SEX HORMONE REGULATION OF THE MUCOSAL IMMUNE SYSTEM

粘膜免疫系统的性激素调节

• 批准号: 2059984
• 负责人: Charles Robert Wira
• 金额: $ 23.15万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-30 至 1996-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2059984
• 关键词: T lymphocyte; antigen presentation; antigen presenting cell; cytokine; estradiol; genital secretion; hormone regulation /control mechanism; immunity; immunoglobulin A; immunoglobulin G; in situ hybridization; interferons; interleukin 1; interleukin 2; laboratory rat; mucosa; progesterone; secretory immune system; sex hormones; uterus

The broad objectives of the research proposed in this application are to understand at the cellular and molecular levels, the physiological actions of sex hormones on the mucosal immune system. These actions account for changes in humoral and cellular immunity and have clinical applications in the treatment of venereal diseases, autoimmune diseases, malignancy, infertility and fertility control. Studies will be undertaken to: (1) examine the regulation by sex hormones and antigens of immune cells in the female reproductive tract; (2) elucidate the role of selected cytokines in the response of the genital tract to antigens and identify the way in which they interact with sex hormones to influence mucosal immunity; (3) identify the mechanism(s) responsible for estradiol-regulated movement of IgA and IgG; and (4) study the role of sex hormones antigens and cytokines in regulating secretory component (SC) and IgA gene expression. (1) As shown in the P.I.'s laboratory, intrauterine, Peyer's patches and intraperitoneal immunization leads to pronounced genital tract IgA- and IgG-antibody responses. These studies indicate that female sex hormones play a central role in genital tract immune responses, which vary with hormone balance, immunization site and secretion analyzed. Effects of the sex hormones on the presence and function of T- and B-lymphocytes, monocytes/macrophages and dendritic cells in the genital tract will be determined both prior to and following antigen exposure. Since uterine cells express MHC class II molecules, we will establish whether uterine immune cells process and present antigen. Sites (uterus, lymph nodes, spleen) of antigen presentation to T-lymphocytes will be identified and the role of sex hormones in the regulation of these events will be determined. (2) Since cytokines are used by immune cells for communication, we will examine the role of selected cytokines in regulating genital tract antibody responses to antigen. Possible cytokine synthesis by immune cells in the genital tract will be investigated. As a part of these studies, we will determine whether cytokine production is regulated by sex hormones and antigen. (3) Because sex hormones and selected cytokines control IgA levels in genital tract secretions, we will define the mechanism(s) whereby sex hormones, IFN-gamma and the interleukins regulate IgA movement in the uterus. Uterine epithelial cells will be grown to confluence on permeable membranes. Sex hormones and cytokine control of IgA transport will be analyzed to determine immunoglobulin specificity, directional movement and rate of transport. Since IgG is also controlled by sex hormones, we will determine whether IgG movement is receptor mediated or due to fluid phase pinocytosis. (4) Secretory component, the receptor for polymeric IgA, is the cornerstone of the efferent arm of the mucosal immune system. By regulating SC production, sex hormones, antigen and IFN-gamma exercise precise control over the presence of IgA in genital tract secretions. To study the mechanism(s) of estrogen, antigen and cytokine action, SC mRNA and IgA mRNA levels will be measured in uterine and cervico-vaginal tissues. If SC and/or IgA mRNA is hormonally regulated, then synthesis of message will be analyzed. In situ hybridization studies will be carried out to identify cells in the reproductive tract that synthesize SC and IgA.

本申请中提出的研究的主要目标是 在细胞和分子水平上了解生理作用 性激素对粘膜免疫系统的影响。 这些行动占 体液和细胞免疫的变化，并具有临床应用 治疗性病、自身免疫性疾病、恶性肿瘤、 不孕不育和生育控制。 将进行研究：（1）检查性激素的调节 以及女性生殖道中免疫细胞的抗原； (2) 阐明选定的细胞因子在生殖器反应中的作用 吸引抗原并识别它们与性相互作用的方式 影响粘膜免疫的激素； (3) 确定机制 负责雌二醇调节的 IgA 和 IgG 运动； (4)学习 性激素抗原和细胞因子在调节分泌中的作用 成分 (SC) 和 IgA 基因表达。 (1) 如 P.I. 实验室所示，宫内、派尔氏集结和 腹膜内免疫导致明显的生殖道 IgA- 和 IgG 抗体反应。 这些研究表明，女性性激素 在生殖道免疫反应中发挥核心作用，其变化随 激素平衡、免疫位点和分泌分析。 的影响 性激素对 T 淋巴细胞和 B 淋巴细胞的存在和功能的影响， 生殖道中的单核细胞/巨噬细胞和树突状细胞将 在抗原暴露之前和之后测定。 自从子宫 细胞表达 MHC II 类分子，我们将确定子宫是否 免疫细胞处理并呈递抗原。 部位（子宫、淋巴结、 脾）将抗原呈递给 T 淋巴细胞，并且 性激素在这些事件的调节中的作用将被确定。 (2) 由于免疫细胞利用细胞因子进行通讯，因此我们将 检查选定的细胞因子在调节生殖道抗体中的作用 对抗原的反应。 免疫细胞可能合成细胞因子 将检查生殖道。 作为这些研究的一部分，我们将 确定细胞因子的产生是否受性激素调节 抗原。 (3) 因为性激素和选定的细胞因子控制着 IgA 水平 生殖道分泌物，我们将定义性行为的机制 激素、IFN-γ和白细胞介素调节 IgA 运动 子宫。 子宫上皮细胞将在可渗透性上生长至汇合 膜。 性激素和细胞因子对 IgA 运输的控制将 分析以确定免疫球蛋白特异性、定向运动和 运输率。 由于 IgG 也受性激素控制，我们将 确定 IgG 运动是受体介导的还是由于液相引起的 胞饮作用。 (4) 分泌成分，聚合IgA的受体，是基石 粘膜免疫系统的传出臂。 通过调节 SC 生产、性激素、抗原和IFN-γ进行精确控制 生殖道分泌物中存在 IgA。 为了研究 雌激素、抗原和细胞因子作用、SC mRNA 和 IgA mRNA 的机制 将测量子宫和宫颈阴道组织中的水平。 如果SC 和/或 IgA mRNA 受到激素调节，然后信息的合成将 分析了。 将进行原位杂交研究以确定 生殖道中合成 SC 和 IgA 的细胞。