The complement system is a major biological effector of host defense mechanisms and the process of inflammation underlying diverse immunological diseases. This program of closely interrelated yet distinct projects recognizes the importance of cell surface receptors in the interplay between molecular mediators and cellular responses.
It aims at the complete structural elucidation of the receptors of the inflammatory mediators C3a, C5a, formyl peptides and LTB4. It also endeavors to solve the primary structure of the receptors for C3b (CR1) and C3dg (CR2), the former being genetically linked to Factor H and C4bp and the latter being the receptor for Epstein Barr virus and of considerable potential importance in the T lymphocyte dependent activation of B lymphocytes. The strategies to be employed are different for each receptor, but all rely on cDNA cloning and sequencing technology. Considerable effort will be expanded on the analysis of transduction and regulation of receptor-initiated signals and the involvement of the external membrane associated electron transport system in the aggregative functions of neutrophils. The structure-function relationship of the chemotactic peptide C5a, to be produced in E. coli, will be explored by creating mutant peptides through oligonucleotide directed mutagenesis. The cell killing process by the membrane attack complex of complement will be compared with that employed by human cytolytic lymphocytes. Structural homology between C9 and the lymphocyte analog will be sought using cDNA technology. The joint recognition function of Factor H and of C3b in the alternative pathway will be addressed and related to a qualitatively similar function of human monocytes inducible by a cytokine of unknown nature. The complete cDNA coding sequence for Factor H will be obtained and the chromosomal locus for the Factor H gene will be determined. The regulatory membrane protein decay accelerating factor, which is functionally closely related to Factor H and C4bp, will be isolated for structural studies from a human cell line. Another membrane protein with host protective function, homologous restriction factor, will also be isolated and studied.
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