Complement Cascade

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1. Pathways of Activation

There are three pathways of complement activation. All converge at C3 cleavage.

Classical Pathway

  • Triggered by antibody-antigen complexes (IgM, IgG) or C-reactive protein (CRP).
  • C1 complex = C1q + 2 C1r + 2 C1s.
  • Activation requires ≥2 Fc regions bound.
  • C1s cleaves C4 → C4a + C4b and C2 → C2a + C2b.
  • Forms C4b2a (classical C3 convertase).

Lectin Pathway

  • Triggered by mannose-binding lectin (MBL) binding sugars on pathogens.
  • MBL activates MASP-1/2 → cleave C4 and C2.
  • Produces same convertase: C4b2a.

Alternative Pathway

  • Spontaneous C3 hydrolysis → iC3.
  • iC3 binds Factor B, cleaved by Factor D → forms iC3Bb (fluid-phase C3 convertase).
  • On microbial surfaces: C3b + Factor B + Factor D → C3bBb.
  • Properdin (Factor P) stabilizes it (extends half-life from 3 → 30 minutes).

2. Convergence: C3 Convertase

All pathways produce C3 convertase, which cleaves C3:

  • C3a: Anaphylatoxin → ↑ vascular permeability, recruits neutrophils & mast cell degranulation.
  • C3b: Opsonin → recognized by CR1 on phagocytes → enhances phagocytosis.

Relative potency of anaphylatoxins: C5a > C3a > C4a.

3. C5 Convertase and the MAC

  • Classical/Lectin: C4b2a3b
  • Alternative: C3b₂Bb

These cleave C5 → C5a + C5b:

  • C5a: Strongest chemoattractant and inflammatory mediator.
  • C5b: Nucleates formation of Membrane Attack Complex (MAC, C5b–C9) → osmotic lysis of bacteria.
Deficiency in C5–C9 → recurrent Neisseria infections (classic board fact).

4. Regulation (to Prevent Host Damage)

  • C1 inhibitor (C1INH): Stops classical pathway initiation.
  • Factor H + Factor I: Inactivate C3b (prevent overactivation).
  • DAF (CD55): Accelerates decay of C3 convertase.
  • Protectin (CD59): Blocks MAC assembly.
  • S protein, Clusterin, Factor J: Block C5b67 membrane insertion.
Regulation ensures self-tissue is spared while pathogens are targeted.

5. Clinical Correlations (Must-Know for Exams)

  • C3 deficiency: Severe recurrent pyogenic infections, especially with encapsulated bacteria.
  • C5–C9 deficiency: Neisseria infections.
  • C1 esterase inhibitor deficiency: Hereditary angioedema (↑ bradykinin).
  • DAF (CD55) or CD59 deficiency: Paroxysmal Nocturnal Hemoglobinuria (PNH).

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