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

皮肤过敏是一种延迟型超敏反应，是由多种天然或人工合成的反应性化学物质（称为过敏原）在反复接触皮肤后引起的。它被认为是人类中最常见的免疫毒性表达。对化学物质的皮肤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偶联物，这些抗原偶联物将被识别并处理后呈递给免疫系统。半抗原-蛋白质相互作用的一般机制是半抗原与蛋白质之间通过亲核-亲电途径形成共价键。然而，许多过敏原并不符合这个模型。生物学上的关键事件是角质形成细胞的激活，角质形成细胞是表皮的主要细胞群，也是与过敏原接触的第一个细胞，树突状细胞（dc）的激活，树突状细胞是具有免疫能力的皮肤抗原呈递细胞，它们识别、吸收和处理半抗原蛋白复合物，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涉及自由基中间体的替代机制改变皮肤中的蛋白质，并特异性地改变细胞环境，为免疫细胞提供信息，然后激活免疫系统，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，这些反应指示了通过自由基中间体对过敏原反应产生的免疫反应。DEFCHEMSKALL提出了三个行动：在化学中，通过进行反应性研究，建立对自由基反应的氨基酸的完整反应性概况；原位研究在重建的人体表皮组织模型中形成的自由基中间体的行为和衰变；通过检测其激活先天免疫系统的特性，即在角质形成细胞的自然背景下的dc，以及影响这一过程的个体易感性因素，通过对患病与健康角质形成细胞的分析进行了研究。该项目分为5个相互关联的化学-生物特定任务，由一个独特的法德财团执行。它是围绕两个主要的跨学科研究线建立的。一项是由皮肤化学实验室（斯特拉斯堡大学）进行的所有化学研究，另一项是由环境毒理学系（特里尔大学）进行的所有生物和细胞研究。在整合所有获得的数据和我们的专业知识之后，我们的目的是建立一种策略，允许根据自由基中间体的化学反应性评估过敏原前体的致敏潜力，并在角质形成细胞的自然环境中使用dc的激活。

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.