Deficiencies of the Complement System

Three biochemical pathways of complement activation are known. The first pathway, defined a century ago, is termed the classical pathway. This pathway is usually activated by antibody, and was identified because of its ability to kill antibody sensitized bacteria. A second pathway, now termed the alternative pathway, was first observed in the 1950s and was studied in detail in the 1970s and 1980s. A third pathway, the lectin pathway, described in the past two decades, is still being defined in detail. The latter two pathways are phylogenetically older than the classical pathway, and do not require antibody to function. They are found in organisms as primitive as sea squirts. All three pathways proceed through a series of protein interactions, discussed in this chapter, to the activation and binding of a plasma protein C3, which is central to all three pathways. The pathways then proceed together through the binding of an additional series of proteins to the lytic and inflammation promoting steps in complement action. Deficiencies of nearly every component have been described. The clinical features are diverse, but cluster into features that align with the known functions of complement: prevention of infection, disposal of apoptotic cells and immune complexes, and protection of endothelial surfaces.