Sex Hormone Regulation of Innate Immunity in Women & Men

描述(由申请人提供)：本次活动的总体目标 方案项目是定义性激素(雄激素、雌激素)的作用 和孕激素)来调节先天免疫系统的功能 在系统和粘膜表面。我们将定义通过哪些机制 性激素影响表型、先天功能和相互间的交流 先天免疫系统和适应性免疫系统。我们的目的是用外周血 来自男性和女性的细胞，细胞系，以及来自 FRT确定性激素在细胞中的作用和致病挑战 和分子水平。我们假设先天免疫(上皮细胞， 中性粒细胞、巨噬细胞和NK细胞)处于男性和女性性激素水平之下 控制，并且，除了授予保护之外，这些单元中的每一个都是 能够启动适应性免疫反应。支持四个项目 将由三个核心提供：管理、组织和技术 支持。项目1将定义性激素如何影响人类的FRT 在整个FRT过程中，上皮细胞启动和调节先天免疫。 我们将验证性激素调节先天功能和 明确上皮抗菌反应与细胞免疫功能的关系 Toll样受体(TLRs)对微生物成分的反应 (病原体相关分子模式分子[PAMP])以及定义 先天免疫和获得性免疫之间的相互作用。项目2将定义 性别和性激素对中性粒细胞的影响 功能。我们的研究发现，中性粒细胞产生干扰素(干扰素)-γ，而且 雌二醇下调中性粒细胞氧化爆发为研究提供基础 验证性激素调节中性粒细胞跨内皮细胞的假说 迁移、效应细胞功能和对凋亡的敏感性，因此， 先天免疫力。项目3将侧重于性激素在 单核细胞向巨噬细胞(和树突状细胞[DC])的分化 免疫细胞功能及其启动适应性的能力 免疫反应。这些研究将验证性激素 影响巨噬细胞/DC对PAMP的反应及对微生物依赖性的影响 这些细胞从抗炎表型转变为促炎表型。 项目4将测试这一假设，即男性和女性的外周NK细胞 而FRT中的NK细胞受雄激素和 雌激素。这些研究将探索性激素的作用机制(S) 调节NK表型和效应功能，增强和/或降低NK 细胞溶解活性、细胞因子的产生和NK细胞的招募 首次公开募股。总体而言，这些研究可能会增加我们对 性激素在调节免疫保护中的作用，并应提供 了解激素在人体内的作用所必需的知识基础 自身免疫性疾病、性传播疾病的预防和管理 疾病，以及对异性恋传播艾滋病毒-1的洞察。

DESCRIPTION (provided by applicant): The overall objective of this Program Project is to define the role of sex hormones (androgens, estrogens and progestins) in regulating the innate immune system as it functions systemically and at mucosal surfaces. We will define the mechanisms whereby sex hormones influence phenotype, innate function, and communication between the innate and adaptive immune systems. Our intent is to use peripheral blood cells from men and women, cell lines, and immune cells and tissues from the FRT to define the role of sex hormone and pathogenic challenge at the cellular and molecular level. We postulate that innate immunity (epithelial cells, neutrophils, macrophages and NK cells) is under male and female sex hormone control and that, in addition to conferring protection, each of these cells is capable of initiating an adaptive immune response. Support for four Projects will be provided by three Cores: Administrative, Tissue, and Technical Support. Project 1 will define how sex hormones influence human FRT epithelial cells to initiate and modulate innate immunity throughout the FRT. We will test the hypothesis that sex hormones regulate innate function and define the relationship between epithelial anti-bacterial response and specific Toll-like receptors (TLRs) in response to microbial components (pathogen-associated molecular pattern molecules [PAMP]) as well as define the interactions between innate and adaptive immunity. Project 2 will define the effect of gender and sex hormones on polymorphonuclear neutrophil (PMN) function. Our findings that PMN produce interferon (IFN)gamma and that estradiol down-regulates PMN oxidative burst provides a foundation for studies to test the hypothesis that sex hormones modulate PMN trans-endothelial migration, effector cell function and susceptibility to apoptosis and, thus, innate immunity. Project 3 will focus on the role of sex hormones on the differentiation of monocytes into macrophages (and dendritic cells [DCs]), on immune cell function and the capacity of these cells to initiate adaptive immune responses. These studies will test the hypothesis that sex hormones influence macrophage/DC responses to PAMP and influence microbe-dependent conversion of these cells from an anti- to pro-inflammatory phenotype. Project 4 will test the hypothesis that peripheral NK cells from men and women and NK cells in the FRT are differentially regulated by androgens and estrogens. These studies will examine the mechanism(s) by which sex hormones regulate NK phenotype and effector function as well as enhance and/or lower NK cytolytic activity, cytokine production, and the recruitment of NK cells to the FRT. Overall, these studies may increase our limited understanding of the role of sex hormones in regulating immune protection and should provide the basis of knowledge essential for understanding the role of hormones in autoimmune diseases, the prevention and management of sexually transmitted diseases, and insight into the heterosexual transmission HIV-1.