The liver is involved in the regulation of serum levels of IgA through the selective transport and catabolism of circulating IgA, and in the removal of IgA-containing immune complexes. At least two types of receptors on hepatocytes are involved in these processes: secretory component (SC) which binds polymeric IgA and mediates its selective transport into the bile by a nondegradative pathway, and asialoglycoprotein receptor (ASGR) which directs bound ligands into the degradative pathway. The objective of this proposal is to investigate the role of the liver in IgA- and asialoglycoprotein-directed selective delivery and elimination of biologically active substances, and in the generation of immune responses at mucosal surfaces. The degradation and elimination of model toxins of plant and bacterial origins coupled with monoclonal antibodies of IgA or IgG isotypes, or with asialoglycoprotein, will be studied in both in vitro and in vivo systems. The biological consequences of the administration of free versus IgA antibody-, or asialoglycoprotein- complexed toxins will be compared. Furthermore, free and IgA- or asialoglycoprotein-linked interferon inducers will be evaluated with respect to their ability to induce interferon production in vitro and in vivo. Finally, the role of the liver in the induction of immune responses in external secretions will be investigated. Because of its central position, as the liver is most likely to be stimulated by antigens absorbed from the large surface area of the gut, and specific antibody-producing cells have been detected first in this organ. We will investigate whether the liver is an integral part of the common mucosal immune system, or whether it is an enriched reservoir of specific IgA antibody-forming cells ultimately destined for homing to other mucosal tissues. Furthermore, the origin of specific IgA antibodies in human hepatic bile will be determine by comparative studies of molecular properties and antigen specificities of IgA antibodies in human bile, serum, and saliva. The versatility of the liver in disposing of environmental substances is manifested by its apparent ability to focus cells that produce antibodies to antigens encountered at the large gastrointestinal surface, at the site where their effectiveness may be maximally utilized.
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