Complement

Question 1

What is Complement?

What are the functions of the Complement system?

Answer 1

• Group of small, soluble, heat-sensitive proteins that combine to activate other members of the complement family in a CASCADE - C1-9
• • Recognises and Tags the target cell
  • Initiates chemotaxis and activation of phagocytic cells, Increases vessel permeability and adhesion of inflammatory cells, Contracts SM cells (Anaphylatoxic effect), and Releases inflammatory mediators from Mast cells (degranulation)
  • Lyse microbes by forming pores in target cells, and Strengthen T and B cell responses

Question 2

CLASSICAL PATHWAY:
What substance is at the start of this pathway? What’s it formed of?

1. What causes the activation of the C1q reactive site? What does this lead to?
2. What does the C4b then do?
3. What then binds to this C4b? What does this lead to?
   → What is this new complex now called?
4. What does the C3 Convertase do?
   → What does the product then do?
   → How many times is then done? What does it form?
5. What is this new complex now called?
6. What does the C5 Convertase do?
7. What do Macrophages require to activate Phagocytosis?

Answer 2

• C1 Complex (Zymogen) with 6 reactive sites - formed of C1r-C1s and C1q

1. • C1q reactive site binds to the Fc of IgG and IgM
   • Once bound to more than one Fc region, it becomes destabilised and the C4 molecule on it is activated and cleaved into C4a (small) and C4B (large)
2. C4b covalently binds to the cell surface
3. C2 binds to C4b to become activated and cleaved into C2A (large) and C2b (small)
   → This C4b2a complex now acts as C3 CONVERTASE
4. Activates and cleaves C3 into C3a (small) C3B (large)
   → C3b covalently binds to cell surface
   → Multiple copies of C3 cleaved and bound to the cell surface to form a “shell” around the particle
5. This C4b2a3b complex now acts as C5 CONVERTASE
6. Activates and cleaves C5 into C5A (small) C5b (large)
7. C3b coating AND C5a

Question 3

LECTIN PATHWAY:
When is it activated? What is triggered by?

What do MBL and Ficolin form a complex with?

1. What do MBL and Ficolin bind to on the target cell?
   → What does this cause?
2. What do the activated MASPs do?

ALTERNATIVE PATHWAY:
What is it activated by?

Answer 3

• In the absence of antibodies, triggered by Mannose Binding Lectin (MBL) and Ficolin
• MASPs, which act like C1r-C1s in the C1 Complex

1. MBL binds to Mannose residues and Ficolin binds
   to N-acetyl glucosamine
   → Activates the MASPs
2. Activates and cleaves C4 and C2, allowing for it to follow the rest of the Classical Pathway

• Factor B, forming a C3bBb complex, which also acts as C3 Convertase
• C3b and a lack of host control factors

Question 4

Last Stages:
What occurs with the C5b formed from the pathways? What does this lead to?

What else occurs as a result of these pathways?

Answer 4

• Create a complex with other complements (C6-9), forming a pore, called the MEMBRANE ATTACK COMPLEX (MAC) - Allows for substances to enter cell, causing Lysis
• Chemotaxis, Phagocytosis, Inflammation, and Opsonisation (C3b)

Question 5

REGULATION OF COMPLEMENT ACTIVATION:
What is controlled in the complement system?
———————

Loss of Regulation:
What does a Lack of C2-4 lead to?

What causes Paroxysmal Nocturnal Haemoglobinuria (PNH)?

What is Complement dysfunction treated with?

Answer 5

• • Control of C1 complex stability
  • Control of C3 Convertase by Plasma and Host cell wall binding proteins
  • Control of the formation/assembly of the MAC
  ———————
• Lupus-like Syndrome
• Erythrocytes accumulating C3 on its surface during stress/infection
• Eculizumab