Functions of complement system
• Make holes on microbial membrane leading to microbial death
• Mark microbial surface for recognition by phagocytes (opsonization)
• Generate inflammatory, chemotatic molecules to recruit cells, molecules to site of infection
C3 (abundant in plasma) normally held in closed position. Changes in microenvironment caused by microbial membrane leads to weak activation of C3 by cleavage of internal sulfhydryl bonds. Active C3 binds B, which allows this complex to bind D. D cleaves B, leaving C3Bb complex (C3 convertase). C3 convertase cleaves C3, creating C3a and C3b.
-C3b covalently binds to microbial cell surface. Bound C3b creates more C3 convertase, leading to more C3a and C3b.
-C3b on microbe surface binds to complement receptors on macrophages to facilitate endocytosis, degradation of microbe.
C5 convertase formation
C3 convertase drives C5 convertase formation. C3b2Bb is C5 convertase, cleaving C5 into C5a and C5b. C5b catalyzes formation of the membrane attack complex (MAC) with other complement proteins. MAC makes a pore in microbe to kill it.
Acute Phase Proteins
During active infection, macrophages produce IL-6 that induces hepatocytes to synthesize acute-phase proteins including mannose-binding lectin (lectin pathway) and c-reactive protein (classical pathway).
Mannose-binding lectin binds to mannose on microbe surface and recruits MASP-1 and MASP-2 (MBL-associated serine protease) that cleave C4 into C4a and C4b and cleaves C2 into C2a and C2b. C4bC2a come together on the microbial surface and become a C3 convertase.
Role of small peptides (C3a, C5a)
Increase vascular permeability, function as chemoattractants, activate phagocytes. Can cause anaphylactic shock.
-C1INH inhibits C1
-CD59 blocks MAC assembly
-H and I inactivate C3
-DAF, MCP, and I dissociate C3 convertase
C-reactive protein binds to lipids on microbial surface or antibody binds to antigen on surface and recruits C1, which activates and becomes a protease that cleaves C4 into C4a and C4b and cleaves C2 into C2a and C2b. C4bC2a come together on the microbial surface and become a C3 convertase.