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MIIM30002 > Lecture 2: The Complement System > Flashcards

Lecture 2: The Complement System Flashcards

1
Q

What is complement?

A

inactive plasma proteins (often pro-enzymes), activated (by proteolysis) to carry out various immunological functions

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2
Q

Where is complement found?

A

widely distributed in tissues and body fluids

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3
Q

What does complement do?

A 
promotes lysis of bacteria, infected cells, transplanted cells etc.
promotes opsonisation (i.e. phagocytosis of targeted cells)
promotes inflammation (i.e. recruitment of leukocytes)
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4
Q

How many complement proteins are there and what are they produced by?

A

there are more than 30 complement proteins and they are produced by liver cells (hepatocytes), monocytes, macrophages and some epithelial (skin) cells

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5
Q

What does complement activation involve? When do proteins carry out their function?

A

an enzyme “cascade”
many active proteins exist but will not carry out their function until a trigger is fired e.g. first inactive protein in the “cascade” is activated

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6
Q

What are the terms given to cleaved products of enzyme cascade?

A

“a” for smaller fragment and “b” for larger fragment e.g. C3 cleaved to C3a and C3b

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7
Q

What is the trigger for the complement cascade?

A

C1 (inactive) -> C1 (active)

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8
Q

Where does activation of the complement system occur?

A

on the surface of pathogens (or other cells)

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9
Q

How do the products of complement activation bind to cell surfaces?

A

either alone, or bound to antibody

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10
Q

Why do host cell surface proteins regulate complement activation?

A

to minimise host damage

these proteins are found on normal (healthy) cells and are absent on microbes (e.g. bacteria)

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11
Q

What is the state of soluble complement components?

A

they are often inactive or transiently active

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12
Q

What are the stages of complement action?

A

pattern recognition trigger -> protease cascade amplification / C3 convertase -> inflammation / phagocytosis / membrane attack

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13
Q

What does the classical pathway of the complement system involve?

A

antigen-antibody complexes

  • > IgM and IgG
  • > formally an “effector mechanism of humoral immunity”
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14
Q

What does the alternative pathway of the complement system involve?

A

directly involves pathogen (bacterial surfaces)
antibody independent
part of the innate response

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15
Q

What does the lectin pathway of the complement system involve?

A

mannan binding lectin

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16
Q

How is the complement cascade initiated?

A

three pathways for activation which utilise different but often homologous components, e.g. C4 and C3, C2 and B
results in formation of different but homologous C3 convertases for classical/lectin and alternative pathways

17
Q

What are the early common stages of the complement cascade?

A 
up to (including) cleavage of C3
-> can be by C3 convertase
18
Q

What are the late steps (effector phase) of the complement cascade?

A

after C3 cleavage, C5 convertases are formed, and C5 hydrolysis results in pore formation, cell lysis and inflammation

19
Q

Which processes and proteins are involved in the common steps of the complement cascade?

A

proteolysis of C3 to C3a (inflammatory mediator) + C3b
binding of C3b to microbe surface
C3 activated by enzyme complex
C3 convertases form the C5 convertases

20
Q

How does C3b act as an opsonin?

A

reactive thioester groups exposed on C3b bind amino and hydroxyl groups on microbial surfaces

21
Q

What is C3 convertase in the different pathways of the complement system?

A

lectin pathway - C4b2a
classical pathway - C4b2a
alternative pathway - C3bBb
fluid phase - C3(H2O)Bb

21
Q

What is C3 convertase in the different pathways of the complement system?

A

lectin pathway - C4b2a
classical pathway - C4b2a
alternative pathway - C3bBb
fluid phase - C3(H2O)Bb

21
Q

What is C5 convertase in the different pathways of the complement system?

A

lectin pathway - C4b2a3b
classical pathway - C4b2a3b
alternative pathway - C3b2Bb

22
Q

How is the alternative pathway of the complement system activated?

A

C3 undergoes spontaneous hydrolysis to C3(H2O), which binds to factor B, allowing it to be cleaved by factor D into Ba and Bb -> the C3(H2O)Bb complex is a C3 convertase, cleaving more C3 into C3a and C3b -> factor B binds noncovalently to C3b on a cell surface and is cleaved by Bb by factor D

23
Q

What happens to C3 before cleavage by C3 convertase?

A

the thioester bond within TED is protected from reacting -> allows thioester bond to react with a chemical group on the pathogen surface

24
Q

What is the role of properdin?

A

stabilises the C3bBb complex

properdin = factor P

25
Q

What are the proteins of the alternative pathway of complement activation?

A

C3b (binds to pathogen surface; binds B for cleavage by D; C3bBb is a C3 convertase and C3b2Bb is a C5 convertase), Ba, Bb, D and P

26
Q

How is the alternative pathway amplified?

A

C3b deposited by classical or lectin pathway C3 convertase -> C3b binds factor B -> bound factor B is cleaved by plasma protease factor D into Ba and Bb -> C3bBb complex is a C3 convertase, cleaving many C3 molecules to C3a and C3b

27
Q

How do mannose-binding lectins allow for the death of bacterial cells and not human cells?

A

they bind to mannose which is only found on bacterial cells -> activation of complement proteins

28
Q

What is C1?

A

a “pathogen sensing complex” which is found in the classical pathway of the complement system

29
Q

How can C1q be activated?

A

by binding antibodies (IgG, IgM) that have bound pathogens and CRP that can bind phosphocholine residues on bacterial surfaces

30
Q

What does C1q binding induce C1r to cleave?

A

C1s to create an active serine protease

31
Q

What must happen in order for C1 activation to occur?

A

antibodies must bind to a surface

this is because C1q cannot bind to “free” IgM and must bind to at least 2 IgG’s

32
Q

What does binding to multimeric cell surface antigen lead to?

A
  • > conformational change of IgM which results in “exposure” of Fc region involved in C1q binding and activation of C1 complex
  • > binding of multimeric IgG which results in activation of C1 complex
33
Q

What are the proteins of the classical pathway of complement activation? What does C1q bind to and allow?

A

C1q, C1r, C1s, C4b, C4a, C2a, C2b, C3b, C3a

binds directly to pathogen surfaces or indirectly to antibody bound to pathogens, thus allowing auto-activation of C1r

34
Q

How is C5 cleaved?

A

C3b binds to both C4b2a and C3bBb, forming the active C5 convertases C4b2a3b and C3b2Bb -> C5 binds to the C3b component of the C5 convertase enzyme -> C5 is cleaved by C2a or Bb to form C5b and C5a

35
Q

What happens when C5 is cleaved?

A

initiates the pathway for the membrane attack complex

MIIM30002 (25 decks)

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