Complement

Question 1

complement system summary

Answer 1

more than 30 proteins present in blood and bodily fluids
mainly produced in liver
three activation pathways in response to pathogens or antibodies bound to pathogens

Question 2

what initiates the classical pathway and what is its structure

Answer 2

C1 complex
C1q with 6 globule arms below that grab Ig Fc regions
C1s and C1r are between arms

Question 3

explain generation of C3 convertase via the classical pathway

Answer 3

C1q heads bind to Fc region of antigen/antibody complex or pathogen surface
conformational change causes C1r to cleave and activate C1s
C1s cleaves C4 to C4a and C4b
C4b binds pathogen surface and recruits C2
C2 cleaved by C1s to make C2a
C4b2a is formed which is a C3 convertase

Question 4

what happens when C4b2a cleaves C3

Answer 4

C3b binds the surface of a pathogen and is recognised by CR1 (on phagocytes) during opsonisation
C3a recruits other immune cells and local inflammation

Question 5

how is the alternative pathway activated
how does this differ from the classical and lectin pathway

Answer 5

activates on microbial surface in the absence of specific antibody by spontaneous hydrolysis of C3
does not depend on a pathogen-binding protein
generates a distinct C3 convertase

Question 6

explain generation of C3 convertase via the alternative pathway

Answer 6

C3 spontaneous hydrolysis leads to recruitment of factor B which recruits factor D
Factor D cleaves B into Ba and Bb
Bb binds back to hydrolysed C3
C3(H20)Bb is a C3 convertase and it is unstable but if it does live long enough it cleaves C3 creating C3bBb
C3bBb is more a stable C3 convertase

Question 7

what is MBL
what is its structure and function

Answer 7

mannose binding lectin
produced by the liver and present in plasma at low concentration
2-6 headed molecule that forms a complex with MBL-associated serine protease-1 (MASP-1) and MASP-2 protease zymogens
form carbohydrate recognition domains

Question 8

what are ficolins
what is their structure and function

Answer 8

similar in structure to MBL but have a different carbohydrate binding domain
also form a complex with MASP-1 and MASP-2
have specificity for oligosaccharide containing N-acetylglucosamine

Question 9

why is bacterial mannose recognised by mannose-binding lectin and human mannose is not

Answer 9

human mannose is usually coated with sugars and covered
bacterial mannose is exposed and can be recognised

Question 10

explain generation of C3 convertase via the lectin pathway

Answer 10

MBL binds mannose which leads to activation of MASP-2
MASP-2 cleaves C4 producing C4a and C4b
MASP-2 also cleaves C2 producing C2a and C2b
C4b2a is formed and is a C3 convertase

Question 10

explain activation of the lectin pathway

Answer 10

does not require antibodies or hydrolysis
requires mannose on the surface of the pathogen
recognised by MBL

Question 11

which two pathways lead to the formation of C4b2a

Answer 11

classical and lectin

Question 12

explain the generation of C5 convertase

Answer 12

a C3 convertase (C4b2a/C3bBb) cleaves C3 producing C3a and C3b
C3b binds back to the convertase forming either C4b2a3b or C3b2Bb which are both C5 convertases

Question 13

what happens when C5 convertase cleaves C5

Answer 13

C5b goes on to begin formation of MAC with others
C5a along with C3a are chemokines that attract immune cells and cause inflammation

Question 14

explain the formation of membrane attack complex

Answer 14

C5b67 complex binds membrane via C7
C8 binds the complex and inserts into membrane
C5b-6-7-8-9
10-16 molecules of C9 form a pore in the lipid bilayer

Question 15

why does the formation of the membrane attack complex cause cell death

Answer 15

loss of cellular homeostasis
disruption of electrochemical gradients
allows penetration of enzymes such as lysozymes
allows water entry

Question 16

what do all activation pathways of complement lead to

Answer 16

cleavage of C3

Question 17

what are the three results of C3 cleavage/complement system activation

Answer 17

C3a and C5a recruit immune cells to site of infection and cause inflammation
phagocytes with CR1 receptors bind C3b on pathogens and phagocytose them
cascade leads to formation of MAC

Question 18

what are the effector molecules that perform opsonisation

Answer 18

C3b
C4b (lesser extent)

Question 19

what effector molecules are responsible inflammation

Answer 19

C3a and C5a
C4a (lesser extent)

Question 20

what effector molecule causes destruction of pathogen

Answer 20

membrane attack complex

Question 21

what negatively regulates initiation of complement
how

Answer 21

C1 inhibitor
binds active C1r/C1s and causes dissociation from C1q

Question 22

what negatively regulate C3 convertase
how

Answer 22

decay accelerating factor: competes with factor B for C3b, displaces Bb
factor I: cleaves C3b to produce iC3b
factor H: competes with factor B t displace Bb
CR1: similar to DAF

Question 23

what negatively regulates formation of MAC
how

Answer 23

CD59/protectin
inhibits binding of C9 to C5b678

Question 24

what positively regulates C3 convertase
how

Answer 24

properdin/factor P
binds C3bBb and enhances its stability