Understand mechanisms of mast cell reactivity and induced anergy and how these are modulated by biologics in food allergy treatment

过敏性疾病，如哮喘、过敏性鼻炎和食物过敏，是一个重要的公共卫生负担，严重影响人们的生活质量，特别是在发达国家。这些疾病的特点是存在针对我们环境中常见事物的IgE抗体，如屋尘螨（哮喘）、花粉（过敏性鼻炎）和花生（食物过敏）。摄入过敏原的途径和频率变化很大。例如，接触草花粉是季节性的，而食物过敏原是偶然通过胃肠道吸收的。与吸入性过敏原相比，后者的症状更为全身性和严重。肥大细胞和嗜碱性细胞是ige介导的过敏反应的主要效应细胞。在过敏反应中，肥大细胞在遇到过敏原时被激活，随后迅速释放颗粒状物质，包括组胺、细胞因子、趋化因子、蛋白酶和脂质介质。此外，受损上皮细胞产生的细胞因子IL-33通过增强ige介导的肥大细胞活化而参与急性过敏反应。对于对多种过敏原过敏的患者，了解哪些过敏原或过敏原的组合导致了症状与临床相关，但迄今为止，这是一个知之甚少的领域。此外，目前尚不清楚过敏原的再次暴露以及不相关过敏原的组合如何影响肥大细胞的活性。此外，目前尚不清楚生物制剂治疗对肥大细胞反应性的影响。因此，该项目的目标是更好地了解人类肥大细胞在复杂的多过敏原主导的过敏反应中的作用，并研究肥大细胞无反应的机制。该项目涉及人类肥大细胞的培养和分化，并通过流式细胞术（如CyTOF）、高级免疫荧光、转录组分析和生物信息学分析评估其功能。此外，该项目将在国际公认的曼彻斯特炎症研究合作中心和莉迪亚贝克尔免疫学和炎症研究所结合肥大细胞为中心的免疫学研究和过敏临床专业知识。

Allergic diseases, such as asthma, allergic rhinitis, and food allergy, are an important public health burden and seriously affect the quality of life of people, particularly in developed countries. These conditions are characterized by the presence of IgE antibodies to common things in our environment, such as house dust mite (asthma), pollen (allergic rhinitis), and peanut (food allergy). The routes of allergens intake and the frequency are highly variable. For example grass pollen exposure is seasonal while food allergens are taken up accidentally and through the gastrointestinal tract. The symptoms associated with the latter are more systemic and severe compare to the inhalant allergen. Mast cells, together with basophils, are the main effector cells in IgE-mediated allergic reactions. During the allergic response, mast cells upon allergen encounter are activated and subsequently release rapidly their granular content, including histamine, cytokines, chemokines, proteases, and lipid mediators.Furthermore, the cytokine IL-33, produced by damaged epithelial cells contributes to acute allergic reactions by enhancing the IgE-mediated activation of mast cells. For patients allergic to multiple allergens, knowing which allergen or combinations of allergens are driving the symptoms is clinically relevant and as of yet is a poorly understood area. Furthermore, it remains unclear how allergen re-exposure, as well as combinations of unrelated allergens, affect mast cell activities. In addition, it is unclear what is the effect of treatment with biologics on mast cell responsiveness Therefore, the goal of the project is to gain a better understanding of the role of human mast cells in complex multi-allergen dominated allergic responses and investigate mechanisms of mast cell unresponsiveness. This project involves culturing and differentiation of human mast cells and the evaluation of their function by flow cytometry (e.g. CyTOF), advanced immunofluorescence, transcriptomic analysis and bioinformatics analysis. Moreover, this project will be combining mast cell-centred immunology research and allergy clinical expertise at the internationally recognised Manchester Collaborative Centre of Inflammation Research and Lydia Becker Institute of Immunology and Inflammation.