Complement deficiency is associated with an increased prevalence of pyogenic infections and immune complex disease. The spectrum of disease in deficient individuals depends on the stage in the complement system at which the block in activation occurs. Here, Paul Morgan and Mark Walport review current knowledge of hereditary complement deficiencies in humans, emphasizing the importance of these'experiments of nature'in defining the roles of complement in vivo.

The study of inherited deficiencies of complement proteins in vivo offers insights into the physiological activities of the complement system that are not readily available from in vitro analysis. While the remarkable normal health of many individuals with complement deficiency testifies to the redundancy of host &fence mechanisms, the complement system is an important component of the innate immune system. Deficiency of complement function is associated with an increased tendency to pyogenic infection, which takes two forms. The first is an increase in infections by pyogenic organisms, such as Staphylococcus and Streptococcus, whose main route of destruction in the body appears to be phagocytosis followed by intracellular killing. There is increased susceptibility to these organisms if any link in the chain of events leading to intracellular killing is disrupted, that is antibody deficiency, complement deficiency or phagocyte dysfunction. The second association with pyogenic infection is with strikingly increased susceptibility to Neisseria infection. This association, probably the only clinically important consequence of inherited deficiency of proteins of the membrane attack complex (MAC), gives insight into the probable role of extracellular cytolysis by complement of Neisseria as a means of host defence.