Lecture 3- Complement

Question 1

What are the 3 major functions of complement?

Answer 1

1- control of inflammation by recruitment of phagocytes and granulocytes (inflammatory cells)
2- opsonization- enhances pathogen uptake and clearance
3- lytic attack of cell membranes (killing bacteria)

Question 2

name the 3 pathways of of complement activation

Answer 2

1- classical
2- mannose-binding lectin (MBL)
3- alternative

Question 3

how is the classical pathway activated?

Answer 3

initiated by antibody or C reactive protein (CRP) binding to pathogen surface

Question 4

how is the MBL pathway activated?

Answer 4

lectin binding to pathogen surface

Question 5

how is the alternative pathway activated?

Answer 5

spontaneous hydrolysis of C3

Question 6

describe the initiation complex of the classical pathway of complement

Answer 6

all C1 components: C1q, C1r, C1s

C1q= stalk-like molecules (6 of them), make contact with antibody or CRP, they are ligand binding sites
C1r and C1s are enzymatic components

C1 binding to CRP on pathogen surface activates pathway

Question 7

what happens after classical pathway is activated

Answer 7

cleavage of C4 and C2 (C2a and C4b- the C3 convertase) can now cleave C3 into C3a and C3b
C3a- an anaphylatoxin that can recruit phagocytes to the site
C3b- binds to bacterial surface and serves as an opsonin- tags bacterium for destruction

Question 8

what happens after MBL pathway is activated?

Answer 8

similar to classical, it begins with cleavage of C4 and C2 to form C3 convertase (C2a and C4b), C3 convertase cleaves C3 to deliver an anaphylatoxin (C3a) and opsonin (C3b)

Question 9

describe the initiating complex of MBL pathway

Answer 9

MBL has enzymatic components MASP1 (dimer) and MASP2 (dimer)
(also 6 stalk-like molecules)

Question 10

how is the alternative pathway different?

Answer 10

activation cascade is initiated without the help of a ligand-binding molecule like antibody or MBL
- complement is fixed on bacterial surfaces spontaneously
- C3 convertase is distinct from other pathways- Bb & C3b
- pathway begins with C3 spontaneously hydrolyzing in serum (C3a is anaphylatoxin and C3b opsonin on bacterial surface)

Question 11

C3 convertase for classical & MBL= _____
C3 convertase for alternative = _____

Answer 11

C2a & C4b

BB & C3b

Question 12

how does complement activation induce phagocyte recruitment?

Answer 12

anaphylatoxins (C3a and C5a) produced at site of infection act on blood vessels to increase vascular permeability
- this allows fluid leakage from blood vessels and extravasation of complement and other plasma proteins at site of infection
- C3a and C5a also act to recruit cells out of vessel and to site where bacteria are to engulf and kill them

Question 13

briefly describe opsonization

Answer 13

C3b on bacterial cell surface
CR1 on macrophage binds C3b on bacterium
- endocytosis of bacterium by macrophage — macrophage membranes fuse, creating a membrane-bounded vesicle, the phagosome —- lysosomes fuse with phagosomes forming phagolysosome

Question 14

list the components involved in membrane attack

Answer 14

C5b
C6
C7
C8
C9

Question 15

describe membrane attack

Answer 15

• cleavage of C3 leads to cleavage of C5
• C5b binds to C6 and C7 which allows them to anchor to bacterial surface- C5b initiates assembly of membrane attack complex (MAC)
• C8 is recruited to complex which allows many C9 molecules to come in and form a pore in bacterial surface

Question 16

name 4 inhibitors of complement

Answer 16

1- C1 inhibitor
2- factor H
3- factor I
4- CD59 (protectin)

Question 17

what does the C1 inhibitor do?

Answer 17

binds to activated C1r and C1s, removing them from C1q ; and binds to activated MASP-2, removing it from MBL (acts on classical and MBL to shut them down very early on)

Question 18

what do factor H and factor I do?

Answer 18

bind C3b, displacing Bb and stop the cascade somewhere in the middle – gives fragment iC3b
- they inhibit complement on the host cell membrane

Question 19

What does CD59 (protectin) do?

Answer 19

prevents formation of MAC by binding to C9 and preventing recruitment of C9 to the C5b678 complex, prevents C9 from forming the pore

Question 20

what does properdin do?

Answer 20

(factor D)- stabilizes the C3 convertase on bacterial surfaces and helps to continue the cascade

Question 21

name 4 important complement deficiencies

Answer 21

C1, C2, C4
C3
C5-C9
Factor I

Question 22

what happens in complement deficiency- C1, C2, C4

Answer 22

immune-complex diseases (autoimmunity)

Question 23

what happens in complement deficiency- C3

Answer 23

susceptibility to capsulated bacteria

Question 24

what happens in complement deficiency- C5-C9

Answer 24

susceptibility to ‘Neisseria’

Question 25

what happens in complement deficiency- Factor I

Answer 25

similar effects to deficiency of C3 (susceptibility to capsulated bacteria)

Question 26

complement components for :
recruitment =
opsonization =
membrane attack =

Answer 26

recruitment = C3a, C5a
opsonization = C3b
membrane attack = C5b, C6, C7, C8, C9