Date Published: August 30, 2018
Publisher: Public Library of Science
Author(s): David R. Martinez, Genevieve G. Fouda, Xinxia Peng, Margaret E. Ackerman, Sallie R. Permar, Donald C. Sheppard.
The transplacental transfer of maternal Immunoglobulin G (IgG) to the fetus is critical for protection against infectious diseases in the first year of life . Maternal protective IgG is transferred from the maternal to the fetal circulatory system via the placenta, and this process begins in the first trimester of pregnancy . By 37–40 weeks of gestation, maternal passively acquired IgG concentrations in newborns can exceed maternal IgG serum levels in normal pregnancies [3–7]. Yet, the molecular mechanisms of transplacental transfer of maternal IgG remain poorly understood. In order to reach the fetal circulatory system, maternal IgG must traverse three distinct placental anatomical barriers: (1) the syncytiotrophoblast cell barrier, (2) the villous stroma containing placental fibroblasts and Hofbauer cells, and (3) fetal endothelial cells. It is well established that IgG crosses the syncytiotrophoblast by binding to the canonical IgG shuttle receptor: Fragment crystallizable (Fc) receptor neonatal (FcRn) [2, 8]. However, how maternal IgG traverses the subsequent placental barriers is not completely understood, as they do not express FcRn, yet recent RNAseq analyses have shown that Fcγ receptors, including FcγRIIIa, FcγRIIa, FcγRIIb, and FcγRI, are expressed in term placentas . However, it should be cautioned that it is not yet known if these noncanonical placental FcRs play a role, if at all, in the transplacental transfer of maternal IgG.
Human FcRn consists of alpha and beta subunits that assemble to form a membrane-bound heterodimer receptor [8, 10]. FcRn is primarily expressed in intracellular endosomes in placental syncytiotrophoblast cells, and it shuttles maternal IgG from the apical side to the basolateral membrane . In the proposed model of the transplacental transfer of IgG in syncytiotrophoblast cells, IgG is first phagocytosed into endosomes containing membrane-bound FcRn . Upon exposure to endosome acidification from pH 7.4 to pH 6, IgG Fc binds to FcRn via electrostatic interactions [2, 10]. Next, the endosome is released on the basolateral side of the syncytiotrophoblast, and once the FcRn:IgG complex is extracellularly exposed to pH 7.4, the complex dissociates, releasing IgG into the villous stroma .
The molecular mechanisms of the transplacental IgG transfer beyond the syncytiotrophoblastic cell barrier remain poorly understood. Importantly, placental cell barriers internal to the syncytiotrophoblast layer, including fibroblasts and Hofbauer cells of the villous stroma, and fetal endothelial cells, do not express the canonical placental IgG shuttle receptor FcRn (Fig 1). Yet, these downstream placental cell barriers express noncanonical Fc receptors. For example, Hofbauer cells express FcγRIII, FcγRII, and FcγRI but not FcRn, whereas placental fibroblasts are not known to express any Fcγ receptors. Finally, while the fetal endothelial cell—the final cell barrier that maternal IgG crosses before reaching the fetal circulatory system—does not express FcRn, it does express FcγRII [2, 14, 15]. Previous studies that examined the transplacental IgG transfer activity of FcγRIIb showed that endocytosed IgG colocalizes with FcγRIIb in endothelial cell endosomes [14–16]. Intriguingly, both IgG-bound FcγRIIb and free FcγRIIb were observed inside these endosomes, suggesting that this low-IgG-affinity receptor may play a role in the shuttling of maternal IgG into the lumen of fetal endothelial vessels . In addition, FcγRIIIa and FcγRI, when engaged with IgG, can signal through Ig tyrosine-activating motif (ITAM), whereas FcγRIIb signals through Ig tyrosine-inhibition motif (ITIM) . However, the Fc receptor IgG-dependent activation or inhibition of downstream placental cell signaling pathways as they relate to transplacental IgG transfer is unknown.
To date, no common single nucleotide polymorphisms (SNPs) have been identified for human FcRn . However, allelic variation near the FcRn promoter has been implicated in altered transcriptional activity of FcRn in distinct human populations. As an example, variable number of tandem repeats (VNTR) variant 3 is more prevalent in Caucasian populations, and this allelic variation in the promoter is associated with increased transcriptional activity compared to VNTR variant 2 . Nonsynonymous polymorphisms can also alter expression levels of FcγRIIb. For example, FcγRIIb can encode a nonsynonymous T > C SNP, which leads to either an I232 or T232 . Interestingly, a T232 has been implicated in reduced localization to the membrane , which could potentially alter the ability of FcγRIIb to shuttle maternal IgG in fetal endothelial cells. Promoter SNPs have also been implicated in modulating gene expression levels of FcγRIIb , suggesting that SNPs regulate both the localization and expression levels of FcγRIIb. Similarly, nonsynonymous polymorphisms in FcγRIIIa, a nucleotide point mutation that leads to either F158 or V158, have been implicated in altering the binding affinity to IgG [31, 32]. For example, FcγRIIIa V158 has a stronger binding affinity for IgG subclasses compared to FcγRIIIa F158. Thus, polymorphisms among placentally expressed Fcγ receptors may play a role in transplacental IgG transfer.
From our current understanding of the placental transfer of IgG, it remains unclear if placentally expressed Fc receptors , such as the Type II Fc receptor Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN), or undiscovered IgG shuttle receptors, play a role, if at all, in transplacental IgG transfer. A deeper understanding of the molecular mechanisms of maternal IgG binding to alternative placental Fc receptors could be important for designing IgG-based therapeutics that increase infant protection against congenital viral infections and in early life. In fact, maternal passive immunization with polyclonal IgG during pregnancy has shown to be protective against congenital cytomegalovirus infection and is also being tested as a treatment strategy against congenital Zika syndrome [34, 35]. Therefore, future studies are needed to (1) define whether or not these noncanonical placentally expressed Fc receptors play a role in mediating the transplacental transfer of maternal IgG and (2) define how Fc receptor allelic variation impacts the transplacental transfer of maternal IgG. These data will guide the design of IgG-based maternal vaccines and therapeutics, fine-tuning transplacental transfer of IgG to improve maternal and infant health.