Enzyme cascades are involved in many processes in the body and are seen in immune, inflammatory and vascular events. They share the common underlying mechanism of cascade action in which the product of one reaction catalyses the subsequent reaction. For example, the blood plasma contains the components of four interlinked cascade systems that are involved in clotting and inflammation (see Table 5). Plasmin, a product of the fibrinolytic cascade, degrades the product of the clotting cascade and activates complement. Hageman factor, or factor XII, is a clotting factor which activates the complement, kinase and fibrinolytic systems (Figure 11). The caspase cascade has already been mentioned in Chapter 4.

At each step of the cascade, an inactive precursor is activated. Thus, the biologically inert components of the cascade can be present in the body ready to be activated, in contrast with systems where the component molecules have to be synthesised by cells when they are required for action. Therefore, cascades allow a rapid response to a stimulus. Also, one activated enzyme can catalyse the activation of a large number of its substrate molecules, so amplification of the response occurs at each step. Furthermore, the activated components can have more than one action, allowing for a large number of possible final effects. In this way, a few molecules of an initiating substance can have huge consequences, as when activation of a small amount of caspase 8 by Fas ligand binding starts a series of reactions that kill the cell (see Ch. 4).

Another characteristic of cascades is that each step of the process can be promoted or inhibited by other factors, allowing for tight control of the cascade. Typically, the active constituents have a short half life and are rapidly broken down or inactivated, so the cascade can be rapidly ‘switched off’ if required.

In summary, the advantages of cascade systems are:

Complement is a system of soluble molecules that forms an important part of the body’s defence system against microbial infection. It is a cascade system and interacts with other components of the immune system (see Ch. 7).

Complement is activated via three pathways: the mannose-binding lectin (MBL, also known as mannan-binding lectin), classical and alternative pathways. The MBL and alternative pathways are triggered by microbial substances and do not require the participation of B cells or T cells. Therefore, these pathways represent part of innate immunity (see Ch. 7). The classical pathway is triggered by antigen–antibody binding. Figure 12 shows the main steps of the classical and alternative pathways leading to the formation of the membrane attack complex. The MBL pathway activates C4. Products of the fibrinolytic and kinin systems can also activate complement.

There are many functional consequences of complement activation (Box 4, Figure 12). Formation of the membrane attack complex is the final common pathway of the different limbs of the cascade; it makes a pore in the membrane of the target cell that leads to cell lysis. The anaphylatoxins are fragments of activated complement components that have cytokine-like effects, activating inflammatory cells and acting as chemoattractants for them. They can also degranulate mast cells. Fragments that remain attached to the target, such as C3b, promote phagocytosis, i.e. they are opsonins.

Complement activation can lead to extensive tissue damage and plays an important part in hypersensitivity reactions (see Ch. 8).