Which antibodies cross the placenta

The findings, reported JAMA Pediatrics , suggest that mothers who have had COVID, or asymptomatic exposure to the coronavirus, can, through this antibody transfer, provide some protection against the virus to their newborns. The vast majority 87 percent of the newborn babies of these women also had significant levels of SARS-CoVspecific antibodies in samples of umbilical cord blood drawn at birth.

Prior, smaller studies also have found evidence that maternal antibodies can cross the placenta to the fetal bloodstream. However, the dynamics and the efficiency of this transfer have been unclear. Puopolo and Hensley and their colleagues used a previously validated blood test kit to check for SARS-CoVspecific antibodies in blood serum samples collected at the time of delivery during a four-month period from April to August of last year at Pennsylvania Hospital in Philadelphia.

Transfer of IgG across the placental barrier is thought to involve interaction between IgG and the neonatal Fc receptor FcRn in the placental syncytiotrophoblast 5. For FcRn to bind IgG, IgG must therefore be taken up from the maternal circulation by the syncytiotrophoblast into endosomes which undergo acidification. The endosomes then fuse with the fetal side of the syncytiotrophoblast, leading to an increase in the pH, and the release of IgG into the stroma 8.

It is not currently known how IgG crosses the stroma and the second placental barrier—the fetal endothelium—but FcRn may also be present in this endothelial layer 9. Other receptors or Fc-binding proteins found in the placenta could also be involved 6. More detail on the process of IgG transfer is available in our recently published review on FcRn-mediated transplacental antibody transfer IgG is divided into four subclasses, which cross the placenta with differential efficiency.

The issue of transplacental transfer of the IgG subclasses is important, as they play diverse roles in immunity, and their production is differentially induced by distinct pathogens and vaccines [reviewed in 11 ]. These usually reference one review 12 that has a graph illustrating data from a single study We have identified 17 papers that have measured maternal and cord levels of the four IgG subclasses 13 — 29 Figure 1. Calculating the mean from these papers produces transfer ratios of 1.

The reasons for these varying reports could be due to many differences in study populations including ethnicity, parity, BMI, placental weight, birth weight, gestation at birth, as well as maternal antigen exposure through vaccination or infection modifying antibody phenotype including subclasses, antigen-specificity, and glycosylation. Figure 1. Overview of studies investigating maternal to fetal transfer ratios of IgG subclasses. We identified 17 papers that measured paired maternal and cord levels of all four IgG subclasses 13 — 22 , 24 — The line graph represents the mean to fetal transfer ratio on a log 2 axis.

The dotted black line indicates the mean of the 16 studies. For Malek et al. For two studies, we performed ratio calculations based on reported maternal and cord concentrations 21 , For two other studies, values were calculated by reading from the published graphs 13 , For Costa-Carvalho et al. In Hay et al. Many previous studies of placental antibody transfer have been relatively small and often have not interrogated the effect of clinical variables other than gestation at delivery.

Later gestation at delivery is associated with an increase in maternal to cord transfer ratios and in concentrations of antibody in cord blood 11 , 30 — However, several additional maternal and fetal factors have the potential to impact on placental antibody subclass transfer. This includes fetal sex, Rhesus status and associated anti-D antibody administration , maternal vaccination, BMI, parity and ethnicity, among others. It is important to understand the role of these factors when performing maternal vaccination studies in diverse patient populations.

We performed IgG subclass analysis on a large number of maternal and cord blood samples, including an assessment of the impact of maternal and fetal factors on IgG subclass levels and transplacental transfer. Serum samples were obtained from corresponding maternal and—cord blood pairs, as part of two maternal vaccination studies.

Healthy women with singleton pregnancies with no known complications nor chronic or acute diseases were recruited. Detailed clinical data including BMI, parity, age, ethnicity, gestation at delivery, infant sex, birth weight, and maternal vaccination status were recorded. Serum samples were obtained from mothers near the time of birth between 1 day before delivery and 3 days after delivery , and from the umbilical cord vein or artery within 1 h of delivery.

Where possible, blood was collected separately from both the umbilical vein and the umbilical artery and this was recorded. Blood was collected into serum-separating tubes BD and left to clot for a minimum of 15 min before spinning at G for 10 min. This kit utilizes a high affinity protein stain which is compatible with subsequent western blotting.

