Characterization of innate and IgE-mediated mast cell functions in honeybee venom allergy using Collaborative Cross mice

使用 Collaborative Cross 小鼠表征蜜蜂毒液过敏中的先天和 IgE 介导的肥大细胞功能

• 批准号: 10681390
• 负责人: Stephen Joseph Galli
• 金额: $ 52.46万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681390
• 关键词: Accounting; Affinity; Allergens; Allergic; Allergic Disease; Allergic Reaction; Anaphylaxis; Animals; Antigens; Bacteria; Binding; Biological Models; CD4 Positive T Lymphocytes; CRISPR/Cas technology; Candidate Disease Gene; Cell Degranulation; Cell physiology; Cell secretion; Cells; Cessation of life; Clinical; Coupled; Cytoplasmic Granules; Development; Disease; Dose; Exposure to; Food; Genes; Genetic; Genetic Variation; Growth Factor; Host Defense; Human; Hymenoptera; Hypersensitivity; IgE; IgE Receptors; IgG1; Immune; Immune response; Immunity; In Vitro; Individual; Inflammation; Inflammation Mediators; Insect Sting; Insecta; Life; Lipids; Maps; Measures; Mediating; Mediator; Medicine; Modeling; Modification; Mus; Outcome; Parasites; Passive Cutaneous Anaphylaxis; Pathology; Peptide Hydrolases; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Predisposition; Prevention approach; Probability; Production; Proliferating; Quantitative Trait Loci; Reaction; Regulatory Pathway; Research; Resistance; Resolution; Role; Severities; Shock; Signs and Symptoms; Snake Venoms; Staphylococcus aureus; Sting Injury; Strongyloides; System; Tissues; Toxic effect; Variant; Venoms; Work; Zebrafish; cardiovascular collapse; chemokine; confocal imaging; crosslink; cytokine; experience; experimental study; functional genomics; genetic analysis; genetic linkage analysis; genomic locus; improved; mast cell; novel; pathogenic bacteria; prevent; response; screening; technology platform; trait

PROJECT SUMMARY/ABSTRACT We will use Collaborative Cross (CC) mice to define how genetic traits influence innate and/or IgE-mediated responses of mast cells (MCs) to honeybee venom. In IgE-dependent allergic reactions, crosslinking of MC high affinity IgE receptors (i.e., FceRI) by the binding of bivalent or multivalent allergen to antigen-specific IgE activates MCs to secrete three major classes of products: 1) preformed mediators stored in cytoplasmic granules, 2) newly synthesized lipid-derived mediators, and 3) cytokines, chemokines and growth factors. These MC products are responsible for many of the signs and symptoms of allergic diseases. MC activation, with or without the involvement of IgE, is also thought to contribute to the inflammation, tissue damage, and even fatal shock induced by envenomation. Components of hymenoptera venoms (e.g., honeybee venom), pharmaceutical agents, and foods are the most common triggers for anaphylaxis in humans. Many people have been sensitized to hymenoptera venoms and some unfortunate individuals react after exposure to such insect stings with serious systemic reactions and even fatal anaphylaxis. However, recent experiments in mice and zebra fish demonstrate that MC-derived proteases can degrade animal venoms and diminish their toxicity. Also, IgE/FceRI-mediated MC activation can enhance the survival of mice challenged with honeybee venom or a snake venom, or with S. aureus bacteria. Yet the benefits of “allergic immune responses”, mediated by IgE/MC- dependent mechanisms, have not been widely recognized. While the exact mechanisms determining whether the outcomes of hymenoptera envenomation are detrimental or favorable have been elusive, we know that genetic factors can significantly influence the development, progression, and severity of allergy and anaphylaxis. We hypothesize that genetic traits, by modulating the strength and/or composition of MC responses to honeybee venom and/or the Th2-IgE-MC immune axis, can influence the outcomes of honeybee stings. In this project, we propose to use genetically diverse CC mice to identify genetic modifiers regulating MC functions in insect venom allergy. In Aim 1, we will screen a panel of CC mice for their susceptibility to the toxicity of honeybee venom, development and features of venom-specific type 2 immunity, and induction of MC activation with or without crosslinking of venom-specific IgE/FceRI. We will also perform quantitative trait locus (QTL) mapping of the venom-induced phenotypes in CC mice to identify distinct genetic loci and novel regulators associated with MC-dependent susceptibility vs. resistance to honeybee venom. In Aim 2, we will confirm, in mouse MCs, important regulators of MC functions that are identified by screening CC mice using QTL analysis to assess the involvement of these regulators in innate and/or IgE-mediated MC functions. We think that the identification of genetic modifiers that distinguish beneficial vs. harmful effects of innate and/or allergic immune responses to honeybee venom will improve the treatment of severe reactions to insect venom and probably other disorders in which IgE and MCs have a critical role. 1

