IgG是在女性生殖道中发现的主要同型抗体,并被视为对抗生殖道感染的一个重要防御机制。美国科学家在最近的一项研究中发现,新生的Fc受体(FcRn)——对于向胎儿和新生儿提供具有保护性的母体抗体是至关重要的——也能够向女性生殖道提供IgG,并促进局部的保护性免疫功能。
科学家已经知道,FcRn在成年人体内的功能是维持IgG的血清水平。因此,马里兰大学的Zili Li、Xiaoping Zhu和同事假设FcRn可能也有助于IgG穿越生殖器上皮细胞的运输。最初的筛查显示,被信使核糖核酸(mRNA)编码的FcRn能够出现在女性生殖器上皮细胞系中,而随后的免疫染色试验则利用组织切片证明,FcRn在人类和小鼠的子宫和阴道上皮细胞中均有很高的表达。利用从一个表达FcRn的人类子宫细胞系所得到的单细胞层,研究人员发现,这些细胞能够沿着细胞腔和脱离细胞腔的两个方向输送IgG。然而,敲掉FcRn后则无法观察到IgG的传输,并且鸡的IgY(在结构上类似于IgG但并未结合FcRn)也无法穿越单细胞层进行传输。
接下来,研究人员转换到一个小鼠系统,旨在探究FcRn在活体生殖器中的功能。值得注意的是,与缺乏FcRn的动物的阴道洗涤物相比,在野生型小鼠阴道洗涤物中发现的IgG具有更高的水平。此外,在使用标记抗体的试验中,在野生型小鼠的阴道洗涤物中接着能够检测到IgG向全身的传输,而在缺乏FcRn的小鼠体内则没有这种现象。由一条阴道内路径进行传播的标记IgG也在野生型小鼠的血清中被发现,但在缺乏FcRn的小鼠中却没有发现,这支持了研究人员在试管中观察到的结果,即FcRn能够促进IgG穿越生殖道上皮细胞的双向传输。
最终,Zili等人研究了FcRn的这一传输功能是否意味着生殖道中的免疫保护。令人吃惊的是,特别针对2型单纯性疱疹病毒(HSV-2)的IgG全身传输能够保护野生型小鼠——而非缺乏FcRn的小鼠——远离一种致命的阴道内HSV-2感染。研究人员在最近出版的美国《国家科学院院刊》上报告了这一研究成果。
这些数据表明,IgG转移到生殖道并非仅仅是被动的,就像从前的想法那样,而是与由FcRn引发的主动传输有关。这项研究对于疫苗的研制具有重要意义,因为它表明了促进系统或局部的IgG响应能够加强生殖道中的免疫保护功能。(生物谷Bioon.com)
生物谷推荐原文出处:
PNAS doi: 10.1073/pnas.1012861108
Transfer of IgG in the female genital tract by MHC class I-related neonatal Fc receptor (FcRn) confers protective immunity to vaginal infection
Zili Lia,b, Senthilkumar Palaniyandia,b, Rongyu Zenga,b, Wenbin Tuoc, Derry C. Roopeniand, and Xiaoping Zhua,b,1
Abstract
IgG is a major Ig subclass in mucosal secretions of the human female genital tract, where it predominates over the IgA isotype. Despite the abundance of IgG, surprisingly little is known about where and how IgG enters the lumen of the genital tract and the exact role local IgG plays in preventing sexually transmitted diseases. We demonstrate here that the neonatal Fc receptor, FcRn, is expressed in female genital tract epithelial cells of humans and mice and binds IgG in a pH-dependent manner. In vitro we show that FcRn mediates bidirectional IgG transport across polarized human endometrial HEC-1-A monolayers and primary human genital epithelial cells. Furthermore, endosomal acidification appears to be a prerequisite for FcRn-mediated IgG transcytosis; IgG transcytosis was demonstrated in vivo by translocation of systemically administered IgG into the genital lumen in WT but not FcRn-KO mice. The biological relevance of FcRn-transported IgG was demonstrated by passive immunization using herpes simplex virus-2 (HSV-2)–specific polyclonal serum, which conferred significantly higher protection against intravaginal challenge infection by the HSV-2 186 strain in WT mice than in FcRn-KO mice. These studies demonstrate that FcRn-mediated transport is a mechanism by which IgG can act locally in the female genital tract in immune surveillance and in host defense against sexually transmitted diseases.