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Chapter 186 : Genetically Determined Disorders of the Complement System

Authors: Kathleen E. Sullivan, Jerry A. Winkelstein

The complement system is composed of a series of plasma proteins and cellular receptors that, when functioning in an ordered and integrated fashion, serve as important mediators of host defense and inflammation. In order for the individual components of complement to subserve their biologic functions, however, they must first be activated. Activation of the complement system can occur via the classical pathway, the alternative pathway, or the lectin pathway. Once activated, individual components act as opsonins, possess chemotactic activity, are potent anaphylatoxins, and can assemble into the membrane attack complex and generate cytolytic activity. In addition, the complement system is important in the processing of immune complexes and the generation of a normal antibody response.

Some of the complement genes have been grouped into supergene families based on similarities in structure, function, and chromosomal location. For example, the genes encoding C2, factor B, and C4 constitute the class III genes of the major histocompatibility complex on chromosome 6; the products of these genes are constituents of the enzymes that activate C3 and C5. The genes for C4-binding protein, factor H, decay-accelerating factor, membrane cofactor protein, and two of the receptors for C3 cleavage products make up another family of complement genes located on the long arm of chromosome l; the products of these genes share their ability to interact with the activation products of C4 and C3. The synthesis of a number of components of complement is regulated by cytokines such as interleukin 1 (IL-1), tumor necrosis factor (TNF), IL-6, and γ-interferon and by endotoxic lipopolysaccharide.

Genetically determined deficiencies have been described for most of the individual components of complement. The usual mode of inheritance is autosomal recessive with only two exceptions; C1-inhibitor deficiency is inherited as an autosomal dominant disorder, and properdin deficiency is inherited as an X-linked recessive disorder. The clinical manifestations of individuals with complement deficiencies have varied. Most individuals have had either an increased susceptibility to infection, rheumatic disorders, or angioedema. Patients with a deficiency of C3 or with a deficiency of a component in the pathways necessary for the activation of C3 have an increased susceptibility to infection with encapsulated bacteria, for which C3b-dependent opsonization is an important host defense. Patients with deficiencies of terminal components, C5 through C9, are markedly susceptible to systemic neisserial infections because serum bactericidal activity is an important host defense against these organisms. The prevalence of rheumatic disorders, such as systemic lupus erythematosus, vasculitis, and membranoproliferative glomerulonephritis, is highest in patients who are deficient in components of the classical activating pathway (C1, C4, and C2) and C3. Finally, patients with C1-inhibitor deficiency present with angioedema.


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