Complement

Question 1

Outline the activation of the Classical complement pathway

Answer 1

Binding of C1q to complexed IgG or IgM results in conformational change in C1 complex

• Activation of C1r then C1s (Serine esterase)
• C1s cleaves C4 to C4b and C4a
• C4b binds to C2 and is then cleaved by C1s, generating classical pathway C3 convertase (aka C4b2a)

Question 2

-Outline the activation of the Lectin pathway of the complement system

Answer 2

• Mannose-binding lectin (MBL) binds to bacterial carbohydrate moieties (Mannose)
• The bound MBL then activates proteases called MASPs
• Cleavage of C4 and C2 then proceeds analogous to the classical pathway

Question 3

Outline the activation of the alternative pathway of the complement system

Answer 3

-C3 undergoes spontaneous hydrolysis (Auto-activation)

binds factor b and factor d and forms c3 convertase

Question 4

Outline the functions (+ regulation?) of the complement system

Answer 4

• Host defence against infection
  
  • Opsonization
  • Chemotaxis and leucocyte activation
  • Lysis of bacteria cells
• Interface between innate and adaptive immunity
• Disposal of waste: Clearance of immune complexes and apoptotic cells
• Regulation: C1 inhibitors, Factor I, CD59

Question 5

-Describe the links between uncontrolled complement activation and haematological disease

Answer 5

• Haemolytic uraemic syndrome (HUS): results from fluid phase dysregulation - factor H is a fluid molecule
• Paroxysmal nocturnal haemoglobinuria (PNH): results from membrane-bound dysregulation
• Coomb’s test is a measure of complement activation

Question 6

How is function of complement regulated?

Answer 6

• Factor H and factor I are brought into contact by sialic acid and this form ic3a which is inactive. Bacteria do not have sialic acid so is not able to inactivate c3a
• Membrane bound proteins such as MCP and CD59 all inhibit the terminal pathway
• Intrinsic “instability” of convertase complexes can also prevent damage to own cells and complement depletion