Noncanonical placental Fc receptors: What is their role in modulating transplacental transfer of maternal IgG?

Martinez, David R.; Fouda, Genevieve G.; Peng, Xinxia; Ackerman, Margaret E.; Permar, Sallie R.

doi:10.1371/journal.ppat.1007161

Cited by 39 publications

(47 citation statements)

References 33 publications

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“…The presence of Fc-receptor binding predictors of placental transfer ( Figures 4D-4G) along with monoclonal-galactosylation-mediated FCGR3A binding differences ( Figure 5E) suggested that Fc-receptors, beyond FcRn, may contribute to placental sieving. Given our emerging appreciation for the expression of FcRs across tissues, including the placenta Martinez et al, 2018), we next aimed to determine whether FcRs could contribute to FcRn-mediated antibody sieving at the placental level. The localization of FcRs and FcRn was examined across placental tissue (Figures 6A-6D and S6).…”

Section: Fc Receptor Expression In the Placentamentioning

confidence: 99%

Fc Glycan-Mediated Regulation of Placental Antibody Transfer

Jennewein

Goldfarb

Dolatshahi

et al. 2019

Cell

185

211

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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).

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Section: Fc Receptor Expression In the Placentamentioning

confidence: 99%

Fc Glycan-Mediated Regulation of Placental Antibody Transfer

Jennewein

Goldfarb

Dolatshahi

et al. 2019

Cell

185

211

View full text Add to dashboard Cite

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“…Of the Fc receptors expressed in placental tissue only the role of FcRn is clear. Other noncanonical Fc receptors, including FcγRI, FcγRII, and FcγRIII, are widely unexplored and may contribute to IgG transport ( 48 ). A recent study pointed to preferential transplacental transfer of antibodies with digalactosylated Fc glycans, binding selectively to FcRn and FcγRIIIa.…”

Section: Discussionmentioning

confidence: 99%

Limited Neonatal Carbohydrate-Specific Antibody Repertoire Consecutive to Partial Prenatal Transfer of Maternal Antibodies

et al. 2020

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Despite the prominence of carbohydrate-specific antibodies in human sera, data on their emergence and antigen specificities are limited. Whereas maternal IgG are transferred prenatally to the fetal circulation, IgM present in cord blood originate from fetal B lymphocytes. Considering the limited exposure of the fetus to foreign antigens, we assessed the repertoire of carbohydrate-specific antibodies in human cord blood and matched maternal blood samples using glycan arrays. Carbohydrate-specific IgM was absent in cord blood, whereas low cord blood IgG reactivity to glycans was detectable. Comparing IgG reactivities of matched pairs, we observed a general lack of correlation in the antigen specificity of IgG from cord blood and maternal blood due to a selective exclusion of most carbohydrate-specific IgG from maternofetal transfer. Given the importance of intestinal bacteria in inducing carbohydrate-specific antibodies, we analyzed global antibody specificities toward commensal bacteria. Similar IgG reactivities to specific Bacteroides species were detected in matched cord and maternal blood samples, thus pointing to an efficient maternal transfer of anti-microbial IgG. Due to the observed selectivity in maternofetal IgG transfer, the lack of fetal antibodies to carbohydrate epitopes is only partially compensated by maternal IgG, thus resulting in a weak response to carbohydrate antigens in neonates.

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“…[16]. Additionally, binding of tetanus toxoid-specific IgG to placental FcγRIIa H131, FcγRIIa R131, and FcγRIIIa F158 (but not canonical FcRn) was positively associated with placental IgG transfer efficiency in HIV-infected women, suggesting that noncanonical placental FcRs may also play a role in IgG placental transfer [17,18]. Fc-mediated differential selection of IgG antibodies in the placenta is likely an adaptive evolutionary mechanism to passively transfer the most effective antibodies to the infant, which can be altered by disease status.…”

Section: The Igg Fc Domain and Its Effector Functions In The Context mentioning

confidence: 99%

Maternal gatekeepers: How maternal antibody Fc characteristics influence passive transfer and infant protection

et al. 2020

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Noncanonical placental Fc receptors: What is their role in modulating transplacental transfer of maternal IgG?

Cited by 39 publications

References 33 publications

Fc Glycan-Mediated Regulation of Placental Antibody Transfer

Fc Glycan-Mediated Regulation of Placental Antibody Transfer

Limited Neonatal Carbohydrate-Specific Antibody Repertoire Consecutive to Partial Prenatal Transfer of Maternal Antibodies

Maternal gatekeepers: How maternal antibody Fc characteristics influence passive transfer and infant protection

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