Complement Activation Initiation: All Roads Lead to C3 Convertase

Three Initiation Pathways

The complement system can be activated through three initiation pathways: the classical pathway, the lectin pathway, and the alternative pathway. These pathways have distinct triggers but converge at the formation of a C3 convertase complex, a central component in the complement cascade.

1. Classical Pathway:
   • Initiation Trigger: Recognition of antigen-antibody complexes.
   • Key Components:
     • C1 complex (C1q, C1r, C1s): Recognizes and binds to antigen-antibody complexes.
     • C4 and C2: Form the classical C3 convertase (C4b2a) after activation.
2. Lectin Pathway:
   • Initiation Trigger: Recognition of pathogen-associated molecular patterns (PAMPs) by mannose-binding lectin (MBL) or ficolins.
   • Key Components:
     • MBL or ficolins: Bind to carbohydrates on the pathogen surface.
     • MBL-associated serine proteases (MASPs): Activate C4 and C2 to form the lectin C3 convertase (C4b2a).
3. Alternative Pathway:
   • Initiation Trigger: Spontaneous hydrolysis of C3 and the presence of foreign surfaces.
   • Key Components:
     • Factor B: Binds to C3b and is cleaved by Factor D to form the alternative C3 convertase (C3bBb).
     • Properdin (Factor P): Stabilizes the alternative C3 convertase.

Convergence at C3 Convertase Formation

• In all three pathways, the common endpoint is the activation of C3, a central component of the complement system.
• The activated C3 molecule undergoes proteolytic cleavage to form two fragments: C3a and C3b.
• C3b can bind covalently to the surface of pathogens or cells, marking them for destruction.

Components of C3 Convertase for Each Pathway

• Classical C3 Convertase (C4b2a):
  • Formed by the sequential activation of C4 and C2 by the C1 complex.
• Lectin C3 Convertase (C4b2a):
  • Formed by the activation of C4 and C2 by MASP proteases associated with MBL or ficolins.
• Alternative C3 Convertase (C3bBb):
  • Formed by the spontaneous hydrolysis of C3, leading to the binding of Factor B to C3b, followed by cleavage by Factor D.

Once C3 convertase is formed, it plays a pivotal role in the amplification of the complement cascade, leading to the activation of downstream components and ultimately the formation of the membrane attack complex (MAC) for pathogen lysis and elimination.

Next Topic: Three Functions for C3 Cleavage Products

Source: ChatGPT response prompted and edited by Joel Graff.

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