1. THE COMPLEMENT SYSTEM & ITS BIOLOGICAL ROLE A Presentation By Isaac U.M. Associate Professor & HOD, Dept. of Microbiology, College of Medicine, International Medical & Technological University, Dar-Es-Salaam, Tanzania

3. 2001 by Garland Science Figure 2.7. Schematic overview of the complement cascade. There are three pathways of complement activation: the classical pathway, which is triggered by antibody or by direct binding of complement component C1q to the pathogen surface; the MB-lectin pathway, which is triggered by mannan-binding lectin, a normal serum constituent that binds some encapsulated bacteria; and the alternative pathway, which is triggered directly on pathogen surfaces. All of these pathways generate a crucial enzymatic activity that, in turn, generates the effector molecules of complement. The three main consequences of complement activation are opsonization of pathogens, the recruitment of inflammatory cells, and direct killing of pathogens.

6. Jules Bordet (1870 – 1961)

7. Paul Ehrlich (1854 – 1915)

8. The Multiple Activities of the Complement System Serum complement proteins and membrane-bound complement receptors partake in a number of immune activities: lysis of foreign cells by antibody-dependent or antibody-independent pathways; opsonization or uptake of particulate antigens including bacteria, by phagocytosis; activation of inflammatory responses; and clearance of circulating immune complexes by cells in the liver and spleen. Soluble complement proteins are schematically indicated by a triangle and receptors by a semicircle; no attempt is made to differentiate among individual components of the complement system here.

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12. Figure 12-8 The classical, lectin, and alternate complement pathways. Despite different activators, the goal of these pathways is cleavage of C3 and C5 to provide chemoattractants and anaphylotoxins (C3a, C5a), an opsonin (C3b) that adheres to membranes, and to initiate the membrane attack complex to kill cells. MASP, MBP-associated serine protease; MBP, mannose-binding protein. (Redrawn from Rosenthal KS, Tan JS: Rapid review microbiology and immunology, St. Louis, 2002, Mosby.) Downloaded from: StudentConsult (on 21 December 2007 12:59 PM) © 2005 Elsevier

13. Complement Pathways

16. Figure 12-9 Cell lysis by complement. Activation of C5 initiates the molecular construction of an oil-well-like membrane attack complex (MAC). Downloaded from: StudentConsult (on 21 December 2007 12:59 PM) © 2005 Elsevier

17. Classical Pathway 2 001 by Garland Science Figure 2.14. Cleavage of C4 exposes an active thioester bond that causes the large fragment, C4b, to bind covalently to nearby molecules on the bacterial cell surface. Intact C4 consists of an α, a β, and a γ chain with a shielded thioester bond on the α chain. This is exposed when the α chain is cleaved by C1s to produce C4b. The thioester bond (marked by an arrow in the third panel) is rapidly hydrolyzed (that is, cleaved by water), inactivating C4b unless it reacts with hydroxyl or amino groups to form a covalent linkage with molecules on the pathogen surface. The homologous protein C3 has an identical reactive thioester bond that is also exposed on the C3b fragment when C3 is cleaved by C2b. The covalent attachment of C3b and C4b enables these molecules to act as opsonins and is important in confining complement activation to the pathogen surface.

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20. Figure 12-8 The classical, lectin, and alternate complement pathways. Despite different activators, the goal of these pathways is cleavage of C3 and C5 to provide chemoattractants and anaphylotoxins (C3a, C5a), an opsonin (C3b) that adheres to membranes, and to initiate the membrane attack complex to kill cells. MASP, MBP-associated serine protease; MBP, mannose-binding protein. (Redrawn from Rosenthal KS, Tan JS: Rapid review microbiology and immunology, St. Louis, 2002, Mosby.) Downloaded from: StudentConsult (on 21 December 2007 12:59 PM) © 2005 Elsevier

22. 2 001 by Garland Science Figure 2.13. Mannan-binding lectin forms a complex with serine proteases that resembles the complement C1 complex. MBL forms clusters of two to six carbohydrate-binding heads around a central collagen-like stalk. This structure, easily discernible under the electron microscope (lower panels) has been described as looking like ‘a bunch of tulips.' Associated with this complex are two serine proteases, MBL-associated serine protease (MASP)-1 and -2. The structural disposition of MASP proteins in the complex is not yet determined. On binding of MBL to bacterial surfaces, these serine proteases become activated and can then activate the complement system by cleaving and activating C4 and C2. Photograph courtesy of K.B.M. Reid.

23. Figure 12-8 The classical, lectin, and alternate complement pathways. Despite different activators, the goal of these pathways is cleavage of C3 and C5 to provide chemoattractants and anaphylotoxins (C3a, C5a), an opsonin (C3b) that adheres to membranes, and to initiate the membrane attack complex to kill cells. MASP, MBP-associated serine protease; MBP, mannose-binding protein. (Redrawn from Rosenthal KS, Tan JS: Rapid review microbiology and immunology, St. Louis, 2002, Mosby.) Downloaded from: StudentConsult (on 21 December 2007 12:59 PM) © 2005 Elsevier

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31. Complement Fixation Test (Positive test)

32. Complement Fixation Test (Negative test)

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