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FIGURE 4-9 Pathways of complement activation. The activation of the complement system may be initiated by three distinct pathways, all of which lead to the production of C3b (the early steps). C3b initiates the late steps of complement activation, culminating in the production of peptides that stimulate inflammation (C5a) and polymerized C9, which forms the membrane attack complex, so called because it creates holes in plasma membranes. The principal functions of major proteins produced at different steps are shown. The activation, functions, and regulation of the complement system are discussed in much more detail in Chapter 12.

Lysis of microbe

FIGURE 4-9 Pathways of complement activation. The activation of the complement system may be initiated by three distinct pathways, all of which lead to the production of C3b (the early steps). C3b initiates the late steps of complement activation, culminating in the production of peptides that stimulate inflammation (C5a) and polymerized C9, which forms the membrane attack complex, so called because it creates holes in plasma membranes. The principal functions of major proteins produced at different steps are shown. The activation, functions, and regulation of the complement system are discussed in much more detail in Chapter 12.

Mannose binding lectin

Ficolin

FIGURE 4-10 C1, mannose-binding lectin, and ficolin. These three homologous pentameric proteins can all initiate complement activation on binding to their ligands on cell surfaces. C-type lectin—like globular heads at the end of collagenous-like stalks in the C1q and mannose-binding lectin proteins bind the Fc regions of IgM or mannose on the surface of microbes, respectively. Fibrinogen-like globular heads on ficolin bind W-acetylglucosamine on the surface of microbes. Binding results in con-formational changes that activate the serine protease activity of C1r and C1s, associated with C1q, or MASP1 and MASP2, associated with mannose-binding lectin and ficolin.

C1r2s2

C1r2s2

Microbial surface antigen

IgM antibody

Mannose on microbe surface

N-acetylglucosamine on bacterial cell wall

Microbial surface antigen

IgM antibody

Mannose on microbe surface

N-acetylglucosamine on bacterial cell wall of the antibodies, two associated serine proteases, called C1r and C1s, become active and initiate a proteolytic cascade involving other complement proteins. The classical pathway is one of the major effector mechanisms of the humoral arm of adaptive immune responses (see Chapter 12). Because IgM natural antibodies are very efficient at binding C1q, the classical pathway also participates in innate immunity. In addition, other innate immune system soluble proteins called pentraxins, discussed later, can also bind C1q and initiate the classical pathway.

• The alternative pathway, which was discovered later but is phylogenetically older than the classical pathway, is triggered when a complement protein called C3 directly recognizes certain microbial surface structures, such as bacterial LPS. C3 is also constitu-tively activated in solution at a low level and binds to cell surfaces, but it is then inhibited by regulatory molecules present on mammalian cells. Because microbes lack these regulatory proteins, the spontaneous activation can be amplified on microbial surfaces. Thus, this pathway can distinguish normal self from foreign microbes on the basis of the presence or absence of the regulatory proteins.

• The lectin pathway is triggered by a plasma protein called mannose-binding lectin (MBL), which recognizes terminal mannose residues on microbial glyco-proteins and glycolipids, similar to the mannose receptor on phagocyte membranes described earlier (see Fig. 4-10). MBL is a member of the collectin family (discussed later) with a hexameric structure similar to the C1q component of the complement system. After MBL binds to microbes, two zymogens called MASP1 (mannan-binding lectin-associated serine protease) and MASP2, with similar functions to C1r and C1s, associate with MBL and initiate downstream proteolytic steps identical to the classical pathway.

Recognition of microbes by any of the three complement pathways results in sequential recruitment and assembly of additional complement proteins into protease complexes (see Fig. 4-9). One of these complexes, called C3 conver-tase, cleaves the central protein of the complement system, C3, producing C3a and C3b. The larger C3b fragment becomes covalently attached to the microbial surface where the complement pathway was activated. C3b serves as an opsonin to promote phagocytosis of the microbes. A smaller fragment, C3a, is released and stimulates inflammation by acting as a chemoattractant for neutrophils. C3b binds other complement proteins to form a protease called C5 convertase that cleaves C5, generating a secreted peptide (C5a) and a larger fragment (C5b) that remains attached to the microbial cell membranes. C5a is also a chemoattractant; in addition, it induces changes in blood vessels that make them leak plasma proteins and fluid into sites of infections. C5b initiates the formation of a complex of the complement proteins C6, C7, C8, and C9, which are assembled into a membrane pore, called the membrane attack complex (MAC), that causes lysis of the cells where complement is activated.

The complement system is an essential component of innate immunity, and patients with deficiencies in C3 are highly susceptible to recurrent, often lethal, bacterial infections. However, genetic deficiencies in MAC formation (the terminal product of the classical pathway) increase susceptibility to only a limited number of microbes, notably Neisseria bacteria, which have thin cell walls that make them especially susceptible to the lytic action of the MAC. The complement system will be discussed in more detail in Chapter 12.

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