The goal of this study is to evaluate the contribution of the epithelial cell to the formation of secretory immunoglobulins (Ig's), which protect the mucosal surfaces of the body. Our work is focused on the human polymeric Ig receptor (PIgR) pathway, which transports polymeric Ig's across epithelial cells and enchances their secretory function. Recent studies have defined the protein sequence and Ig-like domain structure of PIgR and its cleavage product, secretory component (SC), the primary molecules which mediate the conversion of polymeric Ig into secretory Ig. Using a unique panel of monoclonal antibodies which bind to human SC, secretory IgA and tryptic fragments of these molecules, we have developed a hypothetical model for the three dimensional structure of PIgR/SC and its molecular interactions with the polymeric Ig's. The model provides a useful conceptual structure for designing experiments with these antibodies and PIgR cDNA probes to examine the relationship between the structure and function of the various molecular forms of PIgR/SC. We will test the following research hypotheses: 1) The multiple functions of human PIgR and SC are mediated by the structure of specific Ig-like domains of these glycoproteins; and 2) Modulation occurs at several sites in the human PIg/SC pathway. We will biochemically characterize the structures of human PIgR and SC that are responsible for Ig binding, transcrytosis, and proteolytic protection. Our second hypothesis will explore potential sites for regulation or modulation of secretory immunoglobulin production in epithelial cells. The physiological significance in humans of these mechanisms will be explored. Human biological fluids, tissue extracts and thin sections, cultured cells and products of cloned DNA will provide complementatry model systems for examination of the human PIgR/SC pathway from several perspectives. By characterizing the structural and physiological requirements for SIg formation in humans, and identifying mechanisms which may modulate this system, these studies should help to elucidate the molecular and cellular basis for epithelial cell contributions to mucosal immunity. This information may be useful in identifying pathologic abnormalities in the system and designing therapeutic interventions for mucosal infections and/or diagnostic methods for early epithelial malignancies.
