The complement system
The complement system (1) – (3) is one of the body’s cascade systems, and consists of several dozen proteins (Fig. 1). One part of the system consists of a series of plasma proteins, which are activated in a particular sequence and form activation products with various functions. The other part consists of membrane proteins, which function as receptors for the activation products. A large number of the proteins are regulatory proteins, which keep the system under control. Factor H (FH) is crucial here.
There arme three main activation pathways.
Classical activation. In this process, C1q binds antibodies or other molecules, for example C-reactive protein, that are bound to a surface. This causes activation of C1r and C1s, which in turn activate C4 and C2 with subsequent activation of C3, which then cleaves into C3a and C3b. C3a has both pro- and anti-inflammatory effects, while C3b functions as an important opsonin by binding covalently to a surface.
Lectin activation. This takes place when, for example, mannose-binding lectin (MBL) or ficolins react with microbes or damaged tissue, but also when naturally occurring IgM antibodies react with the body’s own structures. This activates mannose-associated serine proteases (MASP1 and MASP2), which are analogues of C1r and C1s in the classical pathway, and which in turn activate C4. The subsequent activation process is the same as in the classical pathway. C1 inhibitor (C1-INH) amd C4b-binding protein (C4BP) are important regulators of both classical and lectin activation.
Alternative activation. Under physiological conditions, this takes place through spontaneous hydrolysis of the C3 molecule, which, however, is kept under control by factor I (FI) and factor H (FH). Under non-physiological conditions, for example contact of blood with a foreign surface, this equilibrium is upset, and alternative pathway activation is reinforced by the action of factor B (FB), factor D (FD) and properdin (FP). C5 cleaves into C5a and C5b. C5a is a highly potent peptide with a number of effects in the inflammatory process. C5b reacts with C6, C7, C8 and C9 and forms the terminal C5b-9 complement complex (TCC), which occurs in a membrane-bound form that can cause lysis, particularly of Neisseria bacteria and red blood cells. In soluble form (sC5b-9) it can be measured in plasma and is a marker for complement activation. sC5b-9 binds the regulators vitronectin (VN) and clusterin (CL), causing the resulting complex to remain in liquid form.
There are a number of complement receptors on the surface of the body cells. They fall into three different categories. Some emit signals to the cells and thus activate them. For example, C5a receptors are stimulated to an inflammatory response by the biologically active C5a peptide. Others are fagocyte receptors (e.g. CR3, CD11b/CD18), while the third group has the important function of protecting cells against attacks from their own complement.
The overarching function of the complement system is precisely to trigger an inflammatory reaction as part of the battle against microbes (infection-induced inflammation) and as part of tissue regeneration after non-microbial damage (sterile inflammation). The activation is very strictly controlled by regulators in both the liquid phase and on the cell surface, to prevent the system being inappropriately activated and causing tissue damage and disease. The receptors CR1, MCP/CD46 and DAF/CD55 are important inhibitors at the C3 level, while CD59 inhibits incorporation of C5b-9 in the membrane. Patients with paroxysmal nocturnal haemoglobinuria (PNH) lack DAF and CD59 receptors on the cell surface, and the red blood cells are then lysed by complement (Fig. 2).