The complement system

Question 1

What are the 3 different activation pathways

Answer 1

classical pathway
alternative pathway
lectin pathway

Question 2

How is the classical pathway activated

Answer 2

Requires the Ag:Ig complex for initiation (Igs are potent activators of complement; IgG and IgM

Question 3

How is the alternative pathway activated

Answer 3

Antibody independent; pathogen surface provides a biochemical environment which is conductive with the complement initiation

Question 4

how is the lectin pathway activated

Answer 4

Mannose binding lectin binds to pathogen surface promotes
initiation process

Question 5

Characteristics of the classical pathway

Answer 5

Involves antibody binding to a specific epitope on antigen surface

Orderly activation of 9 major protein components (C1-C9)

Question 6

What does C1 do

Answer 6

is the first complement to be activated

Activation requires the binding of C1q to C1q specific receptors on the Fc regions of the Ig (at least 2 IgG cross-linking or at least 2 regions on IgM)

Conformational changes in C1q activates C1r/C1s

Question 7

What activates C1q

Answer 7

Ig activates C1q – at least 2 interaction points required

Question 8

What agents do not activate C1q

Answer 8

Hapten or monovalent antigens

Some Ig’s – IgA and IgE (they lack C1q specific receptors)

IgG4 also lacks the C1q receptor – it is the only IgG that does not activate C1q

Question 9

What does C1 activate next

Answer 9

C4

Question 10

Where is C4 synthesised

Answer 10

is synthesised by the liver and macrophages upon activation

Question 11

What are the characteristics of C4

Answer 11

C4a and C4b (which is larger) - splits into 2 parts

C4b binds to pathogen cell membrane next to the Ab-Ag complex and attaches to the component C2

Question 12

What does C4 activate next

Answer 12

C2

Question 13

What happens to C2

Answer 13

Cleaved by the action of C1s and C4b

Question 14

What happens to 2a

Answer 14

remains associated with C4b which leaves C4b2a (an enzyme otherwise known as C3/5 convertase)

Question 15

What does C2 activate

Answer 15

C3

Question 16

What is C3

Answer 16

a beta globulin (180kDa) and is secreted by the liver and macrophages as pro-C3

Question 17

What happens to pro-C3

Answer 17

Pro-C3 is activated by C3 convertase via cleavage

C3a is a smaller fragment (remains in the serum) and C3b is the larger fragment which attaches to the pathogen cell membrane

Question 18

What does C3b do and how is it formed

Answer 18

Formed by C3 convertase in a cleavage reaction and can act as C5 convertase

Initiates the formation of the membrane attack complex – assembly and activation of components C5-C9

Question 19

What does C3b lead to the activation of

Answer 19

Activation of C5,C6 and C7

this is an orderly activation

Question 20

What does the activation of C5,C6 and C7 lead to

Answer 20

This forms the C5b67 complex which associates with cell membranes and focuses the actions of C8 and C9

Question 21

What does the activation of C8 lead to

Answer 21

C5b678 complex interacts with the cell membrane causing small pores to open up leading to lysis

Question 22

What does C5b678 complex do

Answer 22

directs C9 function – this causes polymerisation of C9 and the formation of a perforin-like molecule around C5b678 – this forms a transmembrane protein which disrupts the osmotic potential of the cell leading to lysis

Question 23

summarise the classical pathway

Answer 23

C1>C4>C2>C3>C5>C6>C7>C8>C9

Question 24

What are key events of the classical pathway

Answer 24

IgG / IgM required for C1 cross-linking at least 2 points

C4b2a = C3/5 convertase

Upon C3 cleavage, the whole cascade will follow

C5b678 initiates the membrane attack complex (MAC)

C9 polymerisation triggers cell lysis

Question 25

How does the alternative pathway differ to the classical pathway

Answer 25

C1, C4 and C2 do not need to be activated Activation of C3 is central for the activation of membrane attack complexes as C3b is C5 convertase - this allows the cascade to follow

Question 26

How is the alternative pathway activated

Answer 26

Many initiators of this pathway – it does not require the antibody/antigen complex and C1 activation How is complement activated without antibodies Mechanism of spontaneous C3 cleavage and C3b binding to pathogen Mechanism involves factor B

Question 27

What are anaphlatoxins

Answer 27

An anaphlatoxin is a substance that induces mast cell / basophil degranulation – histamine release

Question 28

What do anaphlatoxins do in the complement system

Answer 28

C3a, C4a, and C5a, are small peptides released during complement activation that trigger inflammation and contribute to the complement system's inflammatory effects induces mast cells/basophils degranulation – histamine release

Question 29

What is a major property of C5a

Answer 29

Attracts phagocytic cells from the area of lesser concentration (of C5a) to an area of higher concentration (of C5a) C5a has a potent effect on neutrophils which express C5aR

Question 30

What is a major property of C3b

Answer 30

Occurs when a particular Ag coated with Ab in the prescence eof complement, mediates adherence to various surfaces (like blood vessels) - it immobilises the pathogen and allows it to be an easy target to phagocytes

Question 31

What does opsonisation do

Answer 31

improves the likelihood of phagocytosis occurring

Question 32

How is the lectin pathway activated

Answer 32

when mannose-binding lectin (MBL) or ficolins recognize and bind to carbohydrate structures on the surface of pathogens

Question 33

What is MASP-2 and what does it share homology with

Answer 33

Mannose-binding protein-associated Serine Protease-2 has homology to C1 and similar biological activity

Question 34

What is a crucial difference between MASP-2 and C1

Answer 34

MASP-2 doesn’t bind Cq specific receptors on FC (thus is does not require Ag : Ag complex for activation)

Question 35

What does MASP-2 bind to

Answer 35

mannose patterns on pathogen surface leading to activation