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Chapter 5 : Complement

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Abstract:

Complement proteins fall into three broad categories, although some complement proteins may actually fit into two of these categories. The first category encompasses the complement serum proteins, which react with foreign bodies in either an antibody-dependent or antibody-independent manner. The second are regulatory proteins present in serum or on the membranes of host cells. The third are cell surface receptors that bind to the products of complement activation and signal host cells to participate in inflammatory and immune reactions. The complement system is designed to mobilize a large number of immune effector mechanisms when it detects infected or injured self tissues. Three pathways of complement activation are now known: the alternative pathway, the classical pathway, and the lectin pathway. A third pathway of complement activation, the lectin pathway, has recently been defined but, like the alternative pathway of complement activation, likely arose during evolution prior to the classical pathway. Serum opsonins include antibody, complement, fibronectin, and C-reactive protein (CRP). Host phagocytes, such as neutrophils and macrophages, have receptor proteins on their cell surfaces that specifically recognize portions of the antibody molecule (Fc receptors), fragments of complement (C3 receptors), and fibronectin. Immune cells attracted to such sites expose cell surface receptor proteins that recognize particular fragments of C3 and fulfill the biologic function of phagocytosis. Thus, complement constitutes the fundamental proinflammatory response system that can trigger and regulate the remainder of the immune response.

Citation: Moore F. 2004. Complement, p 85-109. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch5

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Complement System
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Figures

Image of Figure 5.1
Figure 5.1

Diagram of the complement cascade, which consists of enzymatic steps involving a number of inactive proenzymes (or zymogens). Each step involves the activation of a given proenzyme, usually by proteolytic cleavage. Upon activation, the enzyme acts on a substrate, which is usually another proenzyme in the cascade. The sequence of activation events culminates with two end effects on the foreign surface: deposition of complement proteins (e.g., component C3b) on a foreign surface, which has the ability to target the foreign surface for a number of immune effector functions, such as phagocytosis; and formation on the foreign surface of a large transmembrane pore, called the MAC.

Citation: Moore F. 2004. Complement, p 85-109. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch5
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Image of Figure 5.2
Figure 5.2

The three activation pathways of complement: the alternative pathway, classical pathway, and lectin pathway. Ag-Ab, antigen-antibody.

Citation: Moore F. 2004. Complement, p 85-109. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch5
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Image of Figure 5.3
Figure 5.3

Complement component C1. C1 contains three separate components: one component is C1q, which is composed of six identical protein units that interact with the other two components, C1r and C1s. There are two molecules each of C1r and C1s. C1q is able to bind to Fc regions of antibody when the antibody binds to antigen. C1r and C1s are serine proteases with the enzymatic activity necessary to initiate the complement cascade. Before complement activation, C1r and C1s are associated in an extended conformation, intertwining between the C1q stalks. Binding to an antigen-antibody complex changes the conformation of C1r and C1s to a so-called figure 8 conformation. In this conformation, the catalytic domains of C1r are close enough to the catalytic domains of C1s to permit C1r to cleave (and activate) C1s. Cleaved, the activated C1s is then able to cleave and activate the next two components in the classical pathway: C4 and C2.

Citation: Moore F. 2004. Complement, p 85-109. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch5
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Image of Figure 5.4
Figure 5.4

Diagram of the classical pathway of complement activation. Binding of C1q to antibody alters the C1q collagenous stalk, permitting C1r and C1s to assume active forms. Cleavage of C4 by C1s generates a small, readily diffusable split product, C4a, and a larger fragment, C4b. C4b next binds to complement component C2. C2 can be cleaved by the still-active C1s component of the immunoglobulin-C1 complex, yielding the soluble product C2b and the larger product C2a, which remains associated with C4b. This complex of C4b and C2a is a C3 convertase. The cleavage of C3 is an amplification step. Interaction of C3b directly with C4b transforms the C3 convertase into a C5 convertase. In addition, many molecules of C3 are cleaved, with the 3b fragment binding to the antigenic surface, where it can serve as an opsonin. The C4b2a3b C5 convertase generates two fragments from C5. The small fragment of C5 (C5a) is diffusible. C5b attaches to the activator membrane. Binding of C6 to C5b stabilizes C5b, preventing its rapid inactivation. Next, C7 binds to the C5b6 complex, resulting in a hydrophobic transition in C5b. The C5b67 complex is then bound by a single molecule of C8. Multiple copies of C9 bind to C5b678. C8 and C9 also undergo hydrophobic transitions as they bind to the growing MAC. The C9 components (∼10 to 17) form a circular pore in the activator membrane.

