The overall goal of our research program is to understand some of the factors involved in the modulation of human immune responses so that desirable functions might be enhanced, to both prevent the development of a disease state (as in infection or cancer) and to enhance the body's ability to cope with challenges under conditions in which some part of the defense system is compromised, either by genetic deficiencies or immunosuppression. It has been demonstrated previously that interaction of the complement subcomponent C1q with specific cells of the immune system enhances the phagocytic and killing capacity of those cells. We have isolated candidate C1q receptor molecules by ligand affinity chromatography. This protein was used to produce monoclonal antibodies, two of which inhibit the C1q-mediated enhancement of phagocytosis in monocytes. Amino acid sequencing of the 126,000 Mr molecule recognized by the inhibitory antibodies has led to the isolation of a cDNA fragment encoding part of this molecule. We now intend to clone and sequence the full length cDNA coding for the 126,000 Mr component of the C1q receptor that mediates the enhancement of phagocytosis. Suitable expression systems for this C1qRp will subsequently be developed to further characterize the structure and function of this receptor using both molecular and biochemical approaches. The structural requirements and amino acid sequences of C1q involved in the molecular interaction with the phagocytosis-enhancing C1q Receptor will be delineated. This will facilitate the development of reagents that will enhance the human immune responses to prevent the development of disease or regulate detrimental responses. Finally, we will explore both the relationship of the C1q receptor system with other reported C1q-mediated functions and the possible coreceptor molecules involved in this innate immune response. Individuals genetically deficient in C1q are prone to bacterial infections and/or develop autoimmune disorders. In addition, antibodies to the collagen-like region (that contains the cell binding domain) of C1q are found in sera of patients with SLE, rheumatoid vasculitis and hypocomplementemic urticarial vasculitis syndrome. The research proposed here will provide necessary information for future development of therapeutic strategies for these conditions and other immunodeficient states.
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