CSIM 1.25 Complement Opsonisation and Phagocytosis

Question 1

What is complement?

Answer 1

A protective molecule of the innate immune system which also links between innate and acquired immunity

Question 2

What are the three pathways involved in the complement cascade?

What do these all result in?

Answer 2

• Classical pathway
  
  • Lectin pathway
  • Alternative pathway

The cleavage of C3 into C3a and C3b

Question 3

Describe the classical pathway. Which antibody isotypes activate this?

Answer 3

• An antibody binds to a microbe, which in turn binds to a C1 complex (IMG 66)
  
  • C1s cleaves C4 into C4a and C4b
  • C4b binds to the microbial surface, and cleaves C2 into C2a and C2b
  • C2a binds to C4b to form C4b2a
  • C4b2a cleaves C3 into C3a and C3b (acting as C3 convertase)
  • C3b binds to C4b2a to form C4b2a3b
  • C4b2a3b cleaves more C3 into C3a and C3b (and has a role in C5 activation)

IMG 62

IgG and IgM activated

Question 4

Describe the alternate pathway

Answer 4

• Spontaneous hydrolysis of C3 occurs
  
  • Hydrolysed C3 - C3(H2O) - binds to factor B
  • This complex allows factor B to be cleaved by factor D, into Ba and Bb
  • The factor Bb remains bound to C3(H2O), stabilising it into a C3(H2O)Bb complex
  • This complex acts as a C3 convertase, cleaving C3 into C3a and C3b

Question 5

Describe what happens to naked C3b protein resulting from the three pathways on the surface of cells

How does the body respond to this product when found on host cells and when found on invading cells?

Answer 5

C3b binds to the cell, and another factor B binds to this, again being cleaved into Ba and Bb, again Bb stays bound to C3b, which is still bound to the cell

Host cells
• Complement-regulatory proteins displace Bb

Pathogens
• Factor P stabilises the C3bBb complex

Question 6

What is the function of C3bBb?

Answer 6

It’s a C3 convertase - cleaves C3 into C3a and C3b

Can also form C3b(2)Bb to assist in the formation of MACs

Question 7

What happens to the massive increase in C3b resulting from the three pathways? (MAC)

Answer 7

Binds to:
• C4b2a (from the classical pathway) to form C4b2a3b
• C3bBb (from the alternative pathway) to form C3b₂Bb

C3b₂Bb and C4b2a3b act as C5 convertases:
• C5 binds to the C3b component of each
• C5 is then cleaved by Bb (C3b₂Bb) or C2a (C4b2a3b)
• C5a and C5b are released

C5b binds to C6 and C7 to form C5b67. This binds to C8 and inserts into the cell membrane of a pathogen. Ten C9 molecules bind in a ring to form a pore in the membrane

IMG 64

Question 8

So what happens to C4a, C5a and C3a?

Answer 8

These are known as the anaphylotoxins. They are freely released from the cascade to mediate local inflammatory responses (vascular changes and cell adhesion chemotaxis etc)

Question 9

What is the role of anaphylotoxins in phagocytosis?

Answer 9

We already know that the three pathways coat the bacterium in complement (C3b-containing)

This binds to CR1 on the surface of the macrophage. This binding actually does nothing.

However C5a activates macrophages to then phagocytose the bacterium via CR1 (IMG 65)

Question 10

What are the two kinds of regulators of the complement system?

Answer 10

• Soluble inhibitor molecules

* Membrane-regulatory molecules

Question 11

Which kind of regulator is the C1-inhibitor? Explain what this does

Answer 11

Soluble inhibitor molecule

C1 inhibitors dissociate C1r and C1s from the active C1 complex in the classical pathway (IMG 67)

Question 12

What is an immune complex?

Answer 12

Antigen, antibodies and complement bound together

Question 13

What can happen if immune complexes are not removed or phagocytosed?

Answer 13

They accumulate in tissues, possibly leading to inflammation and subsequent autoimmune disease (IMG 68)

Question 14

How are immune complexes removed? (not phagocytosed)

Answer 14

Binds to soluble immune complexes with CR1 receptor and carries it to the spleen for filtering

Question 15

How does complement help to link the acquired and innate immune systems?

Answer 15

By forming immune complexes, it helps to direct antigen towards APCs to enhance B CELL responses (note: antibody is already present so T cells already active)

Clearing up immune complexes helps in the formation of B memory cells

Question 16

An increase in which infections is attributable to complement deficiencies?

Answer 16

Multiple episodes of meningitis (more than one episode of a rare strain of meningitis is grounds for checking complement deficiency)

Question 17

Describe hereditary angioedema. What are the types?

Answer 17

Autosomal dominant deficiency in C1 inhibitor protein (regulatory protein deficiency). Dominant because one functional gene is insufficient.

Swelling occurs due to increased bradykinin

Type 1:
• 85%
• Mutations leading to non-poduction of C1-inh

Type 2:
• 15%
• Mutations leading to production of inactive C1-inh