Complement Cascade

If a foreign agent penetrates the mechanical barriers, it encounters the complement system. The complement activation cascade is initiated by two different mechanisms. The first method discovered is called the classical pathway although the alternative pathway appears to have developed first since the initiation of the classical pathway requires the participation of the acquired immune system. The alternative pathway can be considered innate immunity, and the classical pathway can be considered acquired immunity, however both will be discussed here.

Figure 2.1. Complement cascade.

As Figure 2.1 illustrates, the classical pathway begins with C1 binding to immune complexes (i.e., a composite of antigen and antibodies). C1 is composed of C1q, C1r, and C1s. C1 must bind to two complement fixation sites for activation. These fixation sites are found on the Fc region of IgG or IgM. Thus activation requires two molecules of IgG because it is a monomer or one molecule of IgM since it is a pentamer. When C1q binds to the antibody, it is activated and converts C1r to an active state. Active C1r then activates C1s. Next active C1s cleaves C4 (note: products of complement cleavage are designated a and b, with a being the smaller fragment and b being the larger fragment) to C4a and C4b. C4a acts as a weak inflammatory mediator that increases local blood flow, vascular permeability, and capillary leak of fluid and protein. C4b covalently attaches to the surface of the antigen where it then binds to C2 making it susceptible to C1s. C1s then cleaves C2 producing C2b which remains bound to C4b forming the C4b,2b complex. This complex possesses the ability to process both C3 and C5 thus it is referred to as C3/ C5 convertase. The C2b portion provides the enzymatic function while C4b keeps the complex anchored to the pathogen insuring the cleavage products are directed at the appropriate target. The C3/C5 convertase then cleaves multiple molecules of C3 producing large amounts of both C3a and C3b. C3a is a more active mediator of local inflammation than C4a. Production of large amounts of C3b is one of the

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Figure 2.2. Process of phagocytotsis.

most important results of the activation of the complement cascade. C3b opsonizes the pathogen making it more readily phagocytized by macrophages and neutrophils (Fig. 2.2). C3b also binds to C5 making it susceptible to the action of the C3/C5 convertase producing C5a and C5b. C5a is the most potent of the mediators of local inflammation produced by the complement cascade. C5a and C3a, to a lesser degree, are chemotaxins for macrophages and neutrophils. The other product of C5 cleavage, C5b, binds to C6 forming C5b,6 which then binds to C7. The C7 portion of this complex has a hydrophobic site which inserts into the membrane of the pathogen anchoring C5b,6,7. Next C8 binds to C5b,6,7, and it also anchors the complex to the pathogen. Finally, the C8 portion of the C5b,6,7,8 complex binds to C9 and causes the polymerization of10 to 16 C9 molecules into a porelike structure called the membrane attack complex (MAC). The MAC then disrupts the integrity of the pathogen's outer membrane allowing free passage of water and solutes across the membrane. This alters cellular homeostasis and eventually the cell lyses.

The activation of the alternative pathway requires no assistance. Spontaneous cleavage of C3 occurs at low levels in serum producing C3b. If an antigen is present, the C3b binds to its surface and then binds a serum protein called Factor B. Another serum protein, Factor D, then acts on bound Factor B converting the complex to C3b,Bb. C3b,Bb, like C4b,2b of the classical pathway, possesses C3/C5 convertase activity. After formation of C3b,Bb a stabilizing molecule known as properdin binds to the complex protecting it from degradation. Once the C3/C5 convertase is formed the classical and alternative pathways are identical. The end results of complement activation are opsonization of the pathogen (C3b), recruitment of inflammatory cells to the site of infection (C3a, C4a, & C5a), and direct killing of the pathogen by the MAC (C5b6789).

Like most effector systems the complement cascade has regulatory systems that prevent the response from becoming too exuberant or being inappropriately activated. If C3b binds to Factor B while free in serum rather than when bound to the

Figure 2.3. Immunoglobulin monomer: L = light chain; H= heavy chain, disulfide bonds, and c and v represent constant and variable regions respectively.

Figure 2.3. Immunoglobulin monomer: L = light chain; H= heavy chain, disulfide bonds, and c and v represent constant and variable regions respectively.

pathogen, the C3b,B complex is unstable and a protein called Factor H displaces Factor B. Factor I then acts on the C3b,H complex converting it to iC3b. Phagocytic cells possess receptors for iC3b which stimulate phagocytosis when they are bound much like the binding of C3b to its receptor, however iC3b does not appear to activate other components of the cascade so the response is not amplified.

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