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.
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