Analysis of basophil function in secondary immune responses

二次免疫反应中嗜碱性粒细胞功能的分析

• 批准号: 8420117
• 负责人: Christopher David Caballero Allen
• 金额: $ 36.83万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8420117
• 关键词: Allergens; Allergic; Allergic Disease; Antibodies; Antigens; Applications Grants; Asthma; B-Lymphocytes; Basophils; Behavior; Binding; Blood Cells; Cells; Cereals; Developed Countries; Disease; Effector Cell; Exposure to; Feedback; Felis catus; Follow-Up Studies; Generations; Goals; Helminths; Hypersensitivity; IgE; Image; Immune response; Immune system; Immunity; Immunologic Memory; Infection; Inflammatory; Laboratories; Learning; Life; Lung; Mediating; Mediator of activation protein; Microscopy; Mus; Parasites; Pathology; Physiological; Pollen; Prevalence; Process; Proteins; Public Health; Reaction; Role; System; T cell response; Testing; Tissues; Urticaria; Visual; Work; Wound Healing; allergic response; cell type; genetic manipulation; improved; in vivo; insight; lymph nodes; macrophage; mast cell; pathogen; public health relevance; response; two-photon

DESCRIPTION (provided by applicant): Allergic diseases are rapidly growing in prevalence in industrialized nations. One of the key factors promoting allergy is the generation of antibodies of the IgE isotype. In allergic disease, the IgE antibodies are directed toward harmless environmental substances, known as allergens, such as proteins in cat dander or pollen grains. These IgE antibodies are captured by specialized cells in tissues, known as mast cells, where they sensitize the mast cells to be able to rapidly release potent proinflammatory mediators upon exposure to the allergens. It is thought that this localized system evolved to provide tissue protection against parasite infection. However, another cell type captures high levels of IgE, known as basophils, yet these cells migrate throughout the body and their function is poorly understood. Specifically, little is known about how the basophils capture allergens, what occurs in vivo after they bind allergens, and whether or not the basophils interact with cells of the innae or adaptive immune system following IgE-mediated activation. We also do not fully understand the contribution of IgE-sensitized basophils to host immunity to parasite infection. We will use two-photon microscopy of the lymph nodes and lungs in order to directly visualize the behavior of basophils that have been coated with antigen-specific IgE and then exposed to antigen. We will consider the cellular interactions between basophils and other cell types of the innate or adaptive immune system. We will also visualize the process by which basophils encounter antigen and how this changes their behavior. We will follow up these studies with genetic manipulations to test the potential functions of basophils. Our direct visual observations in the physiological tissue setting will have the power to provide new paradigm-shifting insights into the function of these enigmatic cells. The specific aims of this study are to: 1) Characterize the IgE-mediated capture and transport of antigen by basophils in the lymph nodes and lungs, 2) Determine whether basophils that have captured antigen via IgE can enhance B or T cell responses, and 3) Test the function of IgE-activated basophils in macrophage polarization, lung pathology, and wound healing. The results from these studies will be helpful in understanding the role of these cells in allergic and parasite immunity as well as the underlying cross-talk and feedback between the innate and adaptive immune systems.

描述（由申请人提供）：过敏性疾病在工业化国家的流行率迅速增长。促进过敏的关键因素之一是产生抗体， IgE同种型。在过敏性疾病中，IgE抗体针对无害的环境物质，称为过敏原，如猫皮屑或花粉粒中的蛋白质。这些IgE抗体被称为肥大细胞的组织中的特化细胞捕获，其中它们使肥大细胞敏感，从而能够在暴露于过敏原时快速释放有效的促炎介质。据认为，这种局部系统的进化提供了组织保护免受寄生虫感染。然而，另一种细胞类型捕获高水平的IgE，称为嗜碱性粒细胞，但这些细胞在全身迁移，其功能知之甚少。具体而言，关于嗜碱性粒细胞如何捕获过敏原，它们结合过敏原后在体内发生了什么，以及嗜碱性粒细胞在IgE介导的激活后是否与抑制性或适应性免疫系统的细胞相互作用，我们知之甚少。我们也不完全了解IgE致敏的嗜碱性粒细胞对寄生虫感染的宿主免疫的贡献。 我们将使用双光子显微镜检查淋巴结和肺，以直接观察嗜碱性粒细胞的行为，这些嗜碱性粒细胞已被抗原特异性IgE包被，然后暴露于抗原。我们将考虑嗜碱性粒细胞和先天性或适应性免疫系统的其他细胞类型之间的细胞相互作用。我们还将可视化嗜碱性粒细胞遇到抗原的过程以及这如何改变它们的行为。我们将通过基因操作来跟踪这些研究，以测试嗜碱性粒细胞的潜在功能。我们在生理组织环境中的直接视觉观察将有能力为这些神秘细胞的功能提供新的范式转变见解。本研究的具体目的是：1）表征淋巴结和肺中IgE介导的嗜碱性粒细胞对抗原的捕获和转运，2）确定通过IgE捕获抗原的嗜碱性粒细胞是否可以增强B或T细胞应答，3）测试IgE激活的嗜碱性粒细胞在巨噬细胞极化、肺病理学和伤口愈合中的功能。这些研究的结果将有助于理解这些细胞在过敏和寄生虫免疫中的作用，以及先天性和适应性免疫系统之间的潜在串扰和反馈。