Human Physiology, 14th edition (2016)

506 Chapter 15

the complement proteins can be subdivided into three com-

ponents: (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 comple-

ment 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.

The classic pathway of complement-dependent cytotoxicity

(destruction of cells by complement) is initiated by the binding

of IgG antibodies to their cell surface receptors. In this process,

complement protein C1 is activated, which catalyzes the hydro-

lysis of C4 into two fragments, C4 a and C4 b ( fig. 15.10 ). The C4 b

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 C3 a and C3 b. Acting through a

different sequence of events, the alternative pathway of comple-

ment activation also results in the conversion of C3 into C3 a and

C3 b , so that the two pathways converge at this point.

The C3 b converts C5 into C5 a and C5 b. The C3 a and C5 a

stimulate mast cells to release histamine. C3 a and C5 a addi-

tionally serve as powerful chemokines to attract macrophages,

neutrophils, monocytes, and eosinophils to the site of the

infection. Meanwhile, C5 through C9 are inserted into the bac-

terial cell membrane to form a membrane attack complex

( fig. 15.11 ). The attack complex is a large pore that can kill the

bacterial cell through the osmotic influx of water. Note that the

Between the processes that occur during antigen-independent
diversification in the bone marrow and the antigen-dependent
diversification in the secondary lymphoid organs, the body can
produce hundreds of billions of different antibodies to combat dif-
ferent pathogens.

The Complement System

The combination of antibodies with antigens does not itself
cause destruction of the antigens or the pathogenic organ-
isms that contain these antigens. Antibodies, rather, serve to
identify the targets for immunological attack and to activate
nonspecific immune processes that destroy the invader. Bac-
teria that are “buttered” with antibodies, for example, are bet-
ter targets for phagocytosis by neutrophils and macrophages.
The ability of antibodies to stimulate phagocytosis is termed
opsonization. Immune destruction of bacteria is also pro-
moted by antibody-induced activation of a system of serum
proteins known as complement.
In the early twentieth century, scientists learned that
rabbit antibodies that bind to the red blood cell antigens of
sheep could not lyse (destroy) these cells unless they added
certain protein components of serum. 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 attach-
ment of antibodies to antigens. In terms of their functions,

Figure 15.10 The fixation of complement proteins. (1) The formation of an antibody-antigen complex causes
(2) complement protein C4 to be split (3) into two subunits—C4 a and C4 b. The C4 b 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
C4 b on the membrane surface.

Complement

fixation

Soluble complement

(involved in

chemotaxis)

Complement

protein C4

2 3

Bacterial membrane

Antibody

1

Bacterium

C4a

C4b