Activation of complement in relation to disease.

Abstract

Activation of the complement system results in the sequential interaction of its protein constituents, producing a series of enzymes from their precursors, each of which acts on the next protein in the chain, forming interprotein complexes of two or more of the cleavage products. The consequences of such activation include increased vascular permeability, attraction of polymorphonuclear leucocytes, the enhancement of phagocytosis, and alterations in cell membranes resulting in lysis and death. The classical complement system involves nine components labelled Cl to C9 which react together in a manner described as a cascade (Macfarlane, 1964). Activation of the system is usually brought about by the combination of an antibody with an antigen, which activates the complement-binding site of the antibody molecule, thought to be situated on the CH2 domain. The antigen may be in solution or on a cell surface. The Cl molecule becomes attached first to the antibody through a specific component Clq (Muller-Eberhard, 1968), fixation of which allows alterations to occur in the rest of the Cl molecule, with the formation of an esterase CIS which is capable of activating later components. The full classical sequence in relation to haemolysis is shown in figure 1. Once activated, each component must become bound to its specific receptor, which may be either the previous component in the sequence or a nearby site on the red cell surface. The half-lives of these activated components can be very short indeed, of the order of milliseconds (Lachmann and Thompson, 1970). If the activated components fail to become bound they lose their binding sites and the capacity to activate later components in the sequence; they circulate in the plasma in their inactivated forms, which are of smaller molecular weight than their parent molecules, and are cleared from the circulation at varying rates. At many of the steps within the complement sequence small molecular weight products are formed with specific physiological functions. Activation of C3 is by far the most important. Increased vascular permeability is caused by the formation of a low molecular weight peptide C3a (Ward, 1969), together with the generation of a chemotactic agent 38 EA