Lecture 8: Compliment and phagocytosis Flashcards
What is a complement?
An essential component of out innate immune system
- A collection of plasma protein zymogens that are rapidly activated on contact with microbial surfaces resulting in opsonisation and phagocytosis
What are the possible complement activation pathways?
- Classical pathway (activation is mediated by antibody)
- Lectin pathway (activation is mediated by carbohydrate recognition)
- Alternative pathway (Activated by direct contact with surface)
Where do all three compliment activation pathways converge?
All three pathways converge on the action of complement C3.
What does complement activation result in?
- Opsonisation and phagocytosis
- Direct Killing
- Leukocyte recruitment
- Inflammation
What are some key features of complement cascades;
- They’re enzymatic (esterases; zymogens, i.e pro enzymes that are activated by cleavage of the proceeding enzyme in the pathway)
- Positive feedback loops (C3)
Describe in broad terms the regulation of the complement cascade;
- Extensive control mechanisms that result in the rapid decay of activated compliment proteins
- Cells are protected from lethal effects of compliments by numerous inhibitors and decay accelerators
What mediates the three compliment pathways?
- Classical ; Antibody Fc mediated
- Alternative ; Pathogen surfaces
- Lectin ; Pathogen carbohydrates
Describe steps 1-3 of the classical pathway;
- Antibodies (IgG and IgM) bind to surface epitopes of pathogen
- C1q binds to exposed Fc region
- C1r and C1s bind via C1q
Describe steps 4-6 of the classical pathway;
- Serine proteases cleaves (C1S) C4 into C4b opsonin (C4a, soluble, diffuses away)
- C2 binds to bound C4b and is cleaved by activation C1s (C2a and C2b- soluble diffuses away)
- Formation of the C4b2a, soluble version of C3 convertase
Describe the structure of C1q;
C1q has six globular heads attached to the central body by collagen like strands
How is C1q activated?
Two C1qs heads must bind AB for activation, so need two IgG.
IgM is a much better compliment activator than igG
Describe the first three steps of the mannose binding lectin pathway compliment activation;
- Bound and stabilised MBL interacts with two serine esterases (MASP-1 and MAPS-2)
- This activates C4 akin to the classical pathway
i.e
- Cleaves C4 into C4b opsonin (C4a, soluble, diffuses away)
- C2 binds to bound C4b and is cleaved by activation C1s (C2a and C2b- soluble diffuses away)
- Formation of the C4b2a, soluble version of C3 convertase
Describe the MBL;
MBL ; six headed protein similar to C1q with mannose binding lectins at the end
Can MBL target host cells?
Mannose is not a terminal sugar on eukaryotic cells so host cells are not normally targets
How else can MBL exist?
Analogous to C1q, but can also exist as dimers, trimers and tetramers
What are MASP analogous to?
MBL associated serine esterases (MASP) is analogous to C1r-C1s
Describe the first step in the alternative pathway;
C3 is a major plasma protein that is spontaneously activated by SURFACE CONTACT.
This is called tick over
What is c3?
A highly unstable thioester.
Half life in miliseconds