Citation: Moore F. 2004. Complement, p 85-109. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch5
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Image of Figure 5.5
Figure 5.5

Activation of components C3 and C4 involves cleavage of an unstable thioester bond (O=C—S) in the α chain of the protein. This cleavage event can be spontaneous (possibly initiating the alternative pathway of activation) or triggered by proteolytic cleavage of C3 by the C3 convertases [C4b2a or C3(HO)Bb]. Cleavage of the thioester linkage generates a highly reactive carbon on the α chain, which can become covalently coupled to proteins or carbohydrates on an antigenic surface.

Citation: Moore F. 2004. Complement, p 85-109. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch5
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Image of Figure 5.6
Figure 5.6

IgG antibodies are weaker activators of complement than are IgM antibodies. IgG binds to complement component C1q via a single C1q-binding site on its Fc region, which binds C1q with low affinity. When the amount of IgG bound to an antigenic surface is low, C1q is unable to bind to the surface with sufficient avidity. When the amount of surface-bound IgG is high, simultaneous binding by C1q to two or more IgG molecules is possible, increasing the avidity of C1q binding and allowing activation of C1. IgM antibodies can activate the complement cascade even if a single IgM molecule is bound to an antigen, since each IgM molecule contains five or six C1q-binding sites, a number sufficient for avid C1q binding.

Citation: Moore F. 2004. Complement, p 85-109. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch5
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Image of Figure 5.7
Figure 5.7

IgM-mediated complement activation can be explained by the conformation that the IgM polymer assumes upon antigen binding. Free IgM before binding to antigen. IgM antibody makes initial contact with one to three binding sites on the antigen. Further stability of the antigen-IgM antibody complex due to increased attachment to antigen via multiple antigen-binding sites on IgM. Formation of a staple binding conformation of IgM, which leads to exposure of the C1q binding sites. High-affinity binding of C1 to the staple conformation of IgM.

Citation: Moore F. 2004. Complement, p 85-109. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch5
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Image of Figure 5.8
Figure 5.8

Early steps of the alternative pathway of complement activation leading to the activation of component C5. C3 can be activated spontaneously through breakage of the thioester linkage in the α chain of C3 and reaction with water to yield C3(HO). C3 can also be activated to C3b by proteolytic cleavage (not shown) by preexisting C3 convertases (such as C4b2a). Activated C3 binds to the antigenic surface. Surface-bound C3(HO) binds factor B. C3(HO)-bound factor B is a substrate for factor D, which cleaves factor B, generating soluble fragment Ba and C3(HO)-bound fragment Bb. The C3(HO) Bb complex functions as a C3 convertase. The fate of the C3 convertase is decided by the relative activities of two other complement components: factor H and properdin. Factor H can bind to and dissociate the C3 convertase. Alternatively, properdin can bind to and stabilize the C3 convertase, permitting subsequent activation steps. The C3 convertase binds to an additional molecule of C3. The Bb component of the C3 convertase is able to bind and cleave multiple molecules of C3, most of which bind directly to the antigenic surface. A small portion of the C3 cleaved by C3(HO)Bb remains associated with C3(HO)Bb to form the C5 convertase C3(HO)Bb3b. The C5 convertase binds and cleaves component C5. Not shown: The cleaved, activated C5 then associates with the antigenic surface, associates with components C6 to C8, inserting into the target membrane, and ultimately forms poly-C9 MACs (i.e., containing multiple copies of the C9 component). These terminal steps of the alternative pathway are exactly the same as in the classical pathway.

