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Another major soluble element of the innate immune system is the complement system. Complement will be discussed in detail in Chapter 4. Briefly, it is made up of approximately 25 proteins, most of which are produced in the liver. They work together to assist or “complement” the action of antibodies in destroying bacteria. Complement also helps to rid the host of antibody‐coated antigens (so‐called opsonized antigens). Certain complement proteins that cause blood vessels to become dilated and then leaky contribute to the redness, warmth, swelling, pain, and loss of function that characterize inflammatory responses.

Complement proteins circulate in the blood in an inactive form. Each component takes its turn in a precise chain of steps known as the complement cascade (Figure 3.7). The end‐products are molecular cylinders called the membrane attack complex (MAC), which are inserted into the cell walls that surround the invading bacteria. This results in the development of puncture holes causing fluids to flow in and out of the bacteria. Consequently, the bacterial cell walls swell and burst (lysis), and the bacteria are killed.

Figure 3.7. The three complement activation pathways: classical, alternative, and lectin.

There are three complement activation pathways, as discussed in detail in Chapter 4. When the first protein in the complement series (C1q) is activated by an antibody that has been made in response to a microbe (e.g., bacteria), this initiates the chain of events resulting in the generation of MAC that causes lysis of the microbe. This is known as the classic activation pathway and is part of complement’s participation in the adaptive immune response. However, the alternative activation pathway involves direct binding of certain complement components, such as C3, to the surfaces of pathogens without the participation of antibody. This binding triggers a conformational change in the protein that initiates the downstream cascade leading to the generation of MAC followed by lysis of the microbe. Finally, the lectin activation pathway involves other complement components such as C2 and C4, which are lectins that also bind directly, in this case to mannan moieties expressed on pathogens. As with the other two pathways, this results in activation of other complement components leading to MAC production and lysis of the pathogen.

By directly binding to bacteria, other components of the complement system make bacteria more susceptible to phagocytosis by innate immune cells. Phagocytic cells express complement receptors, and when they encounter complement‐coated bacteria (opsonized bacteria), this greatly facilitates their binding to and phagocytosis of the bacteria. Complement components generated during the complement cascade can attract other immune cells (phagocytes and other leukocytes) to the area where invading bacteria are present. Thus, complement plays a role in locally mobilizing host defense mechanisms. Finally, like all biologically complex systems involving activation of proteins with the ability to promote potentially harmful consequences to the host (e.g., inflammation), the complement system is endowed with regulatory proteins that help to terminate the process.

TABLE 3.1. Proteins Involved in the Complement Cascade

Binding to Ag:Ab complexes	C1q
Activating enzymes	C1r, C1s, C2b, Bd, D, MASP1,2
Membrane‐binding opsonins	C4b, C3b, MBP
Mediators of inflammation	C5a, C3a, C4a
Membrane attack	C5b, C6, C7, C8, C9
Complement receptors	CR1, CR2, CR3, CR4, C1qR
Complement‐regulatory proteins	C1INH, C4bp, CR1, MCP, DAE,H, I, P, CD59

Table 3.1 summarizes the functional properties of the proteins involved in the complement cascade. These will be discussed further in Chapter 4.