The neonatal Fc receptor, FcRn, transports IgG antibodies from mother to offspring. The acquisition of maternal antibodies is essential for immunologic defense, although autoantibodies and immune complexes of live pathogens are potentially harmful to the neonate. FcRn also protects circulating IgG from catabolism, controlling the level of serum IgG, and prolonging the time for which antibodies of a particular specificity are present at useful concentrations. FcRn serves both of these functions by transporting IgG across cells by a pathway that avoids lysosomal degradation. The long-term objective of this proposal is to describe in molecular terms how FcRn transports IgG across cells. The immediate goal is to identify and characterize amino acid sequences in the cytoplasmic domain of FcRn that direct uptake and targeting of the receptor. This will be done by making specific alterations in the receptor by site-directed mutagenesis, and analyzing the effects of the mutations in a cell culture model of IgG transport. The subcellular route of transport by FcRn will be determined by confocal and immunoelectron microscopy, and mutations that divert FcRn from this pathway will be identified. An FcRn-binding peptide will be used to study the effect of IgG on FcRn transport. Such a peptide will also be used to explore the possibility of blocking the interaction of IgG and FcRn. Related aims are to investigate the regulation of transcription of FcRn, and to determine whether decreased transcription causes the elevated IgG catabolism detected in some myotonic dystrophy patients. The clinical importance of maternal IgG for the defense of the neonate is well established. Another clinical area to which FcRn is relevant is that of monoclonal antibody therapeutics, where slow catabolism of IgG is generally desirable. Knowledge of the mechanism of FcRn function will contribute to a rational basis for clinical intervention in complications of maternofetal antibody transmission, and for manipulation of the half-lives of therapeutic antibodies.