Genetic susceptibility and class III complement genes

The great interest in this genetic region of chromosome 6 in humans relates to the now several decades old observation that individuals with complete deficiency of C4 or C2 come to medical attention with the clinical syndrome of systemic lupus erythematosus (SLE).Thus, these two proteins along with their friends in the early part of the classical pathway are the only known single protein deficiency states that commonly develop SLE. The problem that has been so elusive to solve is how these deficiency states in turn lead to SLE. The focus of this chapter is on this question. After providing background data on the structure and function of the class III genes and their protein products, this discussion first reviews the older data relative to the long appreciated role of the complement system in immune complex (IC) handling and then move into the more recent results on the role of the complement system in the immune response and in the processing of cellular debris. The new tools of this field—knockout mice—have been particularly helpful in more elegantly and firmly establishing an important role for the complement system in innate and adaptive immunity as well as in preventing autoimmunity.