As a consequence of antigen-antibody reactions, important changes occur in the physical state of the antibodies. As antigen and antibody react and form aggregates, the antibody molecule undergoes conformational changes. These events are responsible for changes in the spatial orientation and exposure of biologically active domains or segments located on the Fc region of those antibodies. For example, the Fc region of antigen-bound molecules of IgM, IgG3, IgG1, and to a lesser degree IgG2 are able to bind and activate the first com-ponent of a series of rapidly acting plasma proteins, known as the complement system.
The complement system includes several components that exist in a nonactive state in the serum. When these complement components are converted to their active form, a sequen-tial, rapid, cascading sequence ensues.
Most of the complement glycoproteins are synthesized predominantly by the liver, but macrophages and many other cell types are also sources of various complement compo-nents, especially at sites of infection and/or inflammation. All normal individuals always have complement components in their blood. The synthetic rates for the various comple-ment glycoproteins increase when complement is activated and consumed during an infec-tion. The increased rates appear to be under several regulatory mechanisms, such as the presence of cytokines generated at the site of the infection and the increase of various com-plement fragments or subcomponents that are released due to complement activation.
In addition to antigen-antibody complexes, which play a critical role in the activation of the classical complement pathway , several other substances activate the comple-ment system, but to lesser degrees. Nonspecific direct activators include proteolytic en-zymes, released either from microbes or from host cells (e.g., neutrophils) at the sites of in-fection or dying cells at sites of tissue necrosis/damage. In addition, membranes and cell walls of microbial organisms are potential complement activators; they activate the com-plement system starting at the third complement component via the alternative pathway. A third, newly discovered mech-anism for activating complement is the lectin pathway, which utilizes mannan-binding lectin (MBL) present in human serum. Mannan is a capsular substance of pathogenic fungi (e.g.,Cryptococcus neoformans and Candida albicans) and is only one of several foreign polysaccharide substances to which human MBL binds via Ca2+ -dependant interactions.
At this point, the following important concepts should be stressed:
· Complement exists in a stable and nonactivated form, and the classical pathway is ac-tivated by antigen-antibody complexes.
· Complement is a biologically potent system. Once it is activated, it may promote lo-cal reactions characterized by edema and smooth muscle contraction.
· Complement is a fast-acting, cascading (amplifying) system, with most effects oc-curring within a few minutes.
· Each step in the complement sequence is tightly regulated and controlled to maxi-mize the damage to any foreign substance. Such controls (a) prevent unneces-sary consumption of complement components after sufficient complement has deposited on the antigens and (b) spare the nearby cells of the host from inad-vertent complement attack.
The primary function of the complement system is to bind and neutralize any foreign sub-stance that activates it and then to effectively cause those neutralized complement-coated substances to tightly adhere to phagocytes thereby enhancing phagocytosis. In this regard, the third complement component (C3) is a major factor due to its position in the classical, alternative, and lectin pathways and because of its relatively high concentration in serum.