Which antibody crosses placenta

Groups compared by paired t- test on nLog-transformed data. Transplacental antibody transfer across the synctytiotrophoblast layer of the placenta is mediated through interaction with the neonatal Fc receptor [FcRn; reviewed in 10 ]. To investigate whether inter-individual differences in IgG subclass transfer are due to differences in FcRn levels in the placenta, western blotting of paired placental samples was performed Figure 5.

Figure 5. Correlation of placental FcRn levels with transfer of IgG subclasses. A Western blot for FcRn in lysates of placental villous tissue. Proteins were prepared under reducing denaturing conditions.

B Total protein stain left panel and densitometry analysis right panel. C Correlation between placenta FcRn protein levels normalized to total protein stain and maternal to fetal IgG transfer ratios log 2 transformed analyzed by Spearman's rank correlation coefficient. Unadjusted analyses were performed to explore relationships between clinical variables and maternal and cord IgG concentrations, as well as the maternal to fetal transfer of IgG subclasses Tables 2 — 4.

Table 2. Table 3. Table 4. Maternal BMI and sex of the neonate had no impact on any variables. Tdap vaccination status had no effect on maternal or cord IgG concentrations nor IgG transfer.

Figure 6. Correlation between gestation at Tdap vaccination and placental transfer of total IgG and IgG subclasses. A Correlation between the gestation that pregnant women received the Tdap vaccine and the maternal to fetal IgG transfer ratio for total IgG and IgG subclasses [log 2 Y -axis].

Analysis was performed on log 2 transformed ratios by Spearman's rank correlation coefficient, and resultant p values are stated in the bottom right corner of each plot. Coefficients: Total IgG: 0. B Correlation between the gestation at vaccination and the antibody concentration in maternal blood and cord blood at birth. Analysis performed on log-transformed data by Spearman's rank correlation coefficient. In the adjusted analysis, levels of total IgG in maternal serum was associated with both parity and maternal age, but not with gestation at delivery nor ethnicity Table 5.

Table 5. We investigated the association between the clinical variables in these models. Primiparous women were more likely to be white log-odds: 1. There was no association between maternal age and parity, ethnicity nor gestation at delivery. We have performed a comprehensive analysis of maternal and cord levels of the IgG subclasses and transplacental transfer in a UK pregnancy cohort, and investigated their association with maternal and fetal factors.

As previously observed, maternal concentrations of total IgG and IgG subclasses were positively associated with umbilical cord concentrations Figure 2F and negatively associated with the maternal to fetal transfer ratios Figure 3. As has been previously well established, we found higher levels of total IgG and IgG1 in cord blood compared to maternal blood, reflected in a mean transfer ratio of 1.

The transfer ratio of the other subclasses was near to 1. Maternal antibodies may compete for transplacental transfer through their competition for placental FcRn, which binds IgG in a stoichiometry There have been fewer studies of the association between maternal levels of the IgG subclasses and transplacental transfer. Our analysis performing correlations on continuous data found a negative correlation between maternal total IgG levels and the transfer ratios of total IgG, IgG1, IgG2, and IgG3 subclasses in healthy pregnancy.

This suggests that the higher abundance IgG1, IgG2, and IgG3 may all compete with their respective, and other subclasses, for transfer across the placenta. Thus, the effects observed cannot be necessarily be attributed specifically to a certain subclass, but could be driven by IgG1, which is highest in abundance and transferred with the highest efficiency.

With that said, increased maternal IgG4 levels had limited correlation with IgG transfer, and transfer of IgG4 was not correlated with maternal levels of any antibody, even though maternal IgG4 levels are positively correlated with maternal IgG1. Furthermore, IgG4 had the strongest correlation between maternal and cord IgG concentrations, which altogether suggests that the transfer of this subclass is least affected by changes in amounts of antibody in the mother. The clinical significance of this phenomenon on passive immunity in the neonate is likely to lie in the potential impact on the transfer of antibodies against specific pathogens, which should be explored.

The relative abundance between paired maternal-cord samples is not necessarily a true reflection of transfer efficiency as this could be biased by maternal concentrations, as well as the levels of IgG recycling in fetal and maternal circulations. To partly address this, we have shown that normalization of transfer ratios to total IgG levels in maternal blood show the same pattern of differential transfer of the IgG subclasses Figure 2C.