项目总结/摘要 我们将使用协作杂交（CC）小鼠来定义遗传性状如何影响先天和/或IgE介导的 肥大细胞对蜂毒的反应。在IgE依赖性过敏反应中，MC的交联 高亲和力IgE受体（即，FceRI）通过二价或多价过敏原与抗原特异性IgE的结合 激活MC分泌三种主要类型的产物：1）储存在细胞质中的预先形成的介质 颗粒，2）新合成的脂质衍生的介质，和3）细胞因子、趋化因子和生长因子。 这些MC产品负责过敏性疾病的许多体征和症状。MC激活， 有或没有IgE的参与，也被认为有助于炎症，组织损伤， 甚至是致命的中毒性休克Hypletera毒液的成分（例如，蜜蜂毒液）， 药物制剂和食物是人类过敏反应的最常见触发物。很多人 对雨燕毒液过敏，一些不幸的个体在接触这种昆虫后会发生反应 严重的全身反应甚至致命的过敏反应。然而，最近在小鼠和 斑马鱼证明MC衍生的蛋白酶可以降解动物毒液并降低其毒性。还有， IgE/FceRI介导的MC活化可增强用蜜蜂毒液或其组合攻击的小鼠的存活。 蛇毒或S.金黄色细菌。然而，由IgE/MC介导的“过敏性免疫反应”的益处- 依赖机制尚未得到广泛认可。虽然决定是否 雨燕毒液蛰入的结果是有害的还是有利的一直是难以捉摸的，我们知道， 遗传因素可显著影响变态反应的发生、进展和严重程度， 过敏反应我们假设，遗传性状，通过调节MC的强度和/或组成， 对蜜蜂毒液和/或Th 2-IgE-MC免疫轴的反应，可以影响 蜜蜂蜇人。在这个项目中，我们建议使用遗传多样性CC小鼠来识别遗传修饰剂 调节昆虫毒液变态反应中的MC功能。在目标1中，我们将筛选一组CC小鼠， 对蜂毒毒性的敏感性，蜂毒特异性2型免疫的发展和特征， 以及在有或没有毒液特异性IgE/FceRI交联的情况下诱导MC活化。我们还将表演 CC小鼠中毒液诱导的表型的数量性状基因座（QTL）定位，以鉴定不同的遗传 基因座和新的监管机构与MC依赖的敏感性与蜜蜂毒液的抗性。在 目的2，我们将确认，在小鼠MC，MC功能的重要调节剂，通过筛选CC 小鼠使用QTL分析来评估这些调节剂在先天和/或IgE介导的MC中的参与 功能协调发展的我们认为，识别遗传修饰剂，区分有益与有害的影响， 对蜜蜂毒液的先天性和/或过敏性免疫反应将改善对蜜蜂毒液的严重反应的治疗， 昆虫毒液和可能的其他疾病，其中IgE和MC具有关键作用。 1

项目成果

Conditional neutrophil depletion challenges their contribution to mouse models of anaphylaxis.

条件性中性粒细胞耗竭挑战了它们对小鼠过敏反应模型的贡献。

• DOI: 10.1111/all.15738
• 发表时间: 2023
• 期刊: Allergy
• 影响因子: 12.4
• 作者: Stackowicz,Julien;Gillis,CaitlinM;Godon,Ophélie;Iannascoli,Bruno;Conde,Eva;Leveque,Edouard;Worrall,WilliamPM;Galli,StephenJ;Bruhns,Pierre;Reber,LaurentL;Jönsson,Friederike
• 通讯作者: Jönsson,Friederike