Week 8 S - Complement System Flashcards

Complement System Overview

• Discovered by:
  • Buchner (1893)
  • Bordet (1895) awarded Nobel Prize (1919)
• Key discovery: Heat-stable antibodies (Ab) kill cholera bacteria; heat-labile component needed for this action termed Complement

Structure and Components

• Complexity: Over 20 individual components of the complement system
• Inactive precursors: C1, C2, C3, etc.
• Manufactured in: The liver
• Functions: Low levels in normal serum, activated to become enzymes and effector molecules upon triggering of the Cascade Mechanism.
• Part of the Innate immune system but can also be activated by the Adaptive immune response.

Cascade Mechanism

• Enzyme-amplifying cascade principle:
  • Involves the processing of pro-enzymes into activated enzymes and their corresponding cleavage fragments (CF)
• The complement components act not only as enzymes but also as powerful biological effectors.

Pathways of Activation

• The complement system can be activated through 3 pathways:
  • Classical Pathway:
  • Initiated by antibody (Ab) binding to antigen (Ag), thus dependant on adaptive immunity.
  • Alternative Pathway:
  • Does not rely on antibodies, activated by contact with certain microbes, part of innate immunity.
  • Lectin Pathway:
  • Involves mannose-binding lectin (MBL) binding to mannose on pathogens, part of innate immunity.
• All pathways converge when complement component C3 is cleaved.

Classical Pathway Details

• C1 Component:
  • Contains subcomponents: C1r, C1s (activation), C1q (recognition).
  • Activation requires simultaneous binding of at least 2 Fc regions of antibodies to C1q globular heads.
• Main function of the classical pathway: Trigger subsequent component cleavage (e.g., C4, C2) leading towards the formation of effector molecules.

Central Event: C3 Convertase

• Cleavage of C3 is a critical event in the cascade, generating C3a and C3b:
  • C3b: Functions as an opsonin helping in phagocytosis.
  • C3a: Involved in the recruitment and activation of phagocytes and mediates inflammation.
• Additional forms the C5 convertase crucial for forming the membrane-attack complex (MAC).

Membrane-Attack Complex (MAC)

• Formed by components C5b through C9.
• Creates pores in pathogen membranes leading to osmotic lysis.

Biological Roles of Complement

1. Opsonization:
   • C3b tags microbes for phagocytosis.
2. Inflammation:
   • C3a and C5a recruit phagocytes (e.g., macrophages, neutrophils).
3. Cell Lysis:
   • C5b-C9 complex forms the MAC leading to cell destruction.
4. Degranulation:
   • C3a and C5a stimulate mast cell degranulation, releasing mediators that enhance inflammatory response.

Complement Deficiencies and Disease

• C1, C2, C4 Deficiency:
  • Recurrent infections from pyogenic bacteria (e.g., staphylococci).
• C5-C8 Deficiency:
  • Vulnerability to Neisseria infections (e.g., meningococcal disease).
• Impaired complement receptors:
  • May lead to recurrent infections due to compromised opsonization and phagocytosis.