Transcytosis of IgG in Genital Infections

描述(申请人提供)：性传播疾病(性病)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(Ig)，为抵御原发粘膜感染提供了第一道防线。在人类生殖道的粘膜分泌物中，免疫球蛋白是一种主要的免疫球蛋白，而不是免疫球蛋白A。尽管人类的免疫球蛋白含量丰富，但令人惊讶的是，人们对免疫球蛋白是如何分泌到生殖器腔内的，以及免疫球蛋白在防止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免疫球蛋白在生殖道中转运的分子机制，以及免疫球蛋白对性传播病原体的作用。具体的假设是，FcRN介导了免疫球蛋白G的跨细胞转运，并在粘膜保护中发挥了重要作用，并且FcRN可以通过女性生殖道运送融合到免疫球蛋白Fc片段的抗原，以获得潜在的抗原提呈细胞。这些假说建立在以下观察基础上：1)FcRN可以介导免疫球蛋白在肠道或胎盘上皮细胞系之间的双向转运(顶端到基底侧端，反之亦然)；2)我们最近的研究表明，人和啮齿类动物的FcRN在来源于女性生殖道的上皮细胞中有功能地表达；3)FcRN仅在酸性pH下与IgG结合；而阴道则表现为酸性pH；4)女性生殖道中的IgG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，这项建议的实验重点是了解免疫球蛋白转运和免疫球蛋白介导的生殖器感染。其具体目的是：1.确定FcRN介导的免疫球蛋白在生殖道中的传递；2.确定FcRN介导的对性传播病原体原发感染的免疫球蛋白免疫，如单纯疱疹病毒-2：3。确定FcRN跨越生殖道粘膜屏障运送Ig G Fc融合抗原HSV-2 gD-Fc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了解，并将为预防其他性传播疾病提供必要的基本知识，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.