All three pathways of complement activation lead to the formation of an enzyme called the C3 convertase, which splits C3 into two functionally distinct fragments, C3a and C3b. C3a is released, and C3b becomes covalently attached to the cell or molecule where the complement is being activated. More C3b then binds to the previously generated fragments to form C5 convertase, which cleaves C5 to release C5a and leave C5b attached to the cell surface. C5b binds the late components (C6–C9), culminating in the formation of the membrane attack complex (MAC, composed of multiple C9 molecules). The enzymatic activity of complement proteins provides such tremendous amplification that millions of molecules of C3b can deposit on the surface of a microbe within 2 or 3 minutes!
The complement system has three main functions  (
Fig. 3.11 • Inflammation.C5a, and, to a lesser extent, C4a and C3a, are cleavage products of the corresponding complement components that stimulate histamine release from mast cells and thereby increase vascular permeability and cause vasodilation. They are called anaphylatoxins because they have effects similar to those of mast cell mediators that are involved in the reaction called anaphylaxis (Chapter 5). C5a also is a chemotactic agent for neutrophils, monocytes, eosinophils, and basophils. In addition, C5a activates the lipoxygenase pathway of arachidonic acid metabolism in neutrophils and monocytes, causing release of more inflammatory mediators.
Opsonization and phagocytosis. C3b and its cleavage product iC3b (inactive C3b), when fixed to a microbial cell wall, act as opsonins and promote phagocytosis by neutrophils and macrophages, which bear cell surface receptors for these complement fragments.
Cell lysis. The deposition of the MAC on cells drills holes in the cell membrane, making the cells permeable to water and ions and resulting in their osmotic death (lysis). This function of complement is important mainly for the killing of microbes with thin cell walls, such as Neisseria bacteria. Hence, deficiency of the terminal components of complement predisposes to infections by the Neisseria species meningococci and gonococci. In patients with complement deficiencies, these microbes can cause serious disseminated infections.
The activation of complement is tightly controlled by cell-associated and circulating regulatory proteins. Different regulatory proteins inhibit the production of active complement fragments or remove fragments that deposit on cells. These regulators are expressed on normal host cells and thus prevent healthy tissues from being injured at sites of complement activation. Regulatory proteins can be overwhelmed when large amounts of complement are deposited on host cells and in tissues, as happens in autoimmune diseases, in which individuals produce complement-fixing antibodies against their own cell and tissue antigens (Chapter 5). The most important of these regulatory proteins are the following:
C1 inhibitor blocks the activation of C1, the first protein of the classical complement pathway. Inherited deficiency of this inhibitor is the cause of hereditary angioedema.
Decay accelerating factor (DAF) and CD59 are two proteins that are linked to plasma membranes by a glycophosphatidyl (GPI) anchor. DAF prevents formation of C3 convertases and CD59 inhibits formation of the MAC. An acquired deficiency of the enzyme that creates GPI anchors leads to deficiency of these regulators and excessive complement activation and lysis of red cells (which are sensitive to complement-mediated cell lysis). This gives rise to a disease called paroxysmal nocturnal hemoglobinuria (PNH) (Chapter 12).