Final Complement

Question 1

Whats the history of complement?

Answer 1

• Bordet used serum from one animal to immunize another animal
• identified a heat liable (complement) and heat stable (anti bodies) component of serum

Question 2

How can complement occur?

Answer 2

• classical (antibody activated)
• lectin (polysaccharide structure of microbes)
• alternative (recognition of foreign surface structures by complement)

Question 3

What are the two fragments yielded from cleavage of complement protein

Answer 3

-larger is b fragment
-smaller is a fragment
Except C2a and C2b are opposite

Question 4

What does the larger fragment do?

Answer 4

Binds to nearby targets and is proteolytically active

Question 5

What does the smaller fragment do?

Answer 5

Diffuses away and acts as a pro-inflammatory mediator

Question 6

Describe the classical pathway?

Answer 6

• 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

Question 7

Why is C1 cleavage of C4 efficient?

Answer 7

There are high serum levels of C4

Question 8

Why is C2 cleavage less efficient?

Answer 8

There are lower serum levels of C2

Question 9

How does the pathway compensate for the low levels of C2 and high levels of C4?

Answer 9

-To compensate for this C2 binds to C4b on the target surface and C4b holds the C2 in close proximity to C1

Question 10

What is different about the lectin pathway

Answer 10

The lectin pathway does not involve antibodies and activation of the pathway is mediated by the pathogen itself

Question 11

What two molecules bind to the carbohydrate?

Answer 11

Mannose binding lectin (MBLs) or ficolins

Question 12

Describe the lectin pathway

Answer 12

• 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

Question 13

Describe the alternative pathway

Answer 13

• 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

Question 14

Whats different about the alternative pathway?

Answer 14

Doesn’t involve any initiator molecules

Question 15

What are activator surfaces for the alternative pathway?

Answer 15

• C3b bound to an activator surface has high affinity for Factor B
• this binds Factor P which stabilizes C3 convertase
• on bacterial cell surfaces

Question 16

What are non-activator surfaces for the alternative pathway?

Answer 16

• 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

Question 17

What do all 3 pathways do?

Answer 17

All 3 produce C5b and converge on a common terminator pathway

Question 18

Describe the common terminator pathway

Answer 18

• 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)

Question 19

What, in addition to direct pathogen lysis, can complement do?

Answer 19

Opsonization
Cellular activation
Inflammation

Question 20

What are complement receptors

Answer 20

A group of cell surface receptors that bind the various products of complement activation

Question 21

What is the receptor for C3b, C4b and iC3b

Answer 21

CR1-4

Question 22

What is the receptor for the anaphylatoxic peptides

Answer 22

C3aR and C5aR