An astounding number of immune cells are routinely eliminated from the body's repertoire by apoptosis. The enormity of this burden is matched only by the critical need for the body to quickly and efficiently dispose of effete cells. Failure to do so results in the degeneration of vital processes that maintain membrane integrity as cells progress from apoptosis to necrosis. In normal individuals where cell disposal mechanisms are properly maintained, apoptotic cell clearance suppresses inflammation, preserves lymphocyte tolerance and prevents the development of autoimmunity. However, in certain predisposed individuals, the pathways governing the removal of apoptotic cells are either inherently defective or are compromised by disease processes. Under these circumstances, immune cells interface with modified nuclear antigens in the presence of inflammatory stimuli. These events culminate in inappropriate lymphocyte reactivity to intracellular antigens and the development of systemic autoimmunity.

Insight into the pathways modulating apoptotic cell engulfment is critical to understanding the etiology of autoimmune disease. This document is a record of three investigations, all focused on molecules that regulate corpse clearance. The first study demonstrates the tendency for macrophage phagocytic receptors to co-migrate and associate with a yet unidentified molecule during phagocytosis. This unknown molecule is recognized by the Ab 217 antibody and was originally reported to be the Phosphatidylserine Receptor. The data presented in the first report suggests that although the Ab 217 ligand is involved in corpse clearance, it is not the protein product of the psr gene as originally described. The second investigation examines the opposing roles played by Mer and the proteolytic cleavage product, sMer, in the physiologic regulation of apoptotic cell engulfment. The final study reveals a mechanism for the pathologic suppression of apoptotic cell clearance through the production of autoantibodies by lupus-prone mice that block complement-mediated phagocytosis. In total, this work reaffirms the central roles played by phosphatidylserine and the complement system to promote apoptotic cell engulfment and elucidates mechanisms for the physiological and pathological down-modulation of these processes.