We also show a similar pattern of relative transfer ratios between 37 and 42 weeks gestation. In vitro competition assays in human trophoblast or non-human primate in vivo experiments with spike-in of IgG subclasses are required to fully understand the competition for transplacental transfer between the IgG subclasses.

Nevertheless, our data appears to support the current consensus that although higher IgG levels in the mother will result in higher IgG levels in the offspring, the relative transfer efficiency across the placenta can be reduced when maternal concentrations are elevated.

Given the limited capability for IgG production in the fetus, the majority of antibody in the fetal circulation is maternal in origin. We hypothesized that IgG levels in the umbilical arteries bringing deoxygenated blood from the fetus would be higher than levels in the umbilical vein bringing freshly oxygenated blood from the placenta.

In contrast however, we found no significant difference in the abundance of the IgG subclasses, and only a slightly but significantly higher level of total IgG in the umbilical artery. This was a surprising finding and could suggest that there is greater hemodilution in venous blood compared to arterial blood, or it could reflect efficient total antibody recycling in the fetal circulation leading to higher levels in blood coming from the fetus. No other study has investigated this to our knowledge.

It could be of interest to investigate FcRn levels in the venous and arterial endothelium of the umbilical cord and in the placental vasculature, as this is involved in antibody recycling, thereby increasing half-life.

It would also be of interest to determine whether there are differences in the levels of antigen-specific antibodies between venous and arterial umbilical blood. For a subset of samples, we performed measurement of FcRn in matched placenta.

We found no significant correlation between placental levels of FcRn and the transfer rates of total IgG nor any of the antibody subclasses.

One previous study has correlated placental FcRn with transfer ratios, and concluded that there was a positive association Our measurement of FcRn by western blotting also has its limitations, given that it is measured in a mixed homogenate of placental tissue. Importantly however, we only looked at term placentas, which reduces the effect of gestational changes in placental structure. Our data suggests that inter-individual differences in transplacental transfer are mainly driven by differences in IgG, however this question warrants further investigation in a larger cohort, as well as investigation of other Fc receptors.

Finally, we explored the potential clinical variables that may impact on maternal and cord levels, and transfer ratios of total IgG and the IgG subclasses. Only a few variables impacted on the concentration of IgG in neonatal blood. Babies born at later gestation had significantly higher levels of IgG1 and IgG4. For IgG4 this appears to have been facilitated by significantly higher levels of IgG4 in the mothers, that was then passed to the fetus, rather than an increase in the rate of transplacental transfer which was unchanged.

For IgG1, maternal levels were no different with later gestation, and following adjustment for other associated variables, gestation was also not associated with the IgG1 transfer ratio. This suggests that the higher IgG1 at later gestation may reflect an accumulation of IgG1 in the fetal circulation over time, rather than an increased ability of the placenta to transfer IgG in the last weeks of term pregnancy.

Several other studies have found a positive association between total IgG and antigen-specific IgG and gestation 11 , 30 — Our study shows that even at term, every additional weeks' delay in delivery increases neonatal levels of IgG1 and IgG4. Birth centiles were negatively correlated with neonatal levels of total IgG and of IgG2. This does not appear to be related to a change in maternal levels, nor lower transfer ratio of these subclasses, neither of which were associated with birth centiles.

The reason for this is unclear, but it could be an effect of higher hemodilution of IgG in a larger fetal circulation. It would be difficult to explore this; perhaps an analysis that incorporated both infant birth centiles and placental weight could shed light on this observation.

The transport of IgG antibodies across the placenta is known to occur especially in the third trimester of pregnancy, and as more time passes, more antibodies cross. Scientists also know that an infection with a novel virus can take time to elicit a significant antibody response. The results from Hensley, Puopolo and their colleagues were consistent with these known patterns: placental transfer was greater the longer the time elapsed between maternal COVID infection and delivery.

The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U. Penn Medicine is powered by a talented and dedicated workforce of more than 44, people. Two models were used: model 1 was analyzed based on all maternal sera, and model 2 was based on only positive maternal sera.

All experimental methods were carried out in accordance with the Declaration of Helsinki. Written informed consent was obtained from the enrolled pregnant women ClinicalTrials. How to cite this article : Fu, C. Placental antibody transfer efficiency and maternal levels: specific for measles, coxsackievirus A16, enterovirus 71, poliomyelitis I-III and HIV-1 antibodies. Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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