The complement system

Question 1

Describe the structure and function of the complement system

Answer 1

• it is made up of 30 proteins which are synthesised in the liver as inactive zymogens
• the activated proteins are proteases
• the complement system drives the inflammatory response

Question 2

Describe how proteins of the complement system are named

Answer 2

• they are named in order of discovery and not activation :
  C1, C4, C2, C3, C5, C6, C7, C8, C9
• cleavage products are designated a or b
• a is the smaller fragment and b is the larger fragment but C2 is the exception

Question 3

What are the 3 pathways of the complement system ?

Answer 3

• classical pathway activated by antibodies
• alternative pathway activated by foreign surfaces
• lectin pathway activated by bacterial sugars

Question 4

Describe the classical pathway

Answer 4

1) The classical pathway is driven by antibodies
Antibodies recognise antigens on bacteria
Complement system is activated by lgG or lgM
2) Antibodies in the surface of bacteria cross link C1q
3) C1q binds two molecules of C1r and C1q
C1r and C1s are serine proteases
4) Active C1 complex leaves C4
C4a is released
C4b remains bound to the C1 complex
5) C2 is subsequently recruited and cleaved into C2a and C2b
C2b is released and C2a remains bound
6) C4b2a is known as the classical pathway C3 convertase
C3 is the central molecule of the complement system
C3 convertase cleaves C3 into C3a and C3b
7) C3a is an anaphylatoxin
C3b is an opsonin
8) C3 convertase cleaves multiple C3 molecules
C3b coats the bacteria
9) C4b2a3b is also an active enzyme known as C5 convertase
C5 convertase cleaves C5 into C5a and C5b
10) C5a is a chemoattractant particularly for neutrophils
11) C5b is able to bind to C6 which recruits C7 and C8 and binds to the bacterial surface
12) C5b678 recruits multiple C9 proteins
C9 polymerises forming a pore in the bacteria
13) C5b6789 is known as the membrane attack complex - MAC
14) The presence of multiple MAC disrupts the osmotic balance of the bacteria causing it to rupture

Question 5

Describe the lectin pathway

Answer 5

It is similar to the classical pathway but it involves different proteins

Question 6

Describe the alternative pathway

Answer 6

1) C3 is constantly hydrolysed in fluid phase to form C3(H2O) releasing C3a
2) C3(H2O) interacts with factor B
3) Factor B is cleaved to produce Ba and Bb
C3(H2O)Bb is the fluid phase C3 convertase it is able to cleave more C3
4) If this happens near a surface the C3b is able to bind via amine or ester linkages
5) Surface bound C3b can bind to factor B
6) Factor B is cleaved to Ba and Bb
7) C3bBb is the alternative pathway C3 convertase and binds another molecule of C3
8) During activation over 2 million molecules of C3b can be deposited in 5 minutes
9) The C3 molecule is cleaved to release C3a
C3bBbC3b is another active enzyme capable of cleaving C5
It is therefore known as the alternative pathway C5 convertase
10) The last part of the alternative pathway is identical to the classical and lectin pathways

Question 7

Why is the complement system a balancing act ?

Answer 7

• it needs to be regulated enough to not damage host cells
• it needs to be activated to respond to invading pathogens

Question 8

Give some examples of regulatory proteins

Answer 8

• MCP
• DAF
• factor H
• protectin
• C1 inhibitor