The human body facing and defending from chemical skin allergens reacting by alternative mechanisms: understanding from the molecule to the tissue

• Applicant: Professorin Dr. Brunhilde Blömeke
• Subject Area: Public Health, Healthcare Research, Social and Occupational Medicine
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 284100702

Skin allergy is a delayed-type hypersensitivity reaction caused by a wide range of natural or synthetic man-made reactive chemicals referred to as allergens, after repeated contact with the skin. It is regarded as the most frequent expression of immunotoxicity in humans. Skin allergy to a chemical is the result of a complex multifactorial series of events. The first critical step is chemical. Allergens (haptens) react with skin proteins forming stable antigenic conjugates that will be recognised and processed for presentation to the immune system. The general mechanism for the hapten-protein interaction is the formation of a covalent bond between the hapten and proteins via a nucleophile-electrophile pathway. However, many allergens do not fit this model. Biological key events are the activation of keratinocytes, main cell population of the epidermis and first cells to come into contact with the allergen, and of dendritic cells (DCs), immunocompetent skin antigen-presenting cells that recognize, take up and process the hapten-protein complex ensuring the presentation of altered peptides to T-cells.DEFCHEMSKALL aims at understanding how chemical reactivity of allergens through alternative mechanisms, involving radical intermediates, can alter proteins in the skin and specifically modify the cellular environment providing information to the immune cells that will then activate the immune system inducing the entire process. Our hypothesis is that chemical reactivity translates into specific biological responses in keratinocytes and DCs that dictate the resulting immune responses to allergens reacting through radical intermediates. DEFCHEMSKALL proposes three actions: in chemico by conducting reactivity studies to establish a complete reactivity profile towards amino acids prompt to radical reactions; in situ by studying the behaviour and decay of the formed radical intermediates in reconstructed human epidermis tissue models; in cellulo by examination of their properties to activate the innate immune system, namely DCs in their natural context of keratinocytes, and of individual susceptibility factors influencing this process, investigated by analysis of diseased versus healthy keratinocytes.The project is divided into 5 interlinked chemical-biological specific tasks, carried out by a unique French-German consortium. It is built around two major interdisciplinary lines of research. One concerning all chemistry studies, performed by the Dermatochemistry Laboratory (University of Strasbourg) and another concerning all biological and cellular studies, carried out by the Department of Environmental Toxicology (University of Trier). After integration of all obtained data and with our expertise, the intention is to establish a strategy allowing the evaluation of the sensitizing potential of allergens precursors of radical intermediates based on their chemical reactivity and using the activation of DCs in their natural context of keratinocytes.

• DFG Programme: Research Grants
• International Connection: France
• Partner Organisation: Agence Nationale de la Recherche / The French National Research Agency
• Cooperation Partner: Elena Gimenez-Arnau, Ph.D.