The long term objective of this research program is to define the mechanisms by which the interaction between humoral and cellular elements of the human immune system result in complementary and synergistic responses to invading pathogens. We have chosen to investigate the interaction of C1q, a protein found in blood and additionally secreted by inflammatory cells, with the phagocytic cells of the immune system. These cells ingest and subsequently destroy infectious agents and additionally clear immune complexes and other deleterious substances from the circulation and from tissues. C1q is the recognition subunit of the classical complement pathway and as such interacts with antibody-antigen complexes and various other structures such as bacterial and viruses in the absence of antibody. Thus it has an uncommon potential for participating in a cellular-humoral immune network. The recent demonstration that C1q enhances Fc-mediated and C3b- mediated phagocytosis provides supportive evidence for our current postulate that C1q is an activation ligand for phagocytosis. Furthermore, C1q enhances the generation of toxic oxygen radicals critical in the destruction of invading microorganisms. This proposal specifically outlines the biochemical and immunological characterization of the C1q receptor on human phagocytic cells. The C1q receptor will be isolated, and monoclonal antibodies to the receptor will be generated and used to definitively establish he relationship between the isolated C1q receptor and the C1q-mediated enhancement of phagocytic cell function. Amino acid sequence determination of C1qR will be used to direct synthesis of specific peptides to use as antigens to unique domains of the receptor molecule, as probes of the structure and function of this receptor and as the basis for the synthesis of oligonucleotide probes for use in cloning the receptor gene. These studies will provide the basis for determining the molecular events involved in the C1q enhancement of phagocytic cell function, which compared with that of other ligand-induced effects, should further the general understanding of this critical element in host defense. Ultimately, this research should aid in the development of beneficial therapeutic or prophylactic procedures to augment appropriate protective responses.
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