevant lung-sensitization via the skin. In addition, upon in vivo lung challenge, basophils promote eosinophil infiltration into the lung of skin-sensitized mice. Thus, our preliminary data indicates that basophils foster lung sensitization to skin-encountered antigen. However, underlying mechanisms and involvement of basophils at different steps in antibody formation and sensitization to skin-encountered antigen remain poorly defined. In this project, we want to: 1. Unravel the effect of basophils on skin-encountered antigen-uptake and antibody-mediated inflammation. 2. Characterize the role of basophils in antibody formation and systemic sensitization to skin-encountered antigen. 3. Validate and mechanistically analyse the functional significance of basophils for lung sensitization to skin-encountered antigen. Gained mechanistic insights will contribute to a comprehensive understanding on the role of basophils in systemic sensitization and skin priming-mediated allergic lung inflammation, which might be reflective for the development of distinct asthma endotypes.

• DFG Programme: Research Grants