Citation: Moore F. 2004. Complement, p 85-109. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch5
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Image of Figure 5.9
Figure 5.9

The lectin pathway of complement activation is initiated by a multisubunit complex resembling C1. MBL (also called mannose-binding protein) is a member of the collectin family of proteins, which are composed of several identical subunits, each of which has a lagen-like stalk and a globular head which functions as a (i.e., binds carbohydrates). The globular head domain binds to mannose-rich carbohydrates common on microbial surfaces. Ficolins have a collagen-like stalk but a fibrinogen-like carbohydrate recognition unit. MBL or ficolin forms a complex with two serine proteases called MASP-1/3 and MASP-2, which become activated when MBL binds to carbohydrate. The MBL-MASP complex is therefore structurally and functionally homologous to the C1 complex. Although the MBL-MASP complex is depicted as having six MBL or ficolin subunits to emphasize the homology of this complex with C1, the actual number of MBL or ficolin subunits in the complex is variable.

Citation: Moore F. 2004. Complement, p 85-109. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch5
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Image of Figure 5.10
Figure 5.10

The kallikrein system is a group of serum proteins important in the inflammatory response. The inactive precursor form of kallikrein (prekallikrein) forms a complex with its substrate, kininogen. This complex then binds to activated factor XII, which cleaves prekallikrein to its active form, kallikrein. Activated kallikrein can then cleave kininogen to form the vasoactive peptides bradykinin and kallidin. Kallikrein is also capable of cleaving and activating C5 and factor B, possibly activating or amplifying the complement cascade during inflammation.

Citation: Moore F. 2004. Complement, p 85-109. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch5
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Image of Figure 5.11
Figure 5.11

The various activities of complement proteins are mediated by cell surface complement receptors present on the membranes of immune cells (such as neutrophils, mast cells, and macrophages) and vascular endothelial cells. Injury or infection can trigger activation of the complement cascade, producing numerous complement split products. Some of these split products (e.g., C5a) can act directly on the vascular endothelium to enhance extravasation of leukocytes, and others can act on leukocytes (e.g., neutrophils). Extravasation is also enhanced by changes in vascular permeability induced by histamine, leukotrienes, and prostaglandins released by mast cells following stimulation by C3a and C5a.

Citation: Moore F. 2004. Complement, p 85-109. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch5
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Image of Figure 5.12
Figure 5.12

Signaling through the C5a receptor (C5aR). The receptor is linked to a G protein and following binding of C5a activates signaling transduction pathways leading to production of such factors as ERK and NF-AT.

Citation: Moore F. 2004. Complement, p 85-109. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch5
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Image of Figure 5.13
Figure 5.13

Structure of CR1 and CR3. CR1 contains 30 tandemly aligned short consensus repeats grouped into four LHRs (A, B, C, and D) and extends from the plasma membrane by about 90 nm. LHR A binds to C4b, and LHR B and C bind strongly to C3b and weakly to C4b. LHR D and two membrane-proximal short consensus repeats (gray ovals) can bind C1q. The presence of multiple binding sites for complement proteins gives CR1 molecules the advantage of increased binding to antigens coated with multiple C1q, C4b, and/or C3b molecules. Structure at upper left redrawn from M. Krych-Goldberg and J. P. Atkinson, 112–122, 2001, with permission.

Citation: Moore F. 2004. Complement, p 85-109. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch5
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Image of Figure 5.14
Figure 5.14

CR1 and CR2 work together to enhance the immunogenicity of B-cell antigens. An antigen coated with complement split product C3b binds to the B cell via both the BCR and CR1. CR1 presents C3b to factor I, which cleaves C3b to generate the split product C3d. Conversion of C3b to C3d results in the dissociation of CR1 and the association of CR2. CD19, complexed with CR2, delivers a costimulatory signal to the B cell via the src-related kinases Lyn and Fyn. This costimulatory signal, together with an activational signal delivered through the BCR, activates the B cell.

Citation: Moore F. 2004. Complement, p 85-109. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch5
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Image of Figure 5.15
Figure 5.15

Regulatory proteins of the complement system. Most complement regulatory proteins act by preventing assembly of activated complement components or by inducing their dissociation. CR1, C4BP, DAF, MCP, and factor H are capable of both types of activity, inducing dissociation of preformed C3 and preventing association of new C3 convertases (double red bars). Factor I is capable of proteolytically cleaving and inactivating C3(H2O) and C4b. Factor I requires CR1, C4BP, MCP, or factor H as a cofactor for this activity.

