Abstract
In humans, maternal IgGs are transferred to the fetus from the second trimester of pregnancy onwards. The transplacental delivery of maternal IgG is mediated by its binding to the neonatal Fc receptor (FcRn) after endocytosis by the syncytiotrophoblast. IgGs present in the maternal milk are also transferred to the newborn through the digestive epithelium upon binding to the FcRn. Importantly, the binding of IgGs to the FcRn is also responsible for the recycling of circulating IgGs that confers them with a long half-life. Maternally delivered IgG provides passive immunity to the newborn, for instance by conferring protective anti-flu or anti-pertussis toxin IgGs. It may, however, lead to the development of autoimmune manifestations when pathological autoantibodies from the mother cross the placenta and reach the circulation of the fetus. In recent years, strategies that exploit the transplacental delivery of antigen/IgG complexes or of Fc-fused proteins have been validated in mouse models of human diseases to impose antigen-specific tolerance, particularly in the case of Fc-fused factor VIII (FVIII) domains in hemophilia A mice or pre-pro-insulin (PPI) in the case of preclinical models of type 1 diabetes (T1D). The present review summarizes the mechanisms underlying the FcRn-mediated transcytosis of IgGs, the physiopathological relevance of this phenomenon, and the repercussion for drug delivery and shaping of the immune system during its ontogeny.
Highlights
The existence of a passive transfer of immunity from the mother to the young was documented by P
The establishment of the adaptive immune system and the generation of T and B lymphocytes expressing rearranged T-cell and B-cell receptors, respectively, at their surface is concomitant to the transplacental delivery of maternal IgGs, creating a time window when maternal IgGs, that represent the last step of the expression of the maternal immune system, have the opportunity to impact the developing adaptive immune repertoires of the fetus
We demonstrated that the injection to pregnant factor VIII (FVIII)-KO mice of the immunodominant A2 and C2 domains of FVIII fused to mouse Fcγ1 allows the transplacental delivery of A2Fc and C2Fc
Summary
The existence of a passive transfer of immunity from the mother to the young was documented by P. Ehrlich more than a century ago and more than 50 years ago by Brambell et al [1]; it was a few years before the demonstration that passive transfer of immunity is mediated by maternal IgGs. The maternal and fetal circulations are separated by cellular barriers differently organized depending on the species [hemomonochorial in the human [2] and hemotrichorial in the mouse]. In addition to the transplacental delivery of maternal IgGs, the FcRn is involved in a plethora of functions including the transfer of IgGs present in maternal milk to the newborn through the digestive epithelium, control of IgG and albumin catabolism, uptake of immune complexes by a variety of cells leading, in the case of antigen presenting cells, to the presentation of the endocytosed antigen to T lymphocytes. The present review summarizes the mechanisms underlying the FcRn-mediated transcytosis of IgGs, the physiopathological relevance of this phenomenon and the potential for in utero drug delivery and manipulation of the immune system
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