Medicine & USMLE

Classical Complement Pathway

  1. Common Complement Pathway
  2. Classical Complement Pathway
  3. Alternative Complement Pathway
  4. Lectin Complement Pathway


The Classical Complement Pathway is one of three initiating pathways of the complement system. Specifically, the classical pathway requires antibodies like IgM or IgG to be bound to the target. C1 recognizes this bound antibody, and fixes (binds) to the hinge region in the Fc portion. Activated C1 then cleaves C2 and C4, causing them to activate in turn. Finally, active C2 and C4 combine to form C3 convertase, the final step in the Classical Complement Pathway, and the starting point of the Common Complement Pathway.

Key Points

  • Classical Complement Activation
    • One of three initiating pathways of complement
    • End goal is to kill cells with bound antibody
    • Requires bound Immunoglobulin G (IgG) or Immunoglobulin M (IgM) on surface
      • C1 binds near hinge portion within Fc region of antibody
        • Actually formed by complex of C1q, C1r, and C1s
        • Regulated/Inhibited by C1 esterase inhibitor
          • Defective in hereditary angioedema or with ACE inhibitors
      • Activated C1 cleaves C4 and C2
        • Cleavage of C4 produces C4a and C4b
        • Cleavage of C2 forms C2a and C2b
      • Cleaved C4 and C2 combine to form C3 Convertase (C4bC2b)