18 - The Complement System

Question 1

The complement system provides protection…

a) throughout infection
b) early on in infection
c) during later stages of infection
d) against reccurrent infection

Answer 1

The complement system provides protection…

a) throughout infection

b) early on in infection

c) during later stages of infection
d) against reccurrent infection

Question 2

The complement system link both innate and adaptive immune responses. It is a major branch of which part of the immune system?

Answer 2

Humoral

Question 3

The complement system can be described as a…

Answer 3

A series of proteins which make up a highly regulated enzymatic cascade leading to antigen clearance and inflammatory response.

Question 4

Four main roles of complement proteins are…

Answer 4

• Opsonisation
• Recruitment of phagocytes and inflammatory regulation (fragments)
• Activation of B cells
• Generation of MAC

Question 5

The complement system may be intiated by three pathways…

Answer 5

• Classical pathway (antibody binds to antigen on pathogen surface)
• Lectin pathway (mannose-binding protein binds to pathogen surface)
• Alternate pathway (spontraneous activation due to pathogen’s presence)

Question 6

All 3 complement initiation pathways generate…

Answer 6

C3 convertase

Question 7

C3 convertase leads to (3)…

Answer 7

• Opsonisation
• Inflammatory response
• Production of MAC

Question 8

Complement system nomenclature

Classical pathway proteins are designated by the letter __

Products of clevage reactions are denoted by the addition of a ________ _________

Alternate pathway compoenets are designated by other ________ __________

Answer 8

Complement system nomenclature

Classical pathway proteins are designated by the letter C

Products of clevage reactions are denoted by the addition of a lower case letter (e.g. a/b)

Alternate pathway compoenets are designated by other captial letters (e.g. B, D)

Question 9

The addition of the a/b suffix to the protein name indicates small and large components respectively. The exception to this rule is in the case of…

Answer 9

C2, in which the ‘b’ component is infact larger

Question 10

The classical pathway involves complement proteins…

Answer 10

• C1q, C1r, C1s
• C4
• C2

Question 11

The alternate pathway involves complement proteins…

Answer 11

• Factor D
• Factor B
• Factor P (properdin)

Question 12

Both classical and alternate pathways involve the complement protein…

Answer 12

C3

Question 13

Terminal complement proteins…

Answer 13

C5, C6, C7, C8, C9 - which generate the MAC

Question 14

Classical pathway

Step 1…

Answer 14

• Antibodies bind to antigens on bacterial surface
• C1q binds to IgM molecule OR to 2+ IgG molecules
• C1q undergoes conformational change revealing C1r proteolytic site
• C1r proteolytic site cleaves C1s from the complex

C1 complex -> C1s

Question 15

Classical pathway

Step 2…

Answer 15

• Active C1s cleaves C4 forming C4a and C4b
• C4b binds covalently to pathogen surface
• C4b is bound by C2
• C1s cleaves the C2 resulting in C4b2a complex, aka C3 convertase
• C3 convertase cleaves C3 forming C3a and C3b

C3a promotes inflammation

C3b may opsonise pathogen directly or join the C3 convertase complex

Question 16

The main effect of the classical pathway is the accumulation of…

Answer 16

C3b on the pathogen surface (leading to phagocytosis by cells with complement receptors)

Question 17

Classical pathway

Step 3 (formation of MAC)…

Answer 17

• C5 binds to C4b2a3b complex (generated by the addition of C3b to C3 convertase complex in the previous step) aka C5 convertase
• C5 is cleaved to form C5a and C5b
• C5b binds to pathogen surface
• C6 binds to C5b forming C5bC6 complex
• C5bC6 complex binds C7
• Conformational change allows insertion of C7 into lipid bilayer of pathogen
• C5bC6C7 binds C8
• C5bC6C7C8 attracts C9, which forms pore in the pathogen membrane

C5bC6C7C8C9 is the complete membrane attack complex (MAC)

Question 18

How is C3 hydrolysed in the alternative pathway?

Answer 18

C3 hydrolysis is spontaneous (influenced by local environment)

Question 19

C3bBb is the C3 convertase found in which pathway?

Answer 19

Alternative

(Classical pathway C4b2a)

Question 20

In the alternative pathway C3 convertase (C3bBb) is stabilised by…

a) Factor B
b) Factor P
c) Factor F
d) Factor E

Answer 20

In the alternative pathway C3 convertase (C3bBb) is stabilised by…

a) Factor B

b) Factor P

c) Factor F
d) Factor E

Question 21

In the alternative pathway, factor B is cleaved by…

Answer 21

Factor D (forming C3bBb and Ba)

Question 22

What is the result of adding another C3b to the alternate C3 convertase (C3bBb)?

Answer 22

Formation of C3b₂Bb (C5 convertase), which goes on to form the MAC

Question 23

The lectin pathway differs from the classical pathway in terms of the formation of which complex?

Answer 23

C4b2a (C3 convertase)

Question 24

Describe the formation of the C3 convertase in the lectin pathway…

Answer 24

• MASP-2 associated with MBL or ficolin cleaves C4
• C4b binds to C2
• MASP-2 cleaves C2
• Result is C4bC2a complex (C3 convertase)

Question 25

_Deficiencies in complement_ Deficiency of C3 interferes with which 3 abilities and may lead to what?

Answer 25

* Opsonisation * inflammation * cytolysis May lead to life threatening bacterial infections

Question 26

_Deficiencies in Complement_ Deficiency in C6-9 impairs which process and leads to problems with which type of infection?

Answer 26

Cytolysis (formation of MAC), problems with neisseria infections

Question 27

_Regulation of complement_ Give examples of 3 regulatory proteins involved in the complement system...

Answer 27

* **C1 inhibitor (C1INH)** - dismantles the C1 complex * **Complement receptor 1 (CR1)** - dismantles C3 convertase * **Factor I** - cleaves C3b or C4b