MECHANISMS OF COMPLEMENT ATTACK ON NUCLEATED CELLS

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Studies with erythrocytes and artificial lipid bilayers in many laboratories have yielded the fundamental features of membrane attack mechanisms by complement (C). Consequently, our research during the last few years has been devoted to understanding the mechanism(s) of C-mediated cell death in metabolically active nucleated cells (NC). We have found that cytolysis of NC requires multiple C5b-9 channels, due to the defense mechanism of the cell to survive limited C attack by eliminating the potentially lytic C channels. In addition, the channels, when present in sublytic numbers, cause a transient increase in cellular Ca2+ and exert a variety of biological effects such as activation of phospholipases, lipid methyltransferases, and neutral proteases in the cell. Our program is aimed at studying the mechanisms by which C5b-9 mediates cell death, stimulates the cell to repair limited injury, and modulates cellular functions that are relevant to the pathophysiology of the target cells in inflammation and immunity. Specifically, we want to determine the C-induced biochemical signals that stimulate the repair process. We will also investigate whether cell death elicited by the remaining channels is entirely dependent on colloid-osmotic deregulation, and if applicable which metabolic pathways are involved in the process of cell death. In addition, we will examine whether metabolic stimulation of repair processes similar to those produced by C5b-9 also occur in targets following limited attack by channel-forming proteins derived from CTL or NK-cells. We will continue to study the structure and functional aspects of C8-binding protein, and its role in nucleated cell killing and stimulation by homologous C5b- 9. These studies, collectively, will significantly increase our knowledge on the biological activities of complement channels and other channel forming immune effectors on NC targets.