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

Abstract

The mechanism(s) responsible for the acquisition of maternal antibody isotypes other than IgG are not fully understood. 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. 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. 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. 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.