Fc Glycan-Mediated Regulation of Placental Antibody Transfer

Abstract

Graphical Abstract Highlights d NK cell-activating antibodies are selectively transferred across the placenta d Digalactosylated Fc glycans are preferentially transferred across the placenta d Digalactosylated antibodies bind more effectively to FcRn and FCGR3A d Although immature, neonatal NK cells are highly responsive to immune complexes SUMMARY Despite the worldwide success of vaccination, newborns remain vulnerable to infections. While neonatal vaccination has been hampered by maternal antibody-mediated dampening of immune responses, enhanced regulatory and tolerogenic mechanisms, and immune system immaturity, maternal pre-natal immunization aims to boost neonatal immunity via antibody transfer to the fetus. However, emerging data suggest that antibodies are not transferred equally across the placenta. To understand this, we used systems serology to define Fc features associated with antibody transfer. The Fc-profile of neonatal and maternal antibodies differed, skewed toward natural killer (NK) cell-activating antibodies.This selective transfer was linked to digalactosylated Fc-glycans that selectively bind FcRn and FCGR3A, resulting in transfer of antibodies able to efficiently leverage innate immune cells present at birth. Given emerging data that vaccination may direct antibody glycosylation, our study provides insights for the development of next-generation maternal vaccines designed to elicit antibodies that will most effectively aid neonates. Antibodies against pertussis derived filamentous hemagglutinin (FHA), pertactin (PTN), fimbriae (FIM), and pertussis toxin (PTX) antigens were compared in 14 mother:cord pairs. (A) The flow cytometric plots depict the gating strategy for antibody dependent cellular phagocytosis (ADCP). (B) The connected dot-plot shows the phagocytic activity across mother:cord pairs. (C) The box-and-whisker plot shows the transfer ratio of ADCP. The dotted line indicates a 100% transfer efficiency (equivalent levels across both compartments). (D) The flow plots highlight the gating strategy for antibody dependent neutrophil phagocytosis (ADNP). (E) The dot-plot shows the relationship between ADNP activity across mother:cord pairs for each antigen-specificity. (F) The whisker plots show the transfer ratio for ADNP. (G) The flow plots highlighting the gating strategy for the NK cell activation assay. (H-J) The dot-line plots show NK-dependent degranulation plotted as the percentage of NK cells positive for CD107a (H), IFNg (I), and MIP-1b (J). (K-M) The whisker plots depict the transfer ratio across the three NK cell activation markers, CD107a (K), IFNg (L), and MIP-1b (M).

FcRn, but not FcγRs, drives maternal-fetal transplacental transport of human IgG antibodies

“…Here, using a variety of in vitro and in vivo approaches, we addressed questions also asked by recent studies as to whether FcγRs may be involved in transplacental transfer of human IgGs (9,14,15). Unlike some studies (14,15) but consistent with other (9), we find that there is no enrichment for specific Fc glycoforms in cord blood over paired maternal blood.…”

“…Galactosylation has been observed to increase Fc-FcγRIIIa binding, but only in absence of fucosylation (25). Recently, it has been reported that IgG galactosylation, in the presence of fucosylation, impacts IgG binding to FcγRIIIa and FcRn (14). Given these contrasting reports on the role of Fc galactosylation in modulating FcγR and FcRn affinity, we performed a comprehensive analysis of the FcγR and FcRn affinity of IgG Fc glycoforms with defined, homogenous glycan structures.…”

“…Recent studies suggested that post-translational modifications of IgGs and a specific low-affinity FcγR, FcγRIIIa, have a role in transplacental IgG transfer (14,15). These studies characterized paired maternal and cord blood IgG, reporting a significant increase in digalactosylation on total cord IgGs (but not on antigen-specific IgGs) and suggesting that this modification may direct transplacental transfer of maternal IgGs in a process they term "placental sieving".…”

Natural killer cell activation by respiratory syncytial virus‐specific antibodies is decreased in infants with severe respiratory infections and correlates with Fc‐glycosylation

“…These observations are in line with the gradual replacement of maternal with infant antibodies. Altered glycosylation during pregnancy and preferential transplacental transfer result in increased IgG Fc‐galactosylation of maternal antibodies . In addition, like all adult antibodies, maternal antibodies have lower fucosylation (94%) compared to highly fucosylated infant antibodies, which reach adult levels around the age of 20 years …”

“…Altered glycosylation during pregnancy and preferential transplacental transfer result in increased IgG Fc-galactosylation of maternal antibodies. 35,36,64 In addition, like all adult antibodies, maternal antibodies have lower fucosylation (94%) compared to highly fucosylated infant antibodies, which reach adult levels around the age of 20 years. 35 Surprisingly, we observed similar correlations between glycosylation and age for RSV-specific antibodies.…”