Final Complement Flashcards
Whats the history of complement?
- Bordet used serum from one animal to immunize another animal
- identified a heat liable (complement) and heat stable (anti bodies) component of serum
How can complement occur?
- classical (antibody activated)
- lectin (polysaccharide structure of microbes)
- alternative (recognition of foreign surface structures by complement)
What are the two fragments yielded from cleavage of complement protein
-larger is b fragment
-smaller is a fragment
Except C2a and C2b are opposite
What does the larger fragment do?
Binds to nearby targets and is proteolytically active
What does the smaller fragment do?
Diffuses away and acts as a pro-inflammatory mediator
Describe the classical pathway?
- activated when C1 binds to two Fc regions of antibodies
- either 2 IgG molecules or 1 IgM
- C1 is comprised of C1q (binds antibody), C1r (regulatory) and C1s (serine protease)
- binding to the antibody produces a conformational change in C1 exposing an active site
- the active site cleaves and activates C4 and C2
- activated C4 and C2 associate to form the C3 convertase
- C3 convertase cleaves C3 releasing C3a and allowing the association of C3b with the target surface
- C3b produces the C5 convertase
Why is C1 cleavage of C4 efficient?
There are high serum levels of C4
Why is C2 cleavage less efficient?
There are lower serum levels of C2
How does the pathway compensate for the low levels of C2 and high levels of C4?
-To compensate for this C2 binds to C4b on the target surface and C4b holds the C2 in close proximity to C1
What is different about the lectin pathway
The lectin pathway does not involve antibodies and activation of the pathway is mediated by the pathogen itself
What two molecules bind to the carbohydrate?
Mannose binding lectin (MBLs) or ficolins
Describe the lectin pathway
- MBL or ficolin binds carbohydrate on target surface
- facilitates cleavage of C4
- C4b binds to target surface, binds C2
- MBL or ficolin cleave C2 leaving C3 convertase on surface
- cleavage of C3 by MBL or ficolin, C3b binds target
- opsonin
- also forms C5
Describe the alternative pathway
- small amounts of C3 circulate and can undergo spontaneous activation
- if C3b happens to bind to an activated surface it remains active
- C3b can bind Factor B
- Factor B is cleaved by Factor D yielding Ba and Bb (larger)
- Bb produces the alternative pathway C3 convertase
- C3 convertase cleaves C3 producing more C3b
- C3b binds to things making C5
Whats different about the alternative pathway?
Doesn’t involve any initiator molecules
What are activator surfaces for the alternative pathway?
- C3b bound to an activator surface has high affinity for Factor B
- this binds Factor P which stabilizes C3 convertase
- on bacterial cell surfaces
What are non-activator surfaces for the alternative pathway?
- rich in negatively charged residues
- negatively charged residues bind large amounts of Factor H
- Factor H prevents C3b from binding Factor B inactivating it
- on mammalian cells
What do all 3 pathways do?
All 3 produce C5b and converge on a common terminator pathway
Describe the common terminator pathway
- C5b binds C6
- C5b6 binds C7 introducing a conformational change revealing a hydrophobic domain in C7 which inserts into the target cell membrane
- if properly inserted it will bind C8 and 10-16 C9 molecules
- the C9 polymerize side by side to form a pore in the target cell membrane
- membrane attack complex (MAC)
What, in addition to direct pathogen lysis, can complement do?
Opsonization
Cellular activation
Inflammation
What are complement receptors
A group of cell surface receptors that bind the various products of complement activation
What is the receptor for C3b, C4b and iC3b
CR1-4
What is the receptor for the anaphylatoxic peptides
C3aR and C5aR
