ACTIVATION OF THE COMPLEMENT SYSTEM

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Activation of the complement system results in a selective and control fragmentation of the C4 and C3 molecules via the classical, or the classical and alternative pathways respectively. Interaction of fragments of these two molecules with antigen-antibody complexes and with surface receptors on different cell types serve to modulate complement-dependent functions. Although a great deal of knowledge has been accumulated on the alternative pathway, the same information relating to the classical pathway is less complete. This application proposes studies aimed primarily at delineating some structural and functional aspects of the proteins involved in the formation and some structural and functional aspects of the proteins involved in the formation and function of the classical pathway C3 convertase. Specifically, we plan to 1) Further characterize the major cleavage fragments of C4 produced during activation and inactivation of the molecule. The fragments will be isolated to homogeneity and subjected to chemical analysis. 2) Analysis of the conformational changes accompanying the enzymatic conversion and degradative inactivation of C4 by various methods. These studies will use differential surface labeling which will allow the identification of distinct regions of the molecule involved in these functional changes. 3) Investigation of the structural requirements for the interaction of the control proteins, C4-bp and I, with fluid phase and surface bound C4b. 4) The observation of an abnormal protein seen in humans serum under pathological conditions, C4 nephritic factor, has prompted studies to identify a protein in normal serum capable of stabilizing the C4b2a enzyme. The identification of this protein would complete the analogies to the formation, function and regulation of the classical and alternative C3 convertases. A second part of the application to which the above studies are of interest involves the activation of the complement system by IgA and IgM containing immune complexes. In addition, the mechanisms of complement activation by a non-immunologic mechanism using phototoxic chemicals will be investigated.