Complement activation pathways are crucial defense mechanisms in our immune system. They trigger a cascade of protein interactions that help eliminate pathogens and promote inflammation. The three main pathways - classical, alternative, and lectin - each have unique activation triggers but converge on C3 convertase formation.

C3 convertase is the key player in amplifying the complement cascade. It cleaves C3 into C3a and C3b, leading to opsonization and formation of the membrane attack complex. Regulation of complement activation is essential to prevent damage to host cells and maintain immune homeostasis.

Complement Activation Pathways

Complement activation pathways

• Classical pathway triggers antibody-dependent activation initiated by antigen-antibody complexes on pathogen surfaces (IgG and IgM)
• Alternative pathway enables antibody-independent activation spontaneously activating on microbial surfaces (bacterial cell walls)
• Lectin pathway activates when mannose-binding lectin (MBL) recognizes carbohydrate patterns on pathogens (bacterial capsules)

Steps in complement activation

• Classical pathway:
  1. C1 complex (C1q, C1r, C1s) binds to antibody-antigen complexes
  2. C4 and C2 cleavage forms C3 convertase (C4b2a)
• Alternative pathway:
  1. Spontaneous hydrolysis of C3 to C3(H2O)
  2. Factor B binds C3(H2O), cleaved by Factor D
  3. Forms C3 convertase (C3bBb)
• Lectin pathway:
  1. MBL binds to pathogen carbohydrates (mannose residues)
  2. MBL-associated serine proteases (MASPs) activate
  3. C4 and C2 cleavage forms C3 convertase (C4b2a)

Role of C3 convertase

• C3 convertase cleaves C3 into C3a and C3b amplifying complement cascade
• C3b functions include opsonization of pathogens enhancing phagocytosis and formation of more C3 convertase
• Amplification loop creates exponential increase in complement activation:
  1. C3b joins C3 convertase to form C5 convertase
  2. C5 convertase cleaves C5, initiating membrane attack complex (MAC) formation
• Process results in rapid pathogen elimination and inflammation

Regulation of complement activation

• Membrane-bound regulators prevent excessive activation on host cells:
  • Decay-accelerating factor (DAF) accelerates C3 convertase decay
  • Membrane cofactor protein (MCP) acts as cofactor for Factor I
  • Complement receptor 1 (CR1) facilitates C3b/C4b degradation
• Fluid-phase regulators control activation in plasma:
  • Factor H inhibits alternative pathway C3 convertase
  • C4-binding protein regulates classical and lectin pathways
• Enzymatic inactivation by Factor I cleaves C3b and C4b limiting their activity
• Natural decay of C3 convertase occurs spontaneously
• Host cell protection mechanisms like CD59 prevent MAC formation on healthy cells