Complement Flashcards
In the 1890’s what did Border demonstrate using serum from an animal?
He demonstrated that serum from an animal that was immunized to cholera was able to lyse bacteria
What was complement originally identified as?
The heat liable component
What two components did Jules Bordet find?
Component 1 - Ab
- Heat stable
- Specified “remembered”
Component 2 - Complement
- Heat liable :(
- Kills pathogen
What enhances target lysis?
Adding component 2 to component 1
“complemented Ab”
What did Bordet call component 2?
Alexin
What does the complement system consist of?
> 30 soluble plasma proteins and membrane-bound components
What is required for the activation of complement?
A cascade of proteolytic events performed by serine protease domains
What type of process is complement?
Tightly regulated because it is powerful
More than half of the 30+ components are negative regulators of activation
Complement facilitates what two things?
- Lysis of target
2. Opsonin - labels target so it can be phagocytosed
What are the three pathways that complementation can occur through?
- Classical (Ab activated)
- Alternative (spontaneous)
- Lectin (doesn’t use Ab)
What is the goal of all thre pathways?
C3 and then C5
What does the cleavage of complement proteins yield?
2 fragments
What is the a and b fragment?
Large is b
Small is a
Give an example of C3 fragments
C3 -> C3a (small) and C3b (large)
What is the excpetion to large/small fragments?
C2
C2a is large
C2b is small
What do the larger fragments do?
Large fragments bind to nearby targets and is proteolytically active
What do the small fragments do?
Diffuse away and act as proinflammatory mediators
How is the classical pathway initiated?
The complement protein CI binds to two Fc regions of Ab
2 IgG or 1 pentameric IgM
What 3 things is C1 comprised of?
C1q (binds Ab)
C1r (regulatory)
C1s (serine protease - cuts)
What does binding to Ab induce?
A conformational change in C1, exposing an active enzymatic site that is able to cleave and activate C4 and C2
What does C1 cut?
C4 and C2
What do C4 and C2 do?
They associate to form the C3 Convertase
Is C1 cleavage of C4 efficient?
Yes, bc there are high levels of C4
What happens to C4 once it is cleaved?
C4b is quickly inactivated by iC4b
Some C4b lands on a nearby surface and remains proteolytically active
Is the cleavage of C2 efficient?
Not really, bc there are lower conc.
How does C2 compensate for its low serum conc.
C2 binds to C4b on the target surface
What facilitates the cleavage of C2?
C2 binding to C4b bc it brings it in close proximity to the active C1
What part of C2 is active?
C2a stays with C4b
What is C4b2a called/
C3 convertase
What does the C3 convertase do?
Cleaves C3, releasing C3a and C3b stays associated w/ target surface
Describe C3a
Inflammation
Long-lasting anaphylatoxin which is capable of acting on targets distant to its site of generation
Describe C3b
Keystone molecule
- Short lived (60ns)
- Dangerous, so shut down quick
- Some remains associated w/ C4bC2a producing the C5 convertase (C4bC2aC3b)
What happens to C3b that is not covalently bound to a target surface?
It is inactivated through hydrolysis (iC3b)
What is C4bC2aC3b?
C5 convertase
