A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo

The strongest susceptibility genes for the development of systemic lupus er ythematosus (SLE) in humans are null mutants of classical pathway complemen t proteins. There is a hierarchy of disease susceptibility and severity acc ording to the position of the missing protein in the activation pathway, wi th the severest disease associated with C1q deficiency. Here we demonstrate , using novel in vivo models of apoptotic cell clearance during sterile per itonitis, a similar hierarchical role for classical pathway complement prot eins in vivo in the clearance of apoptotic cells by macrophages. Our result s constitute the first demonstration of an impairment in the phagocytosis o f apoptotic cells by macrophages in vivo in a mammalian system. Apoptotic c ells are thought to be a major source of the autoantigens of SLE, and impai rment of their removal by complement may explain the link between hereditar y complement deficiency and the development of SLE.