Studies of the biosynthesis and catabolism of various immunoglobulin (Ig) isotypes have revealed that in humans and some animal species, IgA is produced in quantities that exceed those of all other isotypes combined. The liver plays an essential role in the transport and catabolism of IgA. The fate of circulating IgA depends on its subclass and molecular form (polymeric-pIgA and monomeric-mIgA) because different receptors on diverse cell types, including hepatocytes, are involved in the binding, transcellular transport, and catabolism. At least 3 different receptors capable of binding IgA have been identified on surfaces of hepatocytes of human and animal origin: secretory component (SC), asialoglycoprotein receptor (ASGP-R), and the enzyme galactosyltransferase (GT). Studies proposed in this application will concentrate on molecular-cellular interactions of IgA with hepatocytes. Because human hepatocytes do not display SC and the primary molecular form in serum is mIgA which does not bind SC, we propose to focus our investigations on the role of """"""""non-SC"""""""" receptors that are involved in binding, internalization, catabolism and possible transport. To achieve this goal we propose to: 1) Identify and characterize receptors on mouse and human hepatocytes, and human epithelial and hepatoma cell lines that bind different molecular forms of human and mouse IgA. Solubilized membranes from surface-labeled cells will be incubated with IgA and other ligands and the properties of the receptor(s) will be determined by biochemical and immunochemical means; 2) Investigate the fate of bound ligands. We shall determine whether radiolabeled ligands remain associated with the cell membrane or are internalized, and whether an internalized ligand is catabolized, or transported and re-resecreted; 3) Study the regulation of the expression of IgA receptors on human and mouse cells by cytokines. Various cytokines will be examined to determine their role in the regulation of the expression of IgA receptors, and in subsequent processing of IgA and other ligands. Because of the large quantities of IgA produced in humans, identification and characterization of the receptors responsible for its binding and subsequent transport or catabolism, and the factors involved in their regulation, will be important in elucidating the processing and disposal of IgA in health and disease.
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