Transcytosis of IgG in Genital Infections

描述（由申请人提供）：性传播疾病（STDs）是人类最常见的传染病之一。局部免疫反应，特别是粘膜免疫球蛋白（Igs），提供了抵抗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占主导地位的一类IgG，其含量高于IgA。尽管人类IgG丰富，但令人惊讶的是，人们对IgG如何分泌到生殖器腔内以及IgG在预防性传播病原体中的确切作用知之甚少。我们的长期目标是阐明IgG在生殖道运输的分子机制以及IgG免疫对性传播病原体的作用。具体的假设是FcRn介导IgG胞吞作用并在粘膜保护中起主要作用，并且FcRn可以将融合到IgG Fc片段的抗原传递到女性生殖道以进入潜在的抗原呈递细胞。这些假设是基于以下观察结果：1)FcRn可以介导IgG在肠道或胎盘上皮细胞系中的双向转运（从根尖到底外侧，或反之）；2)我们最近的研究表明，人类和啮齿类动物的FcRn在人类女性生殖道上皮细胞中功能性表达；3)FcRn仅在酸性pH下与IgG结合；然而，阴道呈现酸性pH值，4)女性生殖道中IgG的水平可以在发情周期的过程中发生变化。我们的新数据显示，激素显著调节FcRn的表达。基于这些观察结果，本建议的实验重点是了解IgG转运和IgG介导的生殖器感染免疫。具体目标是：1。fcrn介导的生殖道IgG转染测定2. 测定fcrn介导的IgG对性传播病原体（如单纯疱疹病毒- 2:3）原发性感染的免疫力。测定FcRn传递IgG fc融合抗原HSV-2 gD-Fc的能力，通过生殖器粘膜屏障产生保护性免疫。这些研究将增加我们目前有限的对生殖道免疫保护的认识，并将为预防其他性传播疾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.