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The complement system consists of approximately 20 proteins that are present in normal human (and other animal) serum. The term complement refers to the ability of these proteins to complement (i.e., augment) the effects of other components of the immune system (e.g., antibody). Complement is an important component of our innate host defenses.

There are three main effects of complement: (1) lysis of cells such as bacteria, allografts, and tumor cells; (2) generation of mediators that participate in inflammation and attract neutrophils; and (3) opsonization (i.e., enhancement of phagocytosis). Complement proteins are synthesized mainly by the liver.


Several complement components are proenzymes that must be cleaved to form active enzymes. Activation of the complement system can be initiated either by antigen–antibody complexes or by a variety of nonimmunologic molecules (e.g., endotoxin).

Sequential activation of complement components (Figure 63–1) occurs via one of three pathways: the classical pathway, the lectin pathway, and the alternative pathway (see later). Of these pathways, the lectin and the alternative pathways are more important the first time we are infected by a microorganism because the antibody required to trigger the classical pathway is not present.


The classical and alternative pathways of the complement system indicate that proteolytic cleavage of the molecule at the tip of the arrow has occurred; a line over a complex indicates that it is enzymatically active. Note that all small fragments are labeled “a,” and all large fragments are labeled “b.” Hence, the C3 convertase is depicted as C4b,2b. Note that proteases associated with the mannan-binding lectin cleave C4 as well as C2.

All three pathways lead to the production of C3b. The presence of C3b on the surface of a microbe marks it as foreign and targets it for destruction. C3b has three important functions:

  1. Formation of the C5 convertase, leading to the membrane attack complex (MAC)

  2. Opsonizing bacteria for phagocytes with receptors for C3b on their surface

  3. Releasing derivatives that bind to a receptor on B cells that provides “signal 2” for T-cell–independent B-cell activation (see Chapter 61).

Classical Pathway

In the classical pathway, complement proteins first become fixed (bound) to an antigen–antibody complex (see Figure 63–1). Only IgM and IgG can fix complement proteins, because only the Fc regions of the γ and μ heavy chains have a C1 binding site. Complement fixation is the gathering together of bound proteins, starting a chain reaction of proteases.

In the classical pathway, C11 binds and is cleaved to form an active protease, which cleaves C2 and C4 to form a C4b,2b complex. The latter is C3 convertase, which cleaves C3 molecules into two fragments, C3a and ...

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