18 - complement

Question 1

what is the complement system?

Answer 1

an enzyme cascade

protection in early infections

leads to antigen clearance and inflammatory response

Question 2

roles of the complement system?

Answer 2

some activated proteins bind covalently to bacteria opsonising them

some small fragments recruit phagocytes to the site

some products activate B cells

terminal component of the system generates membrane attack complex (MAC)

Question 3

what does the membrane attack complex (MAC) do?

Answer 3

leads to lysis of pathogen

puts holes and pouches in the pathogen so that it bursts and is destroyed

Question 4

what are the 3 pathways that activate the initiation of the cascade?

Answer 4

the classical pathway

the lectin pathway

the alternative pathway

Question 5

how is the classical pathway activated?

Answer 5

by antigen-antibody complexes

Question 6

how is the alternative pathway activated?

Answer 6

triggered by some pathogen surfaces

Question 7

how is the lectin pathway activated?

Answer 7

by acute phase proteins that bind glycoproteins or carbohydrates on microorganisms

Question 8

what enzyme do all 3 pathways generate?

Answer 8

C3 convertase

Question 9

what is C3 convertase and what does it do?

Answer 9

a potent enzyme that is made of components of the complement system

enzymes converts C3 into its 2 components: C3a and C3b
• C3a is good for inflammation
• C3b is good at opsonising antigens

Question 10

complement proteins in the classical pathway

Answer 10

C1q, C1r, C1s, C2, C3, C4

Question 11

complement proteins in the alternative pathway

Answer 11

C3, factor D, factor B, properdin (factor P)

Question 12

terminal components in complement

Answer 12

C5, C6, C7, C8, C9

Question 13

what is the first step in the classical pathway?

Answer 13

the activation of C1

Question 14

what are the 5 components of C1?

Answer 14

2 molecules of C1r and 2 molecules of C1s bind to each C1q

Question 15

what is C1q attached to?

Answer 15

globules which bind to antibodies

Question 16

what are the 5 classes of antibodies?

Answer 16

Ig : M, A, D, G, E

Question 17

how does IgM go around?

Answer 17

in 5s - a pentamer

they bind to antigens on bacterial surface and adopt ‘staple’ form

C1q binds to a single IgM molecule to activate complement

Question 18

how does IgG go around?

Answer 18

individually - monomers

bind to antigens on the bacterial surface

C1q binds atleast 2 of these in order to activate complement

Question 19

what does the binding of C1q to either IgM or IgG lead to?

Answer 19

leads to a conformational change in C1q which reveals a proteolytic site on the C1r

C1r can noe cleave C1s to generate a serine protease enzyme C1s

Question 20

what does C1s do?

Answer 20

C1s cleaves C4 to C4a and C4b

C4b binds covalently to the pathogen surface

C2 then binds to C4b on the pathogen surface

C2 is cleaved by C1s leaving the C4b2a complex

C2 is cleaved into C2a (bigger) and C2b (smaller)

Question 21

what is the C4b2a complex also called?

Answer 21

C3 convertase

Question 22

what does C3b do?

Answer 22

has a reactive thioester bond which is exposed after cleavage allowing it to bind covalently to the pathogens surface

if it doesn’t bind almost immediately it is rapidly hydrolysed by water and becomes inactive

Question 23

what happens after C3 convertase has been cleaved?

Answer 23

C3b joins C4b2a complex to form C4b2a3b (C5 convertase)

C5 binds to the C4b2a3b complex and cleaves into C5a and C5b

C5b binds to pathogen surface and binds C6 to make C5bC6

C5bC6 binds C7 to make C5b67

Question 24

what happens after C5b67 has been formed?

Answer 24

leads to a conformational change and C7 inserts itself into the lipid bilayer of the pathogen wall

C5b67 then binds to C8

Question 25

what is C8 made up of?

Answer 25

C8 beta

C8 alpha-gamma

Question 26

what does C8 beta do?

Answer 26

binds to C5b

this allows binding of C8 alpha-gamma

Question 27

what does C8 alpha-gamma do?

Answer 27

inserts in the lipid bilayer

induces polymerisation of 10-16 molecules of C9 forming a ring structure

this is C5b6789

Question 28

what is C5b6789 also known as?

Answer 28

MAC

Question 29

what are the inflammatory mediators of the classical pathway?

Answer 29

C3a, C4a and C5a

Question 30

how is the alternative pathway different?

Answer 30

different C3 convertase:
• C3 undergoes spontaneous hydrolysis 
• C3b binds to surface (thioester bond)
• factor B binds C3b 
• cleaved by factor D to Ba and Bb
• C3 convertase composed of C3b factor Bb - C3bBb
• factor P stabilises the C3 convertase

Question 31

what is the C3 composed of in the alternative pathway?

Answer 31

C3b and factor Bb

= C3bBb

Question 32

what does factor P do in the alternative pathway?

Answer 32

stabilises the C3 convertase

Question 33

how do we get C5 convertase in the alternative pathway?

Answer 33

add another C3b to the C3 convertase

C3b2Bb = C5 convertase

Question 34

the lectin pathway

Answer 34

uses soluble receptors (acute phase proteins) made by the liver

recognises microbial surfaces

activates complement cascade

get complexes of mannose binding lectin and MBL-associated serine proteases - needed to activate the pathway

Question 35

what MBL-associated serine proteases activate the pathway?

Answer 35

MASP-1 and MASP-2

Question 36

what does MASP-2 do?

Answer 36

cleaves C4 followed by C2 to create a C3 convertase (C4b2a complex)

this is the same as the C3 convertase in the classical pathway but is produced used MASP-2 instead of C1