Transcytosis of IgG in Genital Infections

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），提供了抵御原发性粘膜感染的第一道防线。 IgG 是人类生殖道粘膜分泌物中的主要 Ig 类别，其地位优于 IgA。尽管人类 IgG 含量丰富，但令人惊讶的是，人们对 IgG 如何分泌到生殖器腔以及 IgG 在预防性传播病原体方面的确切作用知之甚少。我们的长期目标是阐明 IgG 在生殖道转运的分子机制以及 IgG 对性传播病原体的免疫作用。具体假设是 FcRn 介导 IgG 转胞吞作用并在粘膜保护中发挥重要作用，并且 FcRn 可以将与 IgG Fc 片段融合的抗原穿过女性生殖道，以接近潜在的抗原呈递细胞。这些假设基于以下观察结果：1) FcRn 可以介导 IgG 跨肠道或胎盘上皮细胞系的双向转运（顶端到基底外侧，或反之亦然），2) 我们最近的研究表明，人类和啮齿动物 FcRn 在源自人类女性生殖道的上皮细胞中功能性表达，3) FcRn 仅在酸性 pH 下结合 IgG；然而，阴道呈现酸性 pH 值，4) 女性生殖道中的 IgG 水平可以在动情周期过程中发生变化。我们的新数据表明激素显着调节 FcRn 表达。基于这些观察，本提案的实验重点是了解 IgG 转运和 IgG 介导的生殖器感染免疫。具体目标是： 1. 确定生殖道中 FcRn 介导的 IgG 转细胞作用； 2. 确定 FcRn 介导的 IgG 对性传播病原体（例如单纯疱疹病毒 2）原发感染的免疫： 3. 确定 FcRn 递送 IgG Fc 融合抗原（HSV-2 gD-Fc）穿过生殖器粘膜屏障以产生保护性免疫的能力。这些研究将增加我们目前对生殖道免疫保护的有限认识，并为预防其他性病提供必要的基础知识，包括人类免疫缺陷病毒、阴道炎、梅毒、淋病、乳头瘤病毒、白色念珠菌等。

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.