Lecture 3: Regulation of Complement

Question 1

What is the classical pathway of the complement system activated by?

Answer 1

antibodies -> IgA and IgG

Question 2

What is the lectin pathway of the complement system activated by?

Answer 2

mannose-binding lectin binding to mannose

Question 3

What is the alternative pathway of the complement system activated by?

Answer 3

spontaneous hydrolysis of the C3 protein

Question 4

What is the role of the membrane attack complex?

Answer 4

perforation or lysis of bacterial cells

Question 5

How does complement form the MAC?

Answer 5

cell-bound C5b binds C6 and C7 (hydrophobic)
C5bC6C7 inserts into cell membrane and binds C8
C5bC6C7C8 cause polymerisation of C9 -> forms MAC and promotes cell death by osmotic rupture and apoptosis

Question 6

What is common between all pathways of the complement system?

Answer 6

all pathways generate a C3 convertase, which cleaves C3, leaving C3b bound to the microbial surface and releasing C3a

Question 7

What is a major part of the complement defence system?

Answer 7

opsonisation of the C3b protein

Question 8

What is opsonisation?

Answer 8

coating of cells to promote phagocytosis e.g. C3b or C4b bound to microbes

Question 9

What is an opsonin?

Answer 9

material that coats particles to promote opsonisation e.g. C3b or C4b

Question 10

What are some examples of receptors for complement proteins and what are they expressed by?

Answer 10

CR1 (CD35) and CR3 (Mac-1, CD11bCD18)

expressed predominantly by macrophages and neutrophils

Question 11

What is the main function of CR1 and CR3?

Answer 11

phagocytosis, clearance of immune complexes and adhesion to endothelium

Question 12

What is CR1-mediated phagocytosis enhanced by?

Answer 12

C5a and specific IgG binding to microbe

if both are present then CR1-mediated phagocytosis is enhanced even more

Question 13

How are immune complexes cleared?

Answer 13

small antigen:antibody complexes form in circulation and activate complement -> many molecules of C3b bind covalently to the complex -> bound C3b binds to CR1 on erythrocyte surfaces -> in the spleen and liver, phagocytic cells remove the immune complexes

Question 14

Where is CR2 expressed and what is its function?

Answer 14

expressed on B lymphocytes and FDCs

co-receptor for B cell activation, traps Ag in germinal centres, receptor for EBV

Question 15

What plays a major role in the recognition of cleavage products of C3b?

Answer 15

factor I and MCP cofactor

Question 16

Why is CR2 present on B cells?

Answer 16

allows for activation of a strong antibody response providing that all other important signals have been received

Question 17

What are C3a and C5a and what do they do?

Answer 17

anaphylatoxins which cause inflammation and they bind to C3a and C5a receptors found on mast cells, endothelial cells and phagocytes

Question 18

How does C3a and C5a induce inflammation?

Answer 18

induce TNFa and histamine release by mast cells which causes leakage of blood vessels and migration of leukocytes

Question 19

What does the complement cascade result in?

Answer 19

opsonisation and enhanced phagocytosis, direct lysis, leukocyte chemotaxis and inflammation, B cell activation

Question 20

What can the complement cascade attack?

Answer 20

extracellular bacteria, free virions, parasites

Question 21

Why is the complement cascade tightly regulated?

Answer 21

limits complement-mediated damage on host cells and limits C3 “tick-over” activation

Question 22

What are regulatory elements of the complement cascade?

Answer 22

soluble factors: factor I with assistance from factor H cleaves / inactivates C3b
membrane bound factors: DAF, CR1 and MCP regulate C3 convertase production + CD59 inhibits MAC formation

Question 23

Why are foreign cells attacked by the complement cascade?

Answer 23

because foreign cells do not have regulatory proteins

RBCs have low levels of complement regulators, thus more susceptible to lysis

Question 24

What is the role of C1 INH?

Answer 24

prevents C1r2s2 from becoming proteolytically active

also inactivates MASP2

Question 25

How does factor I inactivate C3b?

Answer 25

acts as a cofactor which proteolytically degrades C3b so that it can’t interact with anything anymore

Question 26

What is the role of C5 convertases?

Answer 26

cleave C5 to C5a and C5b

these proteins can be inhibited to prevent the complement cascade from continuing

Question 27

How is formation of the MAC inhibited?

Answer 27

CD59 inhibits poly-C9 assembly and S protein inhibits membrane insertion of C5b-C7

Question 28

What are other important functions of complement?

Answer 28

solubilisation and clearance of immune complexes

Question 29

How do pathogenic microbes evade the complement system?

Answer 29

recruit host complement regulatory proteins, produce specific proteins to mimic human complement proteins (e.g. C1q binding protein by E. coli) and inhibition of complement mediated inflammation (S. aureus CHIPS)

Question 30

How do pathogenic microbes recruit host complement regulatory proteins?

Answer 30

express or scavenge sialic acid, synthesise proteins to recruit factor H to cell surface and viruses can incorporate multiple host regulatory proteins into their envelopes

Question 31

Which deficiencies lead to issues in the classical pathway?

Answer 31

C1, C2 and C4 deficiencies -> immune complex disease

Question 32

Which deficiencies lead to issues in the alternative pathway?

Answer 32

B, D and properdin deficiencies -> increased infections with Neisseria bacteria

Question 33

Which deficiencies lead to issues in the alternative and classical pathway?

Answer 33

C3 deficiencies (or deficiencies in regulatory proteins I and H) -> increased infections with S. pneumoniae, Neisseria spp. and H. influenzae