Following staining, membranes were imaged on the ImageQuant camera system LAS ; GE Healthcare to enable normalization of subsequent specific protein bands. This approach for normalization was employed due to the high variability of common protein loading controls in the placenta Bound antibody was detected through incubation with 0.

FcRn levels relative to total protein was determined by densitometry ImageJ. Statistical analyses were performed in GraphPad Prism v8. IgG concentrations were log transformed natural Log prior to analysis to achieve normality. Maternal to fetal transfer ratios were calculated by dividing the IgG concentration in cord blood, by the IgG concentration in paired maternal blood. These ratios were then log 2 transformed prior to analysis. Unadjusted and adjusted effects were estimated by simple and multiple linear regression models in Stata v Clinical characteristics of the study subjects are shown in Table 1.

There was no significant effect of timing of maternal bleed and maternal IgG concentrations Supplemental Figure 1. The maternal to fetal transfer ratio of IgG1 1. IgG3 also exhibited a small, but significantly higher transfer ratio 1. When transfer ratios were normalized to total IgG levels in mothers, as a measure of relative transfer efficiency, a similar pattern of transfer was observed, although IgG3 was no longer significantly higher than IgG4 Figure 2C.

Paired comparison revealed significantly higher levels of total IgG and IgG1, and significantly lower levels of IgG2 and IgG4 in cord blood serum compared to matched maternal serum Figure 2E. IgG3 was not significantly different between mothers and infants.

Correlation plots of maternal and cord IgG levels show a positive correlation between maternal and cord antibody for total IgG and all IgG subclasses. Within the subclasses, the strongest correlation between maternal and cord levels is for IgG4, with the weakest correlation for IgG2 Figure 2F. Additional descriptive statistics on the transfer of the subclasses is provided in Supplemental Table 1.

Figure 2. Maternal and cord blood IgG subclass profiles and transfer ratios. B Maternal to fetal transfer ratios of IgG represented on log 2 scale. C Maternal to fetal transfer ratios of IgG1—4 normalized to levels of total IgG in maternal blood as an indicator of transfer efficiency.

D Maternal to fetal transfer ratios of IgG1—4 represented on log 2 scale broken down by gestational age at delivery. E Dot-line plots showing the relationship between IgG concentrations in maternal and cord pairs. Groups compared by paired t test on nLog-transformed data. F Correlations between maternal and cord IgG concentrations. Lines indicate simple linear regression. As maternal levels of antigen-specific antibodies have been associated with reduced placental transfer ratios 11 , 34 , we investigated the association between maternal levels of antibody subclasses and transfer ratios Figure 3.

Maternal concentrations of IgG4 were only negatively associated with the transfer ratios of IgG1. Figure 3. Impact of maternal IgG concentrations on the rate of maternal to fetal IgG transfer. Horizontal dashed line represents equal levels between mother and fetal circulations.

Correlations between nlog-transformed maternal IgG concentrations and log 2 -transformed transfer ratios were analyzed by Spearman's rank correlation coefficient. These glycosylated antibodies bound nonspecifically to other IgG antibodies, as well as to monocytes and neutrophils. Similarly, the researchers speculate that the glycosylated IgG antibodies neutralize the antibodies to which they bind.

The findings suggest that glycoslated IgG may be one way the fetus is shielded from immune attack by the mother. Future studies should provide answers to questions such as how non-threatening, useful maternal antibodies might make it through this defense system, and how this system might interact with other immune-shielding mechanisms.

In a follow-up study in Biology of Reproduction , Gu and his colleagues provide evidence that incoming IgG antibodies are processed in two distinct compartments in syncytiotrophoblasts [ 2 ]. Fab fragment glycosylated IgG may play a central role in placental immune evasion.

Hum Reprod ; 30 : — Two ultrastructural distribution patterns of immunoglobulin g in human placenta and functional implications. Biol Reprod ; 91 : Google Scholar. B cells in pregnancy: functional promiscuity or tailored function? Biol Reprod ; 92 : B cell development undergoes profound modifications and adaptations during pregnancy in mice. For example, if you have had chickenpox , you should have developed immunity against the condition and some of the chickenpox antibodies will be passed to your baby.

Immunity in newborn babies is only temporary and starts to decrease after the first few weeks or months. Breast milk also contains antibodies, which means that babies who are breastfed have passive immunity for longer.

The thick yellowish milk colostrum produced for the first few days following birth is particularly rich in antibodies.