Complement cascade

Category: immune_innate

Overview

Plasma protease cascade with three activation arms converging on C3 cleavage → C5 cleavage → MAC (C5b-9 membrane attack complex). Classical: C1q recognizes antibody-antigen → C1r/s → C4 + C2 → C3 convertase. Alternative: spontaneous C3 tickover, accelerated by surfaces lacking host regulators (DAF, MCP, FH). Lectin: MBL recognizes microbial mannose → MASP → same C4/C2 cleavage. PNH (paroxysmal nocturnal hemoglobinuria) lacks GPI-anchored DAF + CD59 on RBCs → uncontrolled alternative-pathway complement activation → intravascular hemolysis. ECULIZUMAB (anti-C5) prevents C5 cleavage → no MAC formation → PNH + atypical HUS treatment. RAVULIZUMAB is longer-half-life eculizumab analog. Iptacopan is a newer oral factor B inhibitor (alternative pathway).

Organ Systems

Pathway Steps

  1. pattern-recognition → c3-convertase — via classical (C1q → C4 + C2) or alternative (C3b tickover) or lectin (MBL → MASP) arms converge. Complement activation converges on forming a C3 convertase, triggered by three routes: the classical pathway (antibody-antigen via C1q), the lectin pathway (MBL/ficolins recognizing microbial sugars), and the alternative pathway (spontaneous C3 tick-over amplified on unprotected surfaces). Pattern recognition thus funnels diverse triggers into one cascade.
  2. c3-convertase → c3a-c3b — via C3 cleavage — central amplification step. The C3 convertase cleaves C3 into C3a and C3b — the central amplification step of the system. C3a is an anaphylatoxin (inflammation, mast-cell activation), while C3b opsonizes the target for phagocytosis and seeds more convertase (positive feedback) — which is why C3 is the cascade’s hub.
  3. c3b → c5-convertase — via C3b joins C3 convertase → C5 convertase. Deposited C3b joins the convertase to form the C5 convertase, shifting the cascade from amplification to terminal activation. This step couples opsonization to the membrane-attack phase and is a key regulatory checkpoint — the target of anti-C5 therapy (eculizumab) in PNH and aHUS.
  4. c5-convertase → mac-c5b-9 — via C5 cleavage → C5b + C6-C9 = MAC; cell lysis — ECULIZUMAB BLOCKS C5. C5 convertase cleaves C5; C5a is a potent anaphylatoxin/chemoattractant, and C5b nucleates assembly of C6-C9 into the membrane attack complex (MAC, C5b-9). The MAC punches lytic pores in target membranes — killing gram-negative bacteria, and when dysregulated, damaging host cells.

References