Transcytosis of IgG in Genital Infections

生殖器感染中 IgG 的转胞吞作用

• 批准号: 7784421
• 负责人: XIAOPING ZHU
• 金额: $ 25.24万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7784421
• 关键词: Acidity; Address; Adoptive Transfer; Antigen-Presenting Cells; Antigens; Apical; Binding; Candida; Cell Line; Cell surface; Clinic; Communicable Diseases; Data; Dendritic Cells; Endometrial; Epithelial Cells; Estrous Cycle; Exhibits; Fc Immunoglobulins; Female; Gastrointestinal tract structure; Genital system; Glycoproteins; Goals; Gonorrhea; HIV; Herpes Simplex Infections; Hormones; Human; Human Herpesvirus 2; Immune; Immune response; Immunity; Immunization; Immunoglobulin A; Immunoglobulin G; Immunoglobulins; Infection; Intestines; Knockout Mice; Knowledge; M cell; Male Genital Organs; Mediating; Modeling; Molecular; Mucosal Immunity; Mucous Membrane; Mus; Newborn Animals; Papillomavirus; Pathology; Pathway interactions; Patients; Placenta; Play; Prevention; Proteins; Regulation; Research Personnel; Resistance; Rodent; Role; Secretory Immunoglobulin A; Serum; Sexually Transmitted Diseases; Syphilis; System; Tissues; Vagina; Vaginitis; Virulent; base; genital infection; genital secretion; human disease; human female; in vivo; lymph nodes; mucosa-associated lymphoid tissue; neonatal Fc receptor; pathogen; prevent; programs; reproductive; transcytosis; uptake; vaccine development

DESCRIPTION (provided by applicant): Sexually transmitted diseases (STDs) are among the most common infectious diseases in humans. Local immune responses, especially the mucosal immunoglobulins (Igs), provide the first line of defense against primary mucosal infections. IgG is a dominant Ig class in the mucosal secretions of the human genital tract, where it predominates over IgA. Despite the abundance of human IgG, surprisingly less is known about how IgG is secreted into the genital lumen and the exact role of IgG in preventing sexually transmitted pathogens. Our long-term goal is to elucidate the molecular mechanisms of IgG transport in the genital tract and the role of IgG immunity to sexually transmitted pathogens. The specific hypotheses are that FcRn mediates IgG transcytosis and plays a major role in mucosal protection, and that FcRn can deliver an antigen fused to an IgG Fc fragment across the female genital tract to gain access to underlying antigen-presenting cells. These hypotheses were based on the observations that 1) FcRn can mediate the bi-directional transport (apical to basolateral, or vice versa) of IgG across intestinal or placental epithelial cell lines, 2) our recent study showed that human and rodent FcRn were functionally expressed in epithelial cells derived from the human female genital tract, 3) FcRn binds IgG only at acidic pH; whereas, the vagina exhibits acidic pH, 4) the levels of IgG in the female genital tract can be changed over the course of the estrous cycle. Our new data showed that hormone significantly regulated the FcRn expression. Based on these observations, the experimental focus of this proposal is on the understanding of IgG transport and IgG-mediated immunity to genital infections. The specific aims are to: 1. Determine the FcRn-meidated IgG transcvtosis in the reproductive tract; 2. Determine FcRn-mediated IgG immunity to primary infections of sexually transmitted pathogens, such as herpes simplex virus-2: 3. Determine the ability of FcRn to deliver IgG Fc-fused antigens, HSV-2 gD-Fc, across the genital mucosal barrier to generate protective immunity. These studies will increase our presently-limited understanding of immune protection for the genital tract, and will provide the basic knowledge essential for the prevention of other STDs, including human immunodeficiency virus, vaginitis, syphilis, gonorrhea, papillomavirus, Candida albican, etc.

描述（由申请人提供）：性传播疾病（STD）是人类最常见的传染病之一。局部免疫反应，尤其是粘膜免疫球蛋白（IGS），提供了针对原发性粘膜感染的第一道防线。 IgG是人类生殖道的粘膜分泌物中的主要IG类，它占IgA的主导地位。尽管人类IgG丰富，但令人惊讶的是，对于如何将IgG分泌到生殖器管腔中，以及IgG在预防性传播病原体中的确切作用。我们的长期目标是阐明生殖道中IgG转运的分子机制以及IgG免疫对性传播病原体的作用。具体的假设是，FCRN介导IgG跨经细胞增多症并在粘膜保护中起主要作用，并且FCRN可以在跨女性生殖道的IgG FC片段中递送抗原，以获取潜在的抗原抗原抗原促成细胞。这些假设是基于观察结果，即1）FCRN可以介导跨肠道或胎盘上皮细胞系的IgG的双向转运（对基底外侧，反之亦然），2）我们最近的研究表明，人类和啮齿动物FCRN在人类和啮齿动物中的酸中表达了人类的酸性per Incid catien cicatial Genital Tract pern cin Incid，3）FCR，3）FCR，3）而阴道表现出酸性pH，4）在发情循环过程中，女性生殖道中的IgG水平可以改变。我们的新数据表明，激素显着调节了FCRN表达。基于这些观察结果，该提案的实验重点是了解IgG转运和IgG介导的对生殖器感染的免疫力。具体目的是：1。确定生殖道中的FCRN杀手的IgG透眼； 2。确定FCRN介导的IgG免疫对性传播病原体的原发性感染，例如单纯疱疹病毒-2：3。确定FCRN在跨越生殖器粘膜产生保护性免疫的IgG FCN提供IgG FC FC融合的抗原，HSV-2 GD-FC的能力。这些研究将增加我们目前对生殖道免疫保护的理解，并将为预防其他性病所必需的基本知识提供基本知识，包括人类免疫缺陷病毒，阴道炎，梅毒，淋病，淋巴病毒，乳头状瘤病毒，念珠菌，念珠菌等。