The Complement System

The combination of antibodies with antigens does not itself cause destruction of the antigens or the pathogenic organisms that contain these antigens. Antibodies, rather, serve to identify the targets for immunological attack and to activate nonspecific immune processes that destroy the invader. Bacteria that are "buttered" with antibodies, for example, are better targets for phagocytosis by neutrophils and macrophages. The ability of antibodies to stimulate phagocytosis is termed opsonization. Immune destruction of bacteria is also promoted by antibody-induced activation of a system of serum proteins known as complement.

In the early part of the twentieth century, it was learned that rabbit antibodies that bind to the red blood cell antigens of sheep could not lyse (destroy) these cells unless certain protein components of serum were present. These proteins, called complement, constitute a nonspecific defense system that is activated by the bonding of antibodies to antigens, and by this means is directed against specific invaders that have been identified by antibodies.

The complement proteins are designated C1 through C9. These proteins are present in an inactive state within plasma and other body fluids and become activated by the attachment of antibodies to antigens. In terms of their functions, the complement proteins can be subdivided into three components: (1) recognition (C1); (2) activation (C4, C2, and C3, in that order); and (3) attack (C5 through C9). The attack phase consists of complement fixation, in which complement proteins attach to the cell membrane and destroy the victim cell.

There are two pathways of complement activation. The classic pathway is initiated by the binding of antibodies of the IgG and IgM subclasses to antigens on the invading cell's membrane. This is more rapid and efficient than the alternative pathway, which is initiated by the unique polysaccharides that coat bacterial cells.

In the classic pathway, IgG and IgM antibodies activate C1, which catalyzes the hydrolysis of C4 into two fragments, C4a and C4b (fig. 15.12). The C4b fragment binds to the cell membrane (is "fixed") and becomes an active enzyme. Then, through an intermediate step involving the splitting of C2, C3 is cleaved into C3a and C3b. Acting through a different sequence of events, the alternative pathway of complement activation also results in the conversion of C3 into C3a and C3b, so that the two pathways converge at this point.

The C3b converts C5 into C5a and C5b. The C3a and C5a stimulate mast cells to release histamine; C5a additionally serves as a chemokine to attract neutrophils and monocytes to the site

The Immune System

Antibody

Antibody

Bacterium

Complement protein C4

Soluble complement C4a (involved in chemotaxis)

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Soluble complement C4a (involved in chemotaxis)

Bacterium

Figure 15.12 The fixation of complement proteins. The formation of an antibody-antigen complex causes complement protein C4 to be split into two subunits—C4a and C4b. The C4b subunit attaches (is fixed) to the membrane of the cell to be destroyed (such as a bacterium). This event triggers the activation of other complement proteins, some of which attach to the C4b on the membrane surface.

of infection. Meanwhile, C5 through C9 are inserted into the bacterial cell membrane to form a membrane attack complex (fig. 15.13). The attack complex is a large pore that can kill the bacterial cell through the osmotic influx of water. Note that the complement proteins, not the antibodies directly, kill the cell; antibodies serve only as activators of this process in the classic pathway.

Complement fragments that are liberated into the surrounding fluid rather than becoming fixed have a number of effects. These effects include (1) chemotaxis—the liberated complement fragments attract phagocytic cells to the site of complement activation; (2) opsonization—phagocytic cells have receptors for C3b, so that this fragment may form bridges between the phagocyte and the victim cell, thus facilitating phagocytosis; and (3) stimulation of the release of histamine from mast cells and basophils by fragments C3a and C5a. As a result of histamine release, blood flow to the infected area is increased because of vasodilation and increased capillary permeability. This helps to bring in more phagocytic cells to combat the infection, but the increased capillary permeability can also result in edema through leakage of plasma proteins into the surrounding tissue fluid.

Test Yourself Before You Continue

1. Illustrate the structure of an antibody molecule. Label the constant and variable regions, the Fc and Fab parts, and the heavy and light chains.

2. Define opsonization and identify two types of molecules that promote this process.

3. Describe complement fixation and explain the roles of complement fragments that do not become fixed.

■ Figure 15.13 The membrane attack complex. Fixed complement proteins C5 through C9 assemble in the plasma membrane of the victim cell as a membrane attack complex. This complex forms a large pore that punctures the membrane and thereby promotes the destruction of the cell.

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