CMB1003/L20 Complement System

Question 1

Describe the complement system. (3)

Answer 1

Protection in early infections
Major effector system of humoral branch of innate and adaptive immune system
Group of nearly 30 serum and membrane proteins

Question 2

What is the goal of the complement system? (3)

Answer 2

Inflammation
Phagocytosis
Membrane attack to kill pathogen

Question 3

Give 3 roles of the complement system.

Answer 3

Opsonisation
Inflammatory response
Activation of B cells
Generation of membrane attack complex (MAC)

Question 4

Describe the classical pathway of complement activation. (2)

Answer 4

Antibody binds to specific antigen on pathogen surface
Initiated by antigen:antibody complexes

Question 5

Describe the lectin pathway of complement activation. (2)

Answer 5

Mannose-binding protein binds to pathogen surface
Triggered by some pathogen surfaces

Question 6

Describe the alternative pathway of complement activation. (2)

Answer 6

Pathogen surface creates local environment conductive to complement activation
Initiated by acute phase proteins that bind glycoproteins or carbohydrates on micro-organisms

Question 7

What is the nomenclature of components of the classical pathway? (2)

Answer 7

C followed by a number
Products of cleavage reaction have lower case letter added

Question 8

What is the nomenclature of components of the alternative pathway?

Answer 8

Different upper case letters than C

Question 9

What is the difference between C5a and C5b?

Answer 9

C5a is smaller
C5b is larger

Question 10

What is the first component of the classical pathway? (3)

Answer 10

C1
Complex of C1q, C1r & C1s
2 molecules of C1r and C1s bind to each C1q

Question 11

Describe how IgM molecules trigger the classical pathway. (3)

Answer 11

Pentameric IgM molecules bind to antigens on bacterial surface and adopt staple form
C1q binds to a single IgM molecule
Binding of C1q to immunoglobulin activates C1r which cleaves and activates the serine protease C1s

Question 12

Describe how IgG molecules activate the classical pathway. (3)

Answer 12

IgG molecules bind to antigens on bacterial surface
C1q binds to at least 2 IgG molecules
Binding of C1q to immunoglobulin activates C1r which cleaves and activates the serine protease C1s

Question 13

Describe the structure of the C1q molecule.

Answer 13

Six globular heads joined to common stem
Each globular head can bind to one Fc domain on antibody

Question 14

How many globular heads of C1q must bind to Fc domain for activation of C1q?

Answer 14

2

Question 15

What does binding of a single IgM or 2 IgG molecules trigger? (3)

Answer 15

Conformational change in C1q
Reveals proteolytic site on C1r
C1r cleaves C1s to generate serine protease enzyme C1s

Question 16

What is the role of the active C1s in the classical pathway? (4)

Answer 16

C1s cleaves C4 to C4a & C4b
C4b binds covalently to pathogen surface
C2 binds to C4b on antigen/pathogen surface
C2 is cleaved by adjacent C1s leaving C4b2a complex (C3 convertase)

Question 17

What is the role of C3 convertase?

Answer 17

Cleave large numbers of C3 molecules to C3a & C3b

Question 18

What is the main effect of the classical pathway? (3)

Answer 18

Lots of C3b on pathogen surface
Opsonisation of pathogens
Phagocytosis of pathogens

Question 19

What does C3b do? (2)

Answer 19

Acts as an opsonin
With antibody, facilitates recognition by phagocytes

Question 20

What bond on C3b is exposed after cleavage and why is this useful?

Answer 20

Thioester bond
Allows C3b to bind covalently to pathogen surface
Becomes inactive quickly via hydrolysis if not bound

Question 21

Describe what occurs after the formation of C4b2a3b in the classical pathway. (5)

Answer 21

C5 binds to C4b2a3b (C5 convertase)
C5 -> C5a & C5b
C5b binds to pathogen surface and binds C6 -> C5bC6
C5bC6 binds C7 -> C5bC6C7
Conformational change - C7 inserts into lipid bilayer of pathogen wall

Question 22

What is the role of the membrane attack complex (MAC)? (4)

Answer 22

Displaces cell membrane phospholipids
Channel
Disruption of membrane
Cel lysis/death

Question 23

What is the C3 convertase of the classical pathway?

Answer 23

C4b2a

Question 24

What is the C5 convertase of the classical pathway?

Answer 24

C4b2a3b

Question 25

Describe the alternative pathway cascade. (5)

Answer 25

Different C3 convertase
C3 undergoes spontaneous hydrolysis
C3b binds to surface
Factor B binds C3b
Cleaved by factor D -> C3bBb

Question 26

What stabilises C3 convertase in the alternative pathway?

Answer 26

Factor P/ properdin

Question 27

What is the C3 convertase in the alternative pathway?

Answer 27

C3bBb

Question 28

Describe the role of C3bBb in the alternative pathway. (4)

Answer 28

Add another C3b
-> C3b2Bb = C5 convertase
C5 -> C5a & C5b
C5bC6C7C8C9 = MAC

Question 29

What is the role of the lectin pathway? (2)

Answer 29

Recognise microbial surfaces
Activate complement cascade

Question 30

What does the lectin pathway use?

Answer 30

Soluble receptors (acute phase proteins)

Question 31

Describe the cascade of events in the lectin pathway. (4)

Answer 31

Activated MASP-2 associated with MBL or ficolin cleaves C4 to C4a & C4b, which binds to microbial surface
C4b binds C2, which is cleaved by MASP-2 to C2a and C2b forming C4b2a complex
C4b2a (C3 convertase) cleaves C3 to C3a and C3b, which binds microbial surface or convertase itself
One molecule of C4b2a can cleave up to 1000 molecules of C3 to C3b

Question 32

What is the C3 and C5 convertase of the lectin pathway?

Answer 32

C3 - C4b2a
C5 - C4b2a3b

Question 33

What is the consequence of C3 deficiency? (2)

Answer 33

Opsonisation, inflammation and cytolysis affected
Life-threatening infections with range of bacteria

Question 34

What is the consequence of C6-9 deficiency? (2)

Answer 34

Cytolysis affected
May have problems with infection of Neisseria