Evidence that FcRn mediates the transplacental passage of maternal IgE in the form of IgG anti-IgE/IgE immune complexes.

BACKGROUND: The mechanism(s) responsible for acquisition of maternal antibody isotypes other than IgG are not fully understood. This uncertainty is a major reason underlying the continued controversy regarding whether cord blood (CB) IgE originates in the mother or fetus. OBJECTIVE: To investigate the capacity of maternal IgE to be transported across the placenta in the form of IgG anti-IgE/IgE immune complexes (ICs) and to determine the role of the neonatal Fc receptor (FcRn) in mediating this process. METHODS: Maternal and CB serum concentrations of IgE, IgG anti-IgE, and IgG anti-IgE/IgE ICs were determined in a cohort of allergic and non-allergic mother/infant dyads. Madin-Darby canine kidney (MDCK) cells stably transfected with human FcRn were used to study the binding and transcytosis of IgE in the form of IgG anti-IgE/IgE ICs. RESULTS: Maternal and CB serum concentrations of IgG anti-IgE/IgE ICs were highly correlated, regardless of maternal allergic status. IgG anti-IgE/IgE ICs generated in vitro bound strongly to FcRn-expressing MDCK cells and were transcytosed in an FcRn-dependent manner. Conversely, monomeric IgE did not bind to FcRn and was not transcytosed. IgE was detected in solutions of transcytosed IgG anti-IgE/IgE ICs, even though essentially all the IgE remained in complex form. Similarly, the majority of IgE in CB sera was found to be complexed to IgG. CONCLUSIONS AND CLINICAL RELEVANCE: These data indicate that human FcRn facilitates the transepithelial transport of IgE in the form of IgG anti-IgE/IgE ICs. They also strongly suggest that the majority of IgE in CB sera is the result of FcRn-mediated transcytosis of maternal-derived IgG anti-IgE/IgE ICs. These findings challenge the widespread perception that maternal IgE does not cross the placenta. Measuring maternal or CB levels of IgG anti-IgE/IgE ICs may be a more accurate predictor of allergic risk.

FcRn-mediated intestinal absorption of IgG anti-IgE/IgE immune complexes in mice.

BACKGROUND: The mechanism(s) responsible for the acquisition of maternal antibody isotypes other than IgG are not fully understood. OBJECTIVE: To define the ability of the neonatal Fc receptor for IgG uptake (FcRn) to mediate intestinal absorption of IgG(1) anti-IgE/IgE immune complexes. METHODS: C57BL/6 allergic ovalbumin (OVA)-immune foster mothers were generated to nurse naïve FcRn(+/-) or FcRn(-/-) progeny. At the time of weaning, serum levels of OVA-specific antibodies and IgG(1) anti-IgE/IgE immune complexes were determined in allergic foster mothers and FcRn(+/+), FcRn(+/-), or FcRn(-/-) breastfed offspring. In separate experiments, FcRn(+/-) or FcRn(-/-) neonatal mice were gavage fed TNP-specific IgE as IgG(1) anti-IgE/IgE immune complexes, IgG(1) isotype control and IgE, or IgE alone. Mice were killed 2 h after feeding to determine serum levels and biological activity of absorbed TNP-specific IgE. RESULTS: As expected, the absorption of maternal OVA-specific IgG(1) in FcRn(-/-) offspring was at levels 10(3) -10(4) less than observed in FcRn(+/+) or FcRn(+/-) offspring. Surprisingly, FcRn expression also influenced the absorption of maternal IgE. OVA-specific IgE was detected in FcRn(+/+) and FcRn(+/-) offspring, but not in FcRn(-/-) offspring. IgG(1) anti-IgE/IgE immune complexes were detected in allergic foster mothers and correlated strongly with levels in FcRn(+/+) and FcRn(+/-) offspring (ρ = 0.88, P < 0.0001). Furthermore, FcRn expression was required for neonatal mice to absorb TNP-specific IgE when fed as IgG(1) anti-IgE/IgE immune complexes. When immune complexes were generated with IgG(1) anti-IgE directed against the Cε4 domain, the absorbed IgE was able to function in antigen-dependent basophil degranulation. CONCLUSIONS AND CLINICAL RELEVANCE: These data demonstrate a novel mechanism by which FcRn may facilitate absorption of maternal antibodies other than IgG. These findings are clinically relevant because FcRn mediates the transplacental passage of maternal IgG to the fetus. This raises the possibility that FcRn could mediate the transplacental passage of maternal IgE as IgG anti-IgE/IgE immune complexes.