Complement system

Background

• A response of the innate immune system
  • A series of >20 proteins that circulate in the blood, usually inactive but in response to inflammation or immune response, activate in an enzyme cascade which promotes chemotaxis of inflammatory cells, triggers the lytic pathway to break down foreign bodies, causes opsonisation of foreign cells, as well as cause the release/activation of further inflammatory mediators

Mechanisms/Pathways

• There are several ways in which the complement system can be activated
• Classical Pathway
  • Activated by immobilised antigens (antigen-antibody complexes- most effectively by IgM complexes) i.e. antibody dependent
  • Binds to C1q component of the complement system.  This then activates C1r and C1s.
    • This cleaves C4 and then C2 into C4b and C2a (respectively), which form a new enzyme C3 convertase.
    • This cleaves C3 into C3a and C3b.  C3 convertase combines with C3b to form C5 convertase (or C4b2a3b).
    • This cleaves C5 into C5a and C5b.  C5b is the first protein of the membrane attack complex.
• Lectin Pathway
  • Identical to classical pathway except begins with mannose binding protein instead of C1.
  • Mannose binding protein binds to carbohydrates on the cell surface of foreign cells.  Once bound, it can cleave C4 and C2.
• Alternative Pathway
  • 2 mechanisms for alternative pathway activation: Non-self cell absent and non-self cell present
  • Non-self cell absent (fluid phase activation)
    • Occurs continuously, spontaneously and slowly.
    • C3 spontaneous activates by hydrolysis into C3(H20).  This is unstable and usually reverts back to C3.  But on encounter with Factor B, interaction occurs to form C3(H2O)B.
      • This can be cleaved by Factor D into C3(H20)Bb- or fluid phase C3 convertase.  This cleaves C3 and the pathway is completed as in the classical pathway.
  • Non-self cell present
    • Much faster.
    • C3 binds to the non-self cell, which then interacts with Factor B … etc
    • C3 often smothers the cell surface, targeting it for macrocytosis by macrophages and granulocytes with C3b receptors.

Membrane Attack Complex

• C5b binds to C6, C7 and C8, as well as several molecules of C9 to form MAC
• It forms a pore in the lipid bilayer of foreign cell, causing water to rush in the cell and burst (cell lysis).

Other functions of the complement system

• Cell lysis is only effective against cells without cell walls e.g. Gram-negative organisms.  It is not active against cells with cell walls (gram-positive organisms/fungi)
• Other functions include
  • Opsonisation
    • Preparation of cells for phagocytosis (primarily via binding of C3b- which can interact with macrophages and polymorphic neutrophils
  • Inflammation
    • C3a, C4a and C5a are also anaphylotoxins and cause inflammation by binding to mast cells as well as inducing the production of pro-inflammatory cytokines.
    • C5a is also involved in chemotaxis, or attraction of lymphocytes/macrophages to the site of inflammation.
  • Immune clearance
    • C3b also binds to red blood cells and facilitates removal of non-self cells from the blood stream as it passes through the spleen and liver

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