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

皮肤过敏是一种迟发型超敏反应，由广泛的天然或合成的人造反应性化学物质（称为过敏原）与皮肤反复接触后引起。它被认为是人体中最常见的免疫毒性表现。皮肤对化学物质过敏是一系列复杂的多因素事件的结果。第一个关键步骤是化学。过敏原（半抗原）与皮肤蛋白反应，形成稳定的抗原缀合物，这些缀合物将被识别和处理以呈递给免疫系统。半抗原-蛋白质相互作用的一般机制是通过亲核-亲电途径在半抗原和蛋白质之间形成共价键。然而，许多过敏原并不符合这个模型。生物学关键事件是角质形成细胞的活化，角质形成细胞是表皮的主要细胞群，是与过敏原接触的第一个细胞，树突状细胞（DC）是具有免疫活性的皮肤抗原呈递细胞，其识别、摄取和处理半抗原-蛋白质复合物，确保将改变的肽呈递给T细胞。DEFCHEMSKALL旨在了解过敏原的化学反应性如何通过替代机制，涉及自由基中间体，可以改变皮肤中的蛋白质，并特异性地改变细胞环境，向免疫细胞提供信息，然后免疫细胞将激活免疫系统，诱导整个过程。我们的假设是，化学反应性转化为角质形成细胞和DC中的特定生物反应，这些反应决定了对过敏原的免疫反应，这些过敏原通过自由基中间体反应。DEFCHEMSKALL提出了三个行动：在化学方面，通过进行反应性研究，建立一个完整的反应性概况，对氨基酸促进自由基反应;在原位，通过研究重建的人表皮组织模型中形成的自由基中间体的行为和衰变;在细胞中，通过检查它们激活先天免疫系统的特性，即在角质形成细胞的天然环境中的DC，以及影响这一过程的个体易感性因素，通过分析患病与健康的角质形成细胞进行研究。该项目分为5个相互关联的化学-生物学具体任务，由一个独特的法国-德国财团进行。它是围绕两个主要的跨学科研究线。一项涉及所有化学研究，由皮肤化学实验室（斯特拉斯堡大学）进行，另一项涉及所有生物和细胞研究，由环境毒理学系（特里尔大学）进行。整合所有获得的数据和我们的专业知识后，目的是建立一种策略，允许评估过敏原前体的自由基中间体的致敏潜力的基础上，他们的化学反应性和使用激活的DC在其自然环境中的角质形成细胞。

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.