Mutations of Recombinant Aquaporin-4 Antibody in the Fc Domain Can Impair Complement-Dependent Cellular Cytotoxicity and Transplacental Transport.
Mutations of Recombinant Aquaporin-4 Antibody in the Fc Domain Can Impair Complement-Dependent Cellular Cytotoxicity and Transplacental Transport.
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DOI：
10.3389/fimmu.2018.01599
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发表时间：
2018
影响因子：
7.3
通讯作者：
Diamond B
中科院分区：
文献类型：
--
作者：
Mader S;Brimberg L;Soltys JN;Bennett JL;Diamond B
母体抗体为发育中的胎儿提供保护。病原性自身抗体的经胎盘转运可能对发育中的胎儿造成风险。抗体通过新生儿Fc补救受体（FcRn）跨胎盘转运至胎儿循环。在妊娠期间，母体自身抗体能够在功能完整的血脑屏障建立之前穿透胚胎脑。针对水通道蛋白水通道蛋白4（AQP 4）的脑反应性抗体是视神经肌萎缩症（NMO）的标志性发现，这是一种主要影响女性的神经系统疾病，其中许多人处于育龄期。AQP 4-IgG以补体依赖性方式介导星形胶质细胞损伤。最近的研究表明，这些抗体有助于受损的妊娠结局。本研究的目的是研究从NMO患者克隆的单克隆AQP 4-IgG（野生型抗体）的经胎盘转运以及FcRn结合，并与Fc区含有单个氨基酸取代的该抗体的5种不同突变Fc结构域进行比较。所有Fc突变的抗体都缺乏补体依赖性细胞毒性。五个Fc突变抗体中的四个在体内显示出有限的经胎盘转运。经胎盘转运受损的三种突变Fc在pH 6和pH 7.2下均显示出与啮齿动物FcRn的持续结合，表明经胎盘转运受限可能是由于FcRn释放减少所致。一种经胎盘转运有限的突变Fc在pH 6时与FcRn的结合减少。这项研究表明，具有完整的经胎盘转运的突变Fc可用于研究抗体效应子功能，并且具有有限转运的Fc可用作向孕妇递送治疗的载体，同时保留发育中的胎儿。
Maternal antibodies provide protection for the developing fetus. Transplacental transport of pathogenic autoantibodies might pose a risk for the developing fetus. The transport of antibodies across the placenta to the fetal circulation occurs through the neonatal Fc salvage receptor (FcRn). During gestation, maternal autoantibodies are able to penetrate the embryonic brain before a functional intact blood–brain barrier is established. Brain-reactive antibodies to the water channel protein aquaporin-4 (AQP4) are a hallmark finding in neuromyelitis optica (NMO), a neurological disease that predominantly affects women, many of whom are of childbearing age. AQP4–IgG mediate astrocytic injury in a complement-dependent fashion. Recent studies suggest these antibodies contribute to impaired pregnancy outcome. The aim of the study was to investigate the transplacental transport as well as FcRn binding of a monoclonal AQP4–IgG cloned from an NMO patient (wild-type antibody) compared to five different mutated Fc domain of this antibody containing single amino acid substitutions in the Fc region. All of the Fc-mutated antibodies lack complement-dependent cytotoxicity. Four of the five Fc-mutated antibodies showed limited transplacental transport in vivo. Three mutated Fc with impaired transplacental transport showed persistent binding to rodent FcRn at pH 6 but also at pH 7.2, suggesting that limited transplacental transport could be due to diminished release from FcRn. One mutated Fc with modestly limited transplacental transport showed diminished binding to FcRn at pH 6. This study suggests that mutated Fc with intact transplacental transport may be used to study antibody effector functions and Fc with limited transport may be used as a carrier to deliver therapies to pregnant woman, while sparing the developing fetus.
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影响因子：
3.7
作者：
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