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. The hypothesis will be tested that the inhibitor is a fragment of a native serum (or plasma) protein that is generated as a consequence of complement activation (i.e., Bb fragment of factor B). Another objective of the proposed research is to determine 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 human C5a des Arg to exhibit chemotactic activity for human polymorphonuclear leukocytes (PMN). We have found that C5a des Arg plus its cochemotaxin probably accounts for most of the chemotactic activity that is generated in human serum after complement activation. We also have found that the cochemotaxin forms a physical complex with C5a des Arg, possibly by attaching to a sialic acid residue on the oligosaccharide portion of the molecule. Experiments will be performed to characterize the cochemotaxin and to examine further its interactions with C5a des Arg, desialated C5a des Arg, and deglycosylated C5a des Arg. Our final objective is to demonstrate physical interactions between the purified inhibitor and either the cochemotaxin or C5a des Arg. The hypothesis will be tested that the cochemotaxin (not C5a des Arg) is the target of the inhibitor. The studies outlined in this proposal should yield new information that may explain (in part) why patients with SLE have an increased susceptibility to severe bacterial infections. On a more basic level, these studies should provide information concerning structure-activity relationships and mechanisms involved in regulating the biologic activities of complement-derived peptides.
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