The molecular mechanism whereby IgG antibody crosses the trophoblast of the human placenta from the mother to fetus, thereby conferring upon the newborn its mother's full complement of protective antibody, continues to baffle and challenge students of this area. The most promising hypothesis states that an Fc receptor for IgG (Fc-gamma-R) serves to bind and transport IgG across the syncytiotrophoblast shuttling between apical and basal membranes in endocytic transport vesicles. But few details of the molecular mechanism are known. Recently, however, in our laboratories we have described the presence on human trophoblasts of FC-gamma-RIII, a member of the group of human leukocyte Fc-gamma-R. The binding of specific anti-Fc-gamma-RIII monoclonal antibodies indicates the presence of this receptor on both syncytiotrophoblasts in vivo and on cultured purified trophoblasts in vitro. We propose that this molecule is the long-elusive IgG transporter, and we are now poised to analyze the nature of this promising molecule in more detail and to study how it might be responsible for IgG transport across the placental trophoblast barrier. We further propose that the study of placental IgG transcytosis may help us understand how the fetus becomes infected with HIV. We would postulate that HIV crosses the trophoblast bound to anti-HIV antibodies which are being transported by the Fc-gamma-R-mediated transcytotic mechanism used to transport antibody alone. Such a proposal is compatible with several observations such as the lack of CD4 on trophoblasts, the inability to show HIV replication within trophoblast cultures, but the presence of HIV in trophoblasts by electron microscopy. Moreover, remarkable precedence for this mechanism is seen in the capacity of anti-viral antibody to mediate the cellular uptake of Lentiviruses, including HIV, by Fc-gamma-R-bearing phagocytic cells such as monocytes. The long term aims of our proposal, therefore, are to understand the molecular details of transplacental IgG transcytosis and to determine whether HIV is transported to the fetus along with IgG anti-HIV antibody by the same mechanism. The short term aims of the proposal are five fold: 1) to characterize the in vitro trophoblast model of Fc-gamma-RIII expression by culturing purified trophoblasts on plastic with extracellular matrix proteins, 2) to describe several properties of the trophoblast Fc-gamma- RIII including the number and affinity of receptors for ligand by direct binding methods, 3) to determine how the trophoblast Fc-gamma-RIII transports IgG across the cultured trophoblast in Fc-gamma-RIII by culturing trophoblasts on microporous membrane filters, 4) to characterize the structure of the trophoblast Fc-gamma-RIII by both sequencing the cDNA and immunopurifying the receptor protein, and 5) to analyze the postulated role of the trophoblast Fc-gamma-RIII in transplacental HIV passage by studying antibody-mediated transport of cell-free HIV across trophoblast monolayers in vitro by fluorescence interactive laser cytometry and HIV p24 antigen capture assay.
| Leach, J L; Sedmak, D D; Osborne, J M et al. (1996) Isolation from human placenta of the IgG transporter, FcRn, and localization to the syncytiotrophoblast: implications for maternal-fetal antibody transport. J Immunol 157:3317-22 |
| Lairmore, M D; Cuthbert, P S; Utley, L L et al. (1993) Cellular localization of CD4 in the human placenta. Implications for maternal-to-fetal transmission of HIV. J Immunol 151:1673-81 |
