Complement System in Innate Immunity

Overview

• The complement system is a key component of the innate immune response.
• It plays a crucial role in killing and clearing invading pathogens like bacteria, viruses, fungi, and parasites.
• Composed of over 30 proteins:
  • Most are found in serum.
  • Some are membrane-bound proteins and receptors.

Activation of Complement

• Activation occurs via enzymatic cascades generating proteolytic fragments with biological functions.

Classical Pathway

• Activation Mechanism:
  • Typically activated by antigen-antibody complexes.
  • Requires IgM (1 molecule) or IgG (minimum of 2 molecules in close proximity).
• Key Components:
  • C1 (first protein): composed of C1q, C1r, C1s.
  • C1 binds to the FC portion of antibodies, initiating a conformational change and activating serine proteases C1r and C1s.
• C4 Cleavage:
  • Activated C1 cleaves C4 into C4a (small) and C4b (larger).
  • C4b binds to the antigen-antibody complex and provides a binding site for C2.
• Formation of C3 Convertase:
  • C2 is cleaved into C2a and C2b.
  • C4b and C2a form the C3 convertase (C4b2a).
• C3 Convertase Activity:
  • Cleaves C3 into C3a and C3b.
  • C3a: serves as a potent biological mediator.
  • C3b: forms C5 convertase by binding to C3 convertase, resulting in C4b2a3b.
• C5 Convertase:
  • Cleaves C5 into C5a and C5b.
  • C3a and C5a act as chemoattractants:
    • C3a attracts mast cells; induces degranulation.
    • C5a attracts macrophages and neutrophils; primes them for defense functions.

Terminal Complement Pathway

• Membrane Attack Complex (MAC):
  • Formed through terminal complement pathway starting from C5b.
  • C5b associates with C6, C7, C8, resulting in membrane disruption.
  • C9 binds to form a pore that allows lysis of pathogens.

Alternative Pathway

• Activation:
  • Triggered by lipopolysaccharides (LPS) on pathogen surfaces.
  • Active at low levels due to spontaneous hydrolysis of C3 (C3 water).
• Initial Steps:
  • C3 water binds factor B; factor D cleaves B into BA and BB.
  • BB forms the alternative pathway C3 initiation convertase with C3 water.
• C3 Convertase Formation:
  • Cleaves C3 into C3a and C3b.
  • C3b binds to activating surfaces, amplifying the response.
• C5 Convertase Formation:
  • C3b and BB form the C5 convertase of the alternative pathway.
  • Similar functions as classical pathway; C3a and C5a act as chemoattractants.

Summary

• The complement system is vital for innate immunity, facilitating pathogen clearance through various pathways (classical and alternative).
• Key functions include opsonization, chemotaxis, and the formation of the membrane attack complex leading to pathogen lysis.