Infection is a major cause of morbidity and mortality among patients with systemic lupus erythematosus (SLE). One objective of the proposed research is to examine in detail the nature, source and mechanism of action of a cationic protein that we have found in serum from some patients with SLE and that inhibits (in a uniquely specific and reversible fashion) the chemotactic activity of complement (C5)-derived peptides. Studies of patients with SLE have yielded evidence that this inhibitor may contribute (in part) to an increased susceptibility to severe bacterial infections. The other objective is to elucidate the mechanism of action of an anionic polypeptide (""""""""cochemotaxin"""""""") that we have found in normal human serum (and plasma) and that permits low concentrations of C5a des Arg to exhibit chemotactic activity for polymorphonuclear leukocytes. We have found that the """"""""complex"""""""" of C5a des Arg and its """"""""cochemotaxin"""""""" probably accounts for most of the chemotactic activity that is generated in human serum after complement activation. Experiments will be performed to test the hypotheses that the """"""""cochemotaxin"""""""" binds to the oligosaccharide portion of C5a des Arg and that the """"""""cochemotaxin"""""""" (not C5a des Arg) is the """"""""target"""""""" of the inhibitor in SLE serum. The studies outlined in this proposal should provide important new information that is relevant to host defense mechanisms in patients with SLE. It may be possible to explain (in part) why patients with SLE have an increased susceptibility to infections caused by pyogenic microorganisms. It also may be possible to identify patients with SLE who are at risk of developing life-threatening infections. On a more basic level, these studies should provide new information concerning structure-activity relationships of various biologically-active, complement-derived peptides. These studies also should yield new information that is fundamental to our understanding of mechanisms involved in regulating the biologic activities of complement-derived peptides.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases (NIADDK)
Type
Research Project (R01)
Project #
5R01AM028566-06
Application #
3151926
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1980-09-01
Project End
1986-03-31
Budget Start
1985-04-01
Budget End
1986-03-31
Support Year
6
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Perez, H D; Holmes, R; Vilander, L R et al. (1993) Formyl peptide receptor chimeras define domains involved in ligand binding. J Biol Chem 268:2292-5
Roll, F J; Perez, H D; Serhan, C N (1992) Characterization of a novel arachidonic acid-derived neutrophil chemoattractant. Biochem Biophys Res Commun 186:269-76
Perez, H D; Kelly, E; Holmes, R (1992) Regulation of formyl peptide receptor expression and its mRNA levels during differentiation of HL-60 cells. J Biol Chem 267:358-63
Perez, H D; Kelly, E; Elfman, F et al. (1991) Defective polymorphonuclear leukocyte formyl peptide receptor(s) in juvenile periodontitis. J Clin Invest 87:971-6
Lobo, E; Elfman, F; Kelly, E et al. (1990) Effect of phorbol myristate acetate on processing of formyl peptide receptors by human neutrophils. Biochim Biophys Acta 1055:193-6
Kurrasch, R; Elfman, F; Perez, H D (1989) Polymorphonuclear leukocytes cap a derivative of wheat germ agglutinin upon stimulation with formyl peptide and C5a but not leukotriene B4. J Immunol 143:1969-73
Perez, H D; Elfman, F; Marder, S et al. (1989) Formyl peptide-induced chemotaxis of human polymorphonuclear leukocytes does not require either marked changes in cytosolic calcium or specific granule discharge. Role of formyl peptide receptor reexpression (or recycling). J Clin Invest 83:1963-70
Senior, R M; Griffin, G L; Perez, H D et al. (1988) Human C5a and C5a des Arg exhibit chemotactic activity for fibroblasts. J Immunol 141:3570-4
Perez, H D; Kelly, E; Chenoweth, D et al. (1988) Identification of the C5a des Arg cochemotaxin. Homology with vitamin D-binding protein (group-specific component globulin). J Clin Invest 82:360-3
Perez, H D; Kelly, E; Chenoweth, D et al. (1988) Identification of the C5a des Arg cochemotaxin. Trans Assoc Am Physicians 101:242-9

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