FcRn, but not Fc γRs, drives maternal-fetal transplacental transport of human IgG antibodies
FcRn, but not Fc γRs, drives maternal-fetal transplacental transport of human IgG antibodies
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DOI：
10.1073/pnas.2004325117
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发表时间：
2020-06-09
影响因子：
11.1
通讯作者：
Wang, Taia T.
中科院分区：
文献类型：
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作者：
Borghi, Sara;Bournazos, Stylianos;Wang, Taia T.
IgG的Fc结构域能够与多种类型的受体相互作用，包括新生儿Fc受体（FcRn）和Fcγ受体（Fcγ Rs），这赋予了多效性的生物学活性。FcRn调节IgG的上皮运输和再循环，而Fc效应子活性，如抗体依赖的细胞毒性（ADCC）和吞噬作用，则由Fcγ Rs介导，Fcγ Rs在交联时传递信号，调节效应白细胞的功能。尽管FcRn和Fcγ Rs具有明确且不重叠的功能特性，但最近的研究表明Fcγ Rs介导胎盘转运IgG，因为据报道某些Fc糖型在胎儿循环中富集。为了确定Fcγ Rs和FcRn对IgG母婴转运的贡献，我们对来自乌干达和尼加拉瓜患者队列的成对母婴样本中的IgG Fc糖基化进行了表征。未发现IgG1 Fc聚糖谱有差异，IgG2 Fc聚糖仅有极小差异，而IgG1 Fc聚糖上是否存在半乳糖并不改变Fcγ RIIIa或FcRn的结合、半衰期，或它们在Fcγ R/FcRn人源化小鼠中清除靶细胞的能力。在Fcγ/FcRn人源化小鼠中模拟母婴转运证实只有FcRn有助于IgG的胎盘转运；选择性增强FcRn结合的IgG导致母体抗体在胎儿中积累增加。相反，增强Fcγ RIIIa结合并不会导致母婴转运增加。这些结果不支持Fcγ Rs在IgG胎盘转运中的作用，表明对母体给予的抗体进行Fc工程改造以仅增强FcRn结合可作为改善IgG母婴转运的一种方法。
The IgG Fc domain has the capacity to interact with diverse types of receptors, including the neonatal Fc receptor (FcRn) and Fc gamma receptors (Fc gamma Rs), which confer pleiotropic biological activities. Whereas FcRn regulates IgG epithelial transport and recycling, Fc effector activities, such as antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis, are mediated by Fc gamma Rs, which upon cross-linking transduce signals that modulate the function of effector leukocytes. Despite the well-defined and nonoverlapping functional properties of FcRn and Fc gamma Rs, recent studies have suggested that Fc ?Rs mediate transplacental IgG transport, as certain Fc glycoforms were reported to be enriched in fetal circulation. To determine the contribution of Fc gamma Rs and FcRn to the maternal-fetal transport of IgG, we characterized the IgG Fc glycosylation in paired maternal-fetal samples from patient cohorts from Uganda and Nicaragua. No differences in IgG1 Fc glycan profiles and minimal differences in IgG2 Fc glycans were noted, whereas the presence or absence of galactose on the Fc glycan of IgG1 did not alter Fc gamma RIIIa or FcRn bind-ing, half-life, or their ability to deplete target cells in Fc gamma R/FcRn humanized mice. Modeling maternal-fetal transport in Fc gamma/FcRn humanized mice confirmed that only FcRn contributed to trans-placental transport of IgG; IgG selectively enhanced for FcRn binding resulted in enhanced accumulation of maternal antibody in the fetus. In contrast, enhancing Fc gamma RIIIa binding did not result in en-hanced maternal-fetal transport. These results argue against a role for Fc gamma Rs in IgG transplacental transport, suggesting Fc engineering of maternally administered antibody to enhance only FcRn binding as a means to improve maternal-fetal transport of IgG.