The long-term aims of this project are to understand the molecular details of human leucocyte IgG Fc receptor (FcR)-mediated biological events, especially those which underlie FcR-mediated endocytosis by mononuclear phagocytic cells, but also other FcR- mediated events whose analysis would enhance the general knowledge of these receptor. The broad objectives, beyond the scope of this proposal, are analyses of the intermolecular interactions of the purified receptor (and associated membrane-associated molecules such as subunits and signal-modulating molecules) reconstituted in artificial lipid bilayers asking questions suggested by functional experiments performed on the intact cells. With cDNA probes, similar reconstitution experiments will eventually be possible using the transfection methods of molecular genetics. The immediate specific aims are (a) to evaluate whether the receptors recycle constitutively; (b) to determine whether all three FcR are capable of mediating phagocytosis; (c) to determine whether linking FcR into units of pairs signals a biological response; (d) to determine the nature and significance of the recently describe FcRII structural polymorphism; (e) to determine the structure of the B cell FcRII; (f) to determine whether the FcR are associated with other (subunit) molecules within the membrane; (g) and to evaluate the nature of a unique, recently described familial deficiency of functional FcRI. Anti-FcR monoclonal antibodies, receptor-specific ligands, cDNAs of FcR transcripts, human cell lines and purified leukocytes will be employed using the method of cell and molecular -biology and membrane biochemistry. These receptor constitute, along with complement proteins and receptors, the key molecules of a set of vital mechanisms by which the cell of the body react through antibody molecules to harmful antigens in both health and a wide spectrum of disease. These mechanisms include endocytosis of immune complexes; secretion of inflammatory molecules; killing of antibody-coated cells; aggregation and mediator release by platelets; and regulation of the immune response.
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