Nature:新生儿如何获取抗体?

【字体: 时间:2008年10月06日 来源:生物通

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生物通报道:来自霍德华休斯医学院,加州理工学院,新加坡国立大学等处的研究人员利用电子断层扫描方法观测新生儿Fc受体(FcRn)的转胞吞过程,在细胞内细胞器中识别出了单个的FcRn配体,进一步了解了新生儿接受母亲抗体的过程。这一研究结果公布在9月23日的《Nature》杂志上。

新生儿Fc受体(Neonatal Fc receptor, FcRn)是负责上皮细胞主动转运免疫球蛋白IgG的受体。IgG是初乳中含量最丰富的免疫球蛋白成分,哺乳动物新生儿的免疫力主要依赖于从母体获得IgG,而母源IgG向乳汁中的分泌以及被新生儿摄取均需要穿越上皮屏障,这一过程就是FcRn的胞转作用。

FcRn有着独特的免疫学功能:人胎盘合胞体滋养层细胞高表达FcRn,可介导母体血中IgG进入胎儿血循环;通过肠上皮的FcRn,可将母体初乳中IgG转运到新生儿血循环。

在这篇文章中,研究人员利用电子断层扫描技术(electron tomography)观测这一胞转过程中IgG的运输,分辨率达到4–6 nm。并且研究人员还利用一种与高压凝固样品相匹配的新的金放大方法,在细胞内细胞器中识别出了单个的FcRn配体。从所显示出的转胞吞作用通道可以看到被标记的Fc在从根尖向底外侧迁移时穿过囊泡网络的情形。

正电子发射断层扫描仪(PET)是目前最先进的核医学成像设备,已被广泛地应用于医疗诊断、药物开发和基础研究中。它利用正电子核素标记的放射性药物对生物体内的生理或生化过程进行示踪,通过断层成像的方式无创地获得生物体内的功能信息。小型PET是为小型动物实验专门设计的。由于动物实验在生物医学研究中占有非常重要的位置,新的药物和治疗方法需要首先在动物身上进行,因此这种技术已经应用到了许多方面。

原文摘要:

Nature 455, 542-546 (25 September 2008) |
doi:10.1038/nature07255; Received 14 April 2008; Accepted 14 July 2008


FcRn-mediated antibody transport across epithelial cells revealed by electron tomography


Top of pageThe neonatal Fc receptor (FcRn) transports maternal IgG across epithelial barriers1, 2, thereby providing the fetus or newborn with humoral immunity before its immune system is fully functional. In newborn rats, FcRn transfers IgG from milk to blood by apical-to-basolateral transcytosis across intestinal epithelial cells. The pH difference between the apical (pH 6.0–6.5) and basolateral (pH 7.4) sides of intestinal epithelial cells facilitates the efficient unidirectional transport of IgG, because FcRn binds IgG at pH 6.0–6.5 but not at pH 7 or more1, 2. As milk passes through the neonatal intestine, maternal IgG is removed by FcRn-expressing cells in the proximal small intestine (duodenum and jejunum); remaining proteins are absorbed and degraded by FcRn-negative cells in the distal small intestine (ileum)3, 4, 5, 6. Here we use electron tomography to make jejunal transcytosis visible directly in space and time, developing new labelling and detection methods to map individual nanogold-labelled Fc within transport vesicles7 and simultaneously to characterize these vesicles by immunolabelling. Combining electron tomography with a non-perturbing endocytic label allowed us to conclusively identify receptor-bound ligands, resolve interconnecting vesicles, determine whether a vesicle was microtubule-associated, and accurately trace FcRn-mediated transport of IgG. Our results present a complex picture in which Fc moves through networks of entangled tubular and irregular vesicles, only some of which are microtubule-associated, as it migrates to the basolateral surface. New features of transcytosis are elucidated, including transport involving multivesicular body inner vesicles/tubules and exocytosis through clathrin-coated pits. Markers for early, late and recycling endosomes each labelled vesicles in different and overlapping morphological classes, revealing spatial complexity in endo-lysosomal trafficking.
 

 

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