A Hierarchical Role for Classical Pathway Complement Proteins in the Clearance of Apoptotic Cells in Vivo

TLDR

The strongest susceptibility genes for systemic lupus erythematosus are null mutants of classical pathway complement proteins, with disease severity following a hierarchy that correlates with the position of the missing protein in the activation pathway, and apoptotic cells are a major source of autoantigens whose impaired removal by complement may explain the link between hereditary complement deficiency and SLE. We aim to demonstrate a hierarchical role for classical pathway complement proteins in macrophage‑mediated clearance of apoptotic cells during sterile peritonitis. We employ novel in vivo models of apoptotic cell clearance to assess this role. Our results provide the first demonstration of impaired phagocytosis of apoptotic cells by macrophages in vivo in a mammalian system.

Abstract

The strongest susceptibility genes for the development of systemic lupus erythematosus (SLE) in humans are null mutants of classical pathway complement proteins. There is a hierarchy of disease susceptibility and severity according to the position of the missing protein in the activation pathway, with the severest disease associated with C1q deficiency. Here we demonstrate, using novel in vivo models of apoptotic cell clearance during sterile peritonitis, a similar hierarchical role for classical pathway complement proteins in vivo in the clearance of apoptotic cells by macrophages. Our results constitute the first demonstration of an impairment in the phagocytosis of apoptotic cells by macrophages in vivo in a mammalian system. Apoptotic cells are thought to be a major source of the autoantigens of SLE, and impairment of their removal by complement may explain the link between hereditary complement deficiency and the development of SLE.