Analysis of basophil function in secondary immune responses

描述(由申请人提供)：在工业化国家，过敏性疾病的流行率迅速增长。促进过敏的关键因素之一是产生抗体 免疫球蛋白E同型。在过敏性疾病中，IgE抗体针对的是无害的环境物质，即过敏原，如猫皮屑或花粉粒中的蛋白质。这些IgE抗体被组织中被称为肥大细胞的特殊细胞捕获，在那里它们使肥大细胞敏感，能够在暴露于过敏原时迅速释放有效的促炎介质。人们认为，这种局部系统的进化是为了提供组织保护，防止寄生虫感染。然而，另一种细胞类型捕获了高水平的IgE，即嗜碱性粒细胞，但这些细胞在全身迁移，其功能尚不清楚。具体地说，关于嗜碱性粒细胞是如何捕获过敏原的，它们与过敏原结合后在体内发生了什么，以及在IgE介导的激活后，嗜碱性粒细胞是否与鼻腔细胞或适应性免疫系统相互作用，人们知之甚少。我们也不完全了解IgE致敏的嗜碱性粒细胞在宿主免疫中对寄生虫感染的贡献。我们将使用双光子显微镜对淋巴结和肺部进行观察，以便直接观察嗜碱性粒细胞的行为，这些嗜碱性粒细胞被抗原特异性IgE包裹，然后暴露在抗原中。我们将考虑嗜碱性粒细胞和其他细胞类型的先天或获得性免疫系统之间的细胞相互作用。我们还将可视化嗜碱性细胞遇到抗原的过程，以及这如何改变他们的行为。我们将在这些研究的基础上进行基因操作，以测试嗜碱性细胞的潜在功能。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换洞察力。本研究的具体目的是：1)确定IgE介导的嗜碱性粒细胞在淋巴结和肺内捕获和转运抗原的特征；2)确定通过IgE捕获抗原的嗜碱性粒细胞是否能够增强B细胞或T细胞的应答；3)检测IgE激活的嗜碱性粒细胞在巨噬细胞极化、肺病理和伤口愈合中的作用。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，以及天然免疫系统和获得性免疫系统之间的潜在串扰和反馈。

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.