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INTRODUCTION

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.

ACTIVATION OF COMPLEMENT

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 classic 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 classic pathway is not present. The lectin pathway and the alternative pathway are, therefore, participants in the innate arm of the immune system.

FIGURE 63–1

The classic 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 central molecule of the complement cascade. 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) It combines with other complement components to generate C5 convertase, the enzyme that leads to the production of the membrane attack complex (MAC); (2) it opsonizes bacteria because phagocytes have receptors for C3b on their surface; and (3) its derivatives bind to a receptor on B cells and provide “signal 2” for T-cell–independent B-cell activation (see Chapter 61).

  1. In the classic 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 classic pathway, C11 binds and is cleaved to form an active ...

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