MBI - 414 Immunology Principles
MBI - 415 Immunology Principles and Practice

Complement

Alternative Pathways

• C3 convertase generation
• C3 possesses a labile thiolester group that can be exposed via cleavage by plasma proteases or simple autolysis, allowing this component to form a covalent (ester or amide) bond with free hydroxyl or amino groups of polysaccharides or LPS on microbial surfaces
• C3b (cleaved C3) binds factor B in the presence of Mg ions, to form the C3b,B complex
• factor D (in the presence of Mg ions) cleaves factor B to generate factor Bb, which becomes part of the C3b,Bb complex which functions as C3 convertase on the microbial surface (fragment Ba has no known function)
  • C3b,Bb is stabilized by binding of properdin to form the C3b,Bb,P complex
  • C3 convertase cleaves C3 into C3a (anaphylatoxin) and C3b (opsonin)
• C5 convertase
• generated by binding of multiple C3b molecules to C3b,Bb,P complexes on the microbial surface, thus forming C3b_nBbP complexes
• activity - cleaves C5 into C5a (anaphylatoxin and chemotactic factor) and C5b (initiates MAC)
• membrane attack complex (MAC)
  • generated in three steps:
    • C5b,6,7 complex, which binds to the microbial membrane via hydrophobic tails that are unfurled by C6 and C7 as a result of allosteric conformational changes that occur when C6 and C7 bind sequentially to C5
    • C8 binds to the membrane-bound C5b,6,7 complex
    • C9 binds to the membrane-bound C5b,6,7,8 complex
  • lyses (disrupts) enveloped viruses and Gram-negative bacteria
• negative regulation is mediated by a number of components, the most important of which is factor I, also known as C3b inactivator (C3b Ina)
  • factor H binds to neuraminic (sialic) acid residues on cell surface polysaccharides, then substitutes itself for factor Bb in C3b,Bb complexes
  • factor I then cleaves C3b, forming iC3b

Lectin-mediated Alternate Pathway of Complement Activation

C-Reactive Protein-mediated Alternate Pathway of Complement Activation

Antibody-mediated (Classical) Pathway of Complement Activation

• Antibody/complement-mediated lysis - complement is activated by binding to IgG or IgM antibody molecules that have bound to antigens, and causes lysis of microbes via formation of a membrane attack complex (MAC)
  • C3 convertase generation and action
    • generation
      • antibody binds to the surface of a microbe (two adjacent IgG molecules, or a single IgM molecule)
      • C1 (complement component 1 - composed of a Ca ion- stabilized complex of C1q, C1r and C1s) binds two antibody Fc regions
      • C1s is activated by C1r during this process . . . the resulting enzyme is called C1 esterase
      • C1 esterase cleaves C4 to form C4a and C4b
      • C4b binds to C1 esterase and to adjacent cell surfaces (especially membranes)
      • C2 is cleaved by C1,4b complex to form C2a and C2b
      • C2a binds the C1,4b complex, thus forming the C1,4b,2a complex
    • action
      • C1,4b,2a is the C3 convertase of this "classical" pathway of complement activation (C2a possesses the enzymatic activity)
      • cleaves C3 into C3a and C3b
        • C3a induces histamine release (mast cell and basophil degranulation) thus inducing/enhancing inflammation
        • C3b mediates opsonization and induces alternate pathway activation
  • C5 convertase generation and action
    • generation - binding of C3b molecules to C1,4b,2a (either on the microbial surface, or free in solution) generates C1,4b,2a,3b complexes
    • action - C1,4b,2a,3b cleaves C5 into C5a and C5b
      • C5a
        • induces histamine release (mast cell and basophil degranulation) thus inducing/enhancing inflammation
        • mediates phagocyte chemotaxis
      • C5b initiates formation of MAC
  • membrane attack complex (MAC) generation and action
    • generated in three steps:
      • C5b,6,7 complex, which binds to the microbial membrane via hydrophobic tails that are unfurled by C6 and C7 as a result of allosteric conformational changes that occur when C6 and C7 bind sequentially to C5b
      • C8 binds to the membrane-bound C5b,6,7 complex
      • C9 binds to the membrane-bound C5b,6,7,8 complex
    • lyses (disrupts) enveloped viruses and Gram-negative bacteria
• opsonization - antibody and complement both enhance phagocytosis by promoting binding of particles, including pathogens, to phagocytes via C3b receptors (C3bR)