The MHC class I-related receptor, FcRn, plays an essential role in the maternofetal transfer of γ-globulin in humans
The MHC class I-related receptor, FcRn, plays an essential role in the maternofetal transfer of γ-globulin in humans
复制标题
DOI：
10.1093/intimm/13.8.993
复制
发表时间：
2001-08-01
影响因子：
4.4
通讯作者：
Ward, ES
中科院分区：
文献类型：
--
作者：
Firan, M;Bawdon, R;Ward, ES
母体丙种球蛋白（IgG）的转移为新生儿在生命早期提供了体液免疫。在人类中，母体IgG在妊娠晚期通过胎盘转运。MHC I类相关受体FcRn在人胎盘中的表达表明该Fc受体可能参与母体IgG的递送，但缺乏支持这一点的直接证据。在本研究中，已使用离体胎盘模型分析重组人源化（IgG1）抗体（其中His435已突变为丙氨酸（H435A））的母胎转移。使用表面等离子体共振的体外结合研究表明，突变消除了抗体与重组小鼠和人FcRn的结合。相对于野生型抗体，H435A突变体在跨胎盘的转移方面是缺陷的。值得注意的是，该突变不影响与Fc γ RIII的结合，Fc γ RIII是一种在早期研究中被认为介导母体IgG转移的FcR。分析表明，IgG与FcRn的结合是转运穿过灌注胎盘的先决条件。因此，FcRn在IgG的母胎递送中起核心作用，这对使用蛋白质工程来改善治疗性抗体的性质具有意义。
The transfer of maternal gamma -globulin (IgG) provides the neonate with humoral immunity during early life. In humans, maternal IgG is transported across the placenta during the third trimester of pregnancy. The expression of the MHC class I-related receptor, FcRn, in the human placenta suggests that this Fc receptor might be involved in the delivery of maternal IgG, but direct evidence to support this is lacking. In the current study an ex vivo placental model has been used to analyze the maternofetal transfer of a recombinant, humanized (IgG1) antibody in which His435 has been mutated to alanine (H435A). In vitro binding studies using surface plasmon resonance indicate that the mutation ablates binding of the antibody to recombinant mouse and human FcRn. Relative to the wild-type antibody, the H435A mutant is deficient in transfer across the placenta. Significantly, the mutation does not affect binding to Fc gamma RIII, an FcR that has been suggested in earlier studies to mediate the transfer of maternal IgG. The analyses demonstrate that binding of an IgG to FcRn is a prerequisite for transport across the perfused placenta. FcRn therefore plays a central role in the maternofetal delivery of IgG and this has implications for the use of protein engineering to improve the properties of therapeutic antibodies.