Sex Hormone Regulation of Innate Immunity in Women & Men

描述（由申请人提供）：总体目标 计划项目是定义性激素（雄激素，雌激素）的作用 和孕激素）在调节先天免疫系统的功能中的作用 全身和粘膜表面。我们将定义机制， 性激素影响表型、先天功能和 先天免疫系统和适应性免疫系统。我们的目的是利用外周血 来自男性和女性的细胞，细胞系，以及免疫细胞和组织， FRT以确定性激素的作用和病原体在细胞中的挑战 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）是男性和女性性激素 除了提供保护外，这些细胞中的每一个都是 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：行政、组织和技术 支持.项目1将确定性激素如何影响人类FRT 上皮细胞启动和调节整个FRT的先天免疫。 我们将检验性激素调节先天功能的假设， 确定上皮细胞抗菌反应与 响应微生物组分的特异性Toll样受体（TLR） （病原体相关分子模式分子[PAMP]）以及定义 先天免疫和适应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影响 功能我们的研究结果表明，中性粒细胞产生干扰素（IFN）γ， 雌二醇下调中性粒细胞氧化爆发为研究提供了基础 为了验证性激素调节PMN跨内皮细胞的假说， 迁移、效应细胞功能和对凋亡的易感性，因此， 先天免疫项目3将重点关注性激素在 单核细胞分化为巨噬细胞（和树突状细胞[DC]）， 免疫细胞功能和这些细胞启动适应性免疫的能力 免疫反应。这些研究将验证性激素 影响巨噬细胞/DC对PAMP反应和影响微生物依赖性 这些细胞从抗炎表型转化为促炎表型。 项目4将检验男性和女性外周血NK细胞 FRT中的NK细胞受到雄激素的差异调节， 雌激素这些研究将检查性激素 调节NK表型和效应子功能以及增强和/或降低NK 细胞溶解活性、细胞因子产生和NK细胞的募集， 的FRT。总的来说，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， 了解激素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，并深入了解异性传播艾滋病毒-1。

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.