Human Eosinophils: Mechanisms of Functioning

描述(申请人提供)：嗜酸性粒细胞，先天免疫系统的细胞，在健康以及哮喘、过敏和其他疾病的发病机制中具有功能。嗜酸性粒细胞的一些功能是基于它们对释放预先形成的颗粒阳离子蛋白的急性效应反应，而另一些功能是基于它们对各种细胞因子的调节释放，这些细胞因子可以调节组织部位微环境中与其他细胞的相互作用。嗜酸性粒细胞在组织中发挥作用，特别是在没有疾病的情况下，嗜酸性粒细胞也位于粘膜下部位。明确嗜酸性粒细胞细胞因子与组织中其他细胞之间的功能相互作用对于理解嗜酸性粒细胞在持续免疫稳态和急、慢性疾病中的作用是密切相关的。在白细胞中，嗜酸性粒细胞明显含有多种预先形成的细胞因子，储存在形态独特的颗粒和分泌小泡中。炎症组织部位的嗜酸性粒细胞，如哮喘的呼吸道，表现出超微结构的变化，表明一种特殊的基于囊泡运输而不是胞吐的特定的脱颗粒过程，该过程选择性地从嗜酸性粒细胞颗粒中释放出特定的蛋白质。与淋巴细胞(适应性免疫系统的细胞)相比，嗜酸性粒细胞的特殊能力是它们能够迅速释放预先形成的细胞因子；但调节嗜酸性粒细胞来源的细胞因子的选择性释放的机制仍有待描述。研究将探讨包括细胞因子在内的嗜酸性粒细胞衍生蛋白的调节释放机制。总体假设是，嗜酸性粒细胞功能的核心是，相关嗜酸性粒细胞蛋白，包括细胞因子，在细胞内的区隔、运输和释放依赖于调节机制，具有刺激依赖的特异性，可以精细地调节细胞因子的差异性和选择性分泌。目的是确定：1)嗜酸性粒细胞囊泡和颗粒参与细胞因子释放的机制；2)嗜酸性粒细胞细胞因子释放的细胞内机制；3)刺激依赖的嗜酸性粒细胞细胞因子的动员和释放。了解调节嗜酸性粒细胞衍生细胞因子的细胞外释放的分子和细胞机制将有助于深入了解嗜酸性粒细胞的功能，这些功能涉及嗜酸性粒细胞与肺和其他地方组织部位的其他细胞之间的相互作用，并可能确定新的治疗方法。

DESCRIPTION (provided by applicant): Eosinophils, cells of the innate immune system, have functions in health and in the pathogeneses of asthma, allergies and other diseases. While some functions of eosinophils are based on their acute, effector responses to release preformed granule cationic proteins, other eosinophil functions are based on their regulated release of diverse cytokines that can mediate interactions with other cells in the microenvironment of tissue sites. Eosinophils function in tissues, especially submucosal sites where eosinophils localize even in the absence of disease. Defining eosinophil cytokine-mediated functional interactions between eosinophils and other cells in tissues is germane to understanding eosinophil functions in both ongoing immune homeostasis and acute and chronic diseases. Amongst leukocytes, eosinophils distinctly contain multiple preformed cytokines stored within morphologically unique granules and secretory vesicles. Eosinophils in tissue sites of inflammation, such as asthmatic airways, exhibit ultrastructural alterations indicative of a specific "piecemeal degranulation" process based on vesicular transport, not exocytosis, that releases, with selectivity, specific proteins from eosinophil granules. In contrast to lymphocytes, cells of the adaptive immune system, a special capacity of eosinophils is their potential to rapidly release preformed cytokines; but mechanisms regulating selective release of eosinophil-derived cytokines remain to be delineated. Studies will investigate mechanisms involved in the regulated release of eosinophil-derived proteins, including cytokines. The overall hypothesis is that, central to the functions of eosinophils, the intracellular compartmentalization, trafficking and release of relevant eosinophil proteins, including cytokines, are dependent on regulatory mechanisms that with stimulus dependent specificity can finely regulate the differential and selective secretion of cytokines. Aims are to define: 1) eosinophil vesicle and granule mechanisms involved in cytokine release; 2) intracellular mechanisms for specificity of eosinophil cytokine release; and 3) stimulus-dependent mobilization and release of eosinophil cytokines. Understanding molecular and cellular mechanisms that regulate the extracellular release of eosinophil-derived cytokines will provide insights into eosinophil functions that involve interactions between eosinophils and other cells in tissue sites in the lung and elsewhere and may identify new therapeutic approaches.