A central question in innate immunity is how do the various innate immune systems distinguish between potential targets and the host. The molecular mechanisms by which the molecules of these systems recognize and elicit responses (i.e., to potential pathogens) or prevent responses (i.e., to the host) has recently been recognized to be fundamental to understanding target selection by the adaptive immune systems of higher organisms. Complement is the major non-cellular system of innate immunity in humans. Complement has the ability to kill directly, to mark the target with ligands (C3b, iC3b, C3d) for receptors of the cellular innate immune system (CD35, CD21, CD11b, CD11c) and to stimulate numerous cellular and humoral responses from systems of acquired immunity. The alternative pathway of complement is the major innate defense system of complement in adults. It uses a complex set of control proteins to select its targets and to regulate amplification of bound C3 fragments. The cell-bound regulators (DAF, CR1, CD59, MCP) and humoral control factors (factors H and I) protect host cells from cytolysis by inadvertent or misdirected complement activation. Biological particles lacking these regulators may or may not be activators of the alternative pathway of complement. The six proteins of the human alternative pathway of complement are capable of discriminating between host and targets and initiating activation without the aid of immunoglobulins, lectins, receptors or other products of adaptive immunity. The mechanism of alternative pathway host/target discrimination has been the subject of intense study since the discovery in the 1970's of a complement activating pathway that did not rely on antibodies for target identification. It is now known that one of the six proteins, factor H, plays the major discriminatory role in this pathway. The goal of the proposed research is to understand the molecular mechanisms of the host and target discrimination by the alternative pathway of human complement, to understand the control mechanisms which limit or enhance activation and to describe the alternative pathway activation and control processes leading to C5 activation. The two major aims of this proposal are: l) to describe in molecular detail the functions of the recently discovered multiple sites on factor H and to understand how these sites interact with C3b and host and target markers to control activation of the alternative pathway, and 2) to study the structure and function of the alternative pathway C5 convertase enzymes including their formation, subunit structures, enzymatic properties and the normal processes that control convertase formation and inactivation.
Showing the most recent 10 out of 58 publications
