The complement system consists of several plasma proteins that work together to opsonize microbes, to promote the recruitment of phagocytes to the site of infection, and in some cases to directly kill the microbes (Fig. 1). Complement activation involves proteolytic cascades in which an inactive protein, called a zymogen, is altered to become an active protease that cleaves and thereby induces the proteolytic activity of the next complement protein in the cascade. Enzymatic cascades result in tremendous amplification of the amount of proteolytic products that are generated at each step. These products perform the effector functions of the complement system.

Fig1. 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 C3a, which stimulates inflammation, and C3b (early steps). C3b initiates the late steps of complement activation, culminating in the production of peptides that also stimulate inflammation (C5a) and polymerized C9, which forms the membrane attack complex (MAC) (late steps). The activation, functions, and regulation of the complement system are discussed in much more detail in Chapter 13.

The first step in activation of the complement system is recognition of molecules on microbial surfaces, and this occurs in three ways, each referred to as a distinct pathway of complement activation.

• The classical pathway, so-called because it was discovered first, uses a plasma protein called C1q to detect antibodies bound to the surface of microbes or other structures. Once C1q binds to the Fc portion 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. Innate immune system soluble proteins called pentraxins, which are 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 constitutively activated at a low level in blood and extra vascular fluid 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 path way 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 glycoproteins and glycolipids, similar to the mannose receptor on phagocytes described earlier. MBL is a member of the collectin family (discussed later) with a hexameric structure similar to that of the C1q component of the complement system. After MBL binds to microbes, two zymogens called MASP1 (mannose-associated serine protease 1 or mannan-binding lectin-associated serine protease) and MASP2, with functions similar to those of 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. 1). One of these complexes, called C3 convertase, 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. The sequential enzymatic activity of complement proteins provides such tremendous amplification that millions of C3b molecules can deposit on the surface of a microbe within 2 or 3 minutes. C3b serves as an opsonin to promote phagocytosis of the microbes. The smaller fragment, C3a, is released and stimulates inflammation by acting as a chemoattractant for neutrophils, by inducing mast cell degranulation, and by directly increasing vascular permeability so that plasma proteins and fluid leak into sites of infections. C3b binds other complement proteins to form a protease called C5 convertase, which cleaves C5, generating a released peptide (C5a) and a larger fragment (C5b) that remains attached to the microbial cell membranes. C5a exerts the same proinflammatory effects as C3a and is more potent. 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, activated by the alternative and lectin pathways, is an essential component of innate immunity, and patients with deficiencies in C3 are highly susceptible to recurrent, often lethal, bacterial infections. Genetic deficiencies in MAC formation (the terminal product of the classical path way) cause increased 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 also contributes to cell and tis sue injury in many inflammatory and autoimmune diseases; drugs targeting complement proteins are now approved for several inflammatory disorders.

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مواضيع ذات صلة

The Immune Receptor Family

Collectins and Ficolins

Soluble Effector Molecules of Innate Immunity: Pentraxins

MHC Genes

Cytokine-Producing Innate Lymphoid Cells

Epithelial Barriers

C-Type Lectins: Receptors for Microbial Carbohydrates

Antigen Capture and the Functions of Antigen-Presenting Cells

Cytosolic DNA Sensors and the STING Pathway

RIG-Like Receptors

Inflammasomes

Antigens