The complement system is a major effector system of host defense against invading microorganisms; however, when excessively activated or misdirected, it can produce damage to host tissues. The latter has been demonstrated in animal models of autoimmune diseases such as collagen- induced arthritis and membranous nephropathy, as well as in non- immunologically mediated forms of primary tissue damage such as myocardial ischemia and thermal injury. While several advances have been made concerning the regulation of complement activity by cell-surface Components of host tissues, little is known about how extracellular components regulate complement-mediated inflammation. We recently demonstrated that decorin, a dermatan-sulfate proteoglycan widely distributed as a component of extracellular matrices, binds complement component C1q. Binding is mediated by the decorin core protein, and the interaction results in a concentration-dependent inhibition of the classical pathway of complement activation. In addition, preliminary data shows that decorin also inhibits C1q-mediated superoxide production by neutrophils. This proposal will test the hypothesis that decorin and possibly other structurally related proteoglycans bind C1q and regulate C1q-mediated reactions. Specifically, we will examine the mechanism by which decorin inhibits the activity of the classical complement pathway, map the C1q binding site on the decorin core protein by mutagenesis of the cDNA of human decorin, and determine the specificity and mechanism by which decorin inhibits C1q-mediated superoxide production in neutrophils. Lastly, we will examine whether two other structurally related proteoglycans, biglycan and lumican, also bind C1q and interfere with C1 activity.