Citation: Moore F. 2004. Complement, p 85-109. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch5
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Image of Figure 5.16
Figure 5.16

Regulation of C3 by factor H. The diagram shows the structure of factor H, with each complement control protein repeat (CCP) represented as a red or pink oval. CCPs 1 to 4 are essential for both dissociation of the C3 convertase and recruitment of factor I.

Citation: Moore F. 2004. Complement, p 85-109. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch5
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Image of Figure 5.17
Figure 5.17

Transcriptional regulation of complement protein synthesis. Inflammatory cytokines such as IL-1 trigger the synthesis of transcription factors C/EBPδ and NF-IL6, which in turn mediate enhanced complement transcription.

Citation: Moore F. 2004. Complement, p 85-109. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch5
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Image of Figure 5.18
Figure 5.18

The role of complement in clearing immune complexes from the circulation. Circulating immune complexes become substrates for activation of the classical complement cascade. Complement fragment C3b attaches to these immune complexes, mediating attachment of the complexes to red blood cells (RBC) via CR1. The RBC circulates to the liver, where CR1 acts as a cofactor for factor I-mediated cleavage of fragment C3b, forming the two products iC3b and C3f. iC3b is not bound by CR1, and so the RBC releases the immune complex, which is immediately bound by macrophages via CR3 or CR4 (not shown). The macrophage ingests the immune complex. Genetic defects that impair classical pathway complement activation and genetic defects in CR1 impair this clearance mechanism. The result is persistence of circulating immune complexes, which eventually become embedded on blood vessel walls, triggering complement activation. MAC-mediated injury ensues, and complement split products generated during complement activation (C3a and C5a) attract neutrophils to the site (black arrow). The neutrophils can cause further tissue injury by releasing hydrolytic enzymes and oxidative products such as superoxide (red arrow).

Citation: Moore F. 2004. Complement, p 85-109. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch5
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References

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1. Barrington, R.,, M. Zhang,, M. Fischer,, and M. C. Carroll. 2001. The role of complement in inflammation and adaptive immunity. Immunol. Rev. 180:515.
2. Fujita, T. 2002. Evolution of the lectin-complement pathway and its role in innate immunity. Nat. Rev. Immunol. 2:346353.
3. Law, S. K.,, and A. W. Dodds. 1997. The internal thioester and the covalent binding properties of the complement proteins C3 and C4. Protein Sci. 16:263274.
4. Molina, H. 2002. The murine complement regulator Crry: new insights into the immunobiology of complement regulation. Cell. Mol. Life Sci. 59:220229.
5. Nielsen, C. H.,, and R. G. Leslie. 2002. Complement’s participation in acquired immunity. J. Leukoc. Biol. 72:249261.
6. Sahu, A.,, and J. D. Lambris. 2001. Structure and biology of complement protein C3, a connecting link between innate and acquired immunity. Immunol. Rev. 180:3548.
7. Smith, G. P.,, and R. A. Smith. 2001. Membrane-targeted complement inhibitors. Mol. Immunol. 38:249255.
8. Spear, G. T.,, M. Hart,, G. G. Olinger,, F. B. Hashemi,, and M. Saifuddin. 2001. The role of the complement system in virus infections. Curr. Top. Microbiol. Immunol. 260:229245.
9. Walport, M. J. 2001. Complement. First of two parts. N. Engl. J. Med. 344:10581066.
10. Walport, M. J. 2001. Complement. Second of two parts. N. Engl. J. Med. 344:11401144.

Tables

Generic image for table
Table 5.1

Primary proteins of the complement cascade

Citation: Moore F. 2004. Complement, p 85-109. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch5
Generic image for table
Table 5.2

Microbial surface structures capable of activating the complement system

Citation: Moore F. 2004. Complement, p 85-109. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch5
Generic image for table
Table 5.3

Complement receptors

Citation: Moore F. 2004. Complement, p 85-109. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch5
Generic image for table
Table 5.4

Microbial factors that inactivate or divert the complement system to protect against complement-mediated killing

Citation: Moore F. 2004. Complement, p 85-109. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch5

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