Acquisition of maternal antibodies is critical to the immunologic defense of the newborn. In suckling rats and mice, a receptor for the Fc region of immunoglobulin G (IgG) transports IgG from milk across the intestinal epithelium into the blood. This receptor, FcRn, for neonate, is similar in structure to class I major histocompatibility complex proteins. Late in gestation the same receptor appears to transport IgG across the fetal yolk sac in these species. Prenatal transport accounts for only a small fraction of the maternal IgG that rodents receive, but in humans IgG transport occurs mostly, and perhaps only, before birth. A homolog of FcRn is expressed in human placenta and is likely to mediate materno- fetal IgG transport. A major goal of this proposal is to determine whether human FcRn is indeed responsible for placental IgG transport.
Specific aims toward this goal include the localization of FcRn in human placenta by immunocytochemistry and in situ hybridization. The presence of the receptor in one or both of the cellular barriers between maternal and fetal blood, the syncytiotrophoblast and fetal vessel endothelia, would be consistent with a transport role. The specificity of human FcRn for different human IgG subclasses, measured by a competitive binding assay, will be compared with the relative efficiency of placental transport of these subclasses. A relatively low affinity for IgG2, which is transported poorly, would suggest that FcRn has a role in IgG transport from mother to fetus. The molecular mechanism of transcytosis of IgG by FcRn is not known. The second major goal of this proposal is to determine how this process occurs.
Specific aims related to this goal include the characterization of the trafficking of rat FcRn functionally expressed in the polarized Madin-Darby canine kidney cell line. Sorting signals in the cytoplasmic region of rat FcRn will be located by site-directed mutagenesis and expression of mutant receptors in MDCK cells. Proteins that interact with sorting signals will be sought using a yeast two-hybrid method. The clinical importance of maternal IgG for the immunologic defense of the neonate is well established. Because most IgG is transmitted to the fetus late in pregnancy, very premature infants have low serum IgG and are especially vulnerable to infection. Not all antibodies are beneficial, however: the health of the newborn may be compromised by the acquisition of anti-rhesus and anti-ABO antibodies. Transmission of autoantibodies in systemic lupus erythematosus, myasthenia gravis, and other autoimmune diseases of the mother may also be damaging to the fetus. This proposal aims to contribute to our understanding of the mechanism of antibody transport from mother to young, and thus to increase the basis for rational intervention in pregnancies complicated by potentially harmful maternal immune responses.
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