The Amplification Loop of the Complement Pathways

The C3 amplification loop lies at the core of all the complement pathways, rather than the alternative pathway alone. It is, in evolutionary terms, the oldest part of the complement system and its antecedents can be seen in insects and in echinoderms. The amplification loop is the balance between two competing cycles both acting on Ob: the C3 feedback cycle which enhances amplification and the C3 breakdown cycle which downregulates it. It is solely the balance between their rates of reaction on which amplification depends. The C3 breakdown cycle generates iC3b as its primary reaction product. iC3b, through its reaction with the leukocyte integrins (and complement receptors) CR3 (CD11b/CD18) and CR4 (CD11c/CD18), is the most important mechanism by which complement mediates inflammation. A variety of genetic polymorphisms in components of the amplification loop have been shown to predispose to two kidney diseases-dense deposit disease and atypical haemolytic uraemic syndrome-and to age-related macular degeneration. All predisposing alleles enhance amplification, whereas protective alleles downregulate amplification. This leads to the conclusion that there is a "hyperinflammatory complement phenotype" determined by these polymorphisms. This hyperinflammatory phenotype protects against bacterial infections in early life but in later life is associated with immunopathology. Besides the diseases already mentioned, there is evidence that this hyperinflammatory complement phenotype may predispose to accelerated atherosclerosis and also shows an association with Alzheimer's disease. Downregulation of the amplification loop therefore constitutes an important therapeutic target.