Complement system

• Activation pathways
  • All three pathways converge at the generation of C3 convertase, which cleaves C3 → C3a + C3b. This is the central and most critical step.
  • Classical Pathway
    • Activated by IgM or IgG bound to antigen (antigen-antibody complexes).
    • C1 binds to the Fc portion of IgG or IgM, initiating the cascade.
    • “GM makes Classics” (IgG, IgM).
  • Alternative Pathway
    • Activated spontaneously or by microbial surfaces (e.g., bacterial endotoxin/LPS).
    • Uses Factor B/D
    • Does not require antibodies.
  • Lectin Pathway
    • Activated by mannose-binding lectin (MBL) binding to mannose residues on pathogen surfaces.
• Effect
  • Membrane attack complex (MAC)
    • Formed by C5b–C9
    • Lysis of bacteria (especially gram‑negative bacteria) by perforation of the cell wall
  • Opsonization
    • Increases the susceptibility of target particles (e.g., bacteria) to phagocytosis
    • Attachment of opsonins (e.g., immunoglobulins) causes structural changes that facilitate interaction with immune cells.
    • C3b and IgG are the two main opsonins for bacteria
    • C3b is also involved in eliminating immune complexes.
      • Deficiency of C3b will increase risk of SLE
      • C3 is decreased in PSGN, DPGN
  • Anaphylaxis: activation of mast cells and granulocytes via C3a/C4a/C5a
  • Chemotaxis: attraction of neutrophils via C5a

Mnemonic

• C3b binds to bacteria.
• C3a, C4a, C5a lead to mast-cell activation and anaphylaxis.

Complement disorders

C1 esterase inhibitor deficiency

Just think it as C1 inhibitor, as it actually has nothing to do with esterase.

• Etiology
  • Autosomal dominant inheritance
  • Unregulated activation of kallikrein → ↑ bradykinin → angioedema
• Clinical features
  • Causes hereditary angioedema
    • Recurrent angioedemas provoked by triggers (e.g., trauma, surgery, infections, and drugs)
  • Not associated with itching or urticaria
    • Not involve histamine, which is released in Type I hypersensitivity reaction by mast cells
• Diagnostic findings
  • ↑ Bradykinin levels
  • Low C4 levels
  • Strong contraindication for ACE inhibitors

Complement deficiencies

• Recurrent, severe childhood infections (e.g., upper respiratory tract infections, pneumonia, meningitis) with encapsulated bacteria (e.g., N. meningitidis, H. influenzae, S. pneumoniae)