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

Abstract

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.

Half-life of IgE in serum and skin: Consequences for anti-IgE therapy in patients with allergic disease

“…Recent evidence indicates that FcRn can mediate the transfer of IgE complexed to IgG anti-IgE molecules both across the placenta and in breastmilk. 50 If anti-IgE mAb–IgE complexes do in fact bind to FcRn, as we suggest, then it might be possible for them to cross the placenta and be transferred in breastmilk. Thus, in theory, fetuses of mothers treated with anti-IgE mAb could become passively sensitized through this route if the IgE were to somehow become dissociated from the anti-IgE mAb complex.…”

“…Thus, in theory, fetuses of mothers treated with anti-IgE mAb could become passively sensitized through this route if the IgE were to somehow become dissociated from the anti-IgE mAb complex. 50 …”

“…2,3 FcRn is a β 2 -microglobulin–associated MHC class I–like molecule that binds all IgG subclasses (although IgG 3 binds poorly) and plays a critical role in prolonging the half-life of IgG in serum. 44–50 The best-supported mechanism by which FcRn prolongs the half-life of IgG is by binding it in endosomes in vascular endothelial cells and protecting it from degradation. IgG is either recycled back into the circulation or trancytosed into tissues for eventual return to the circulation through the lymphatics (Fig 2, A ).…”

Cord blood IgE: fetal or maternal?

“…In contrast to this belief, Bundhoo et al. show in an interesting article in this issue of Clin Exp Allergy that IgE can be transported across the placenta. This transport is mediated by IgG autoantibodies directed against IgE.…”

Immunobiological aspects of vaccines in pregnancy: Maternal perspective

“…Of the immunoglobulins in the maternal circulation, only IgG is transferred transplacentally [68,103]. Studies suggest that maternal IgE could be transported complexed with IgG [104]. Transfer of antibodies is an active process beginning at the end of the first trimester of pregnancy.…”