module 08 section 05 (membrane attack complex)

Question 1

what is the purpose of the membrane attack complex (MAC)?

Answer 1

form a pore in the target cell membrane leading to its destruction

Question 2

what is step 1 of the complement cascade after C5 convertase formation?

Answer 2

• cell-associated C5 convertase cleaves C5 into C5a and C5b

- C5b remains bound to C5 convertase

Question 3

what is step 2 of the complement cascade after C5 convertase formation?

Answer 3

• C6 and C7 sequentially bind to C5b

- C5bC6C7 complex becomes directly inserted into the lipid bilayer of the target cell membrane

Question 4

what is step 3 of the complement cascade after C5 convertase formation?

Answer 4

after insertion of the C5bC6C7 complex into the lipid bilayer, C8 is bound to C7 to stabilize the complex

Question 5

what is step 4 of the complement cascade after C5 convertase formation?

Answer 5

up to 15 C9 molecules polymerize around the C5bC6C7C8 complex to form the membrane attack complex (MAC)

Question 6

each pore made by the MAC is made of what protein?

Answer 6

C9

Question 7

what does a pore in the membrane result in?

Answer 7

spilling of the inracellular components, initiating cell death

Question 8

can complement activation result in normal cell damage? why or why not?

Answer 8

• yes - constantly occuring at a low level, so can cause damage if not regulated
• also fragment complement proteins can diffuse to adjacent cells and injure them

Question 9

what is complement activation inhibited by?

Answer 9

regulatory proteins present on normal host cells but not on microbes

Question 10

what are C1r and C1 complexess inactivated by? how?

Answer 10

• plasma protein called C1 inhibitor (C1 INH)
• normally C1q binds to antigen-complexed antibodies resulting in activation of the C1 complex, C1 INH prevents C1 complex from becoming proteolytically active

Question 11

what is the formation of C3 convertase inhibited by (in all pathways)?

Answer 11

• DAF (decay-accelerating factor)
• MCP (membrane cofactor protein)
• CR1 (type-1 complement receptor

Question 12

what is C3b inactivated by? how?

Answer 12

MCP and CR1 act as cofactors for Factor I which mediates the proteolytic cleavage of C3b, producing iC3b and a fragment C3f

Question 13

how is the formation of MAC inhibited?

Answer 13

by membrane protein CD59 and plasma protein S

Question 14

what does the timeline for complement pathway activation depend on?

Answer 14

the type of activator component

Question 15

explain the lectin pathway timeline

Answer 15

lectin pathways involved in the first line of defence as its activated by pathogen surfaces

Question 16

explain the alternative pathway timeline

Answer 16

involved in the first line of defense (after lectin tho) as its activated by pathogen surfaces

Question 17

explain the classical pathway timeline

Answer 17

involved later, after antibodies have been produced

Question 18

what pathway(s) are C5-C9 involved in

Answer 18

all three (classical, lectin and alternative)

Question 19

what pathway(s) is MBL involved in?

Answer 19

lectin only

Question 20

what pathway(s) is factor B involved in?

Answer 20

alternative only

Question 21

what pathway(s) is C4 involved in?

Answer 21

classical and lectin

Question 22

what pathway(s) is C3 involved in?

Answer 22

all three (lectin, classical and alterantive)

Question 23

what pathway(s) is C1 involved in?

Answer 23

classical only

Question 24

what pathway(s) is MASP-1/2 involved in?

Answer 24

lectin only

Question 25

what pathway(s) is factor D involved in?

Answer 25

alternative only

Question 26

recall - each of the fragments produced through the complement activation act as:

Answer 26

mediators of inflammation and phagocytic recruitment

Question 27

what is an anaphylatoxin?

Answer 27

a substance produced by complement activation that causes the release of histamine and other mediators, from basophils and mast cells, producing signs and symptoms of anaphylaxis

Question 28

explain anaphylatoxin in terms of the fragments produced by complement activation

Answer 28

each of the fragments has a unique anaphylatoxin potency

Question 29

what is the most anaphylatoxin potnent complement protein?

Answer 29

C5a

Question 30

what does anaphylatoxin potency promote?

Answer 30

mast cell degranulation and contraction of the vasculature

Question 31

what are the anaphylatoxin complement proteins?

Answer 31

C3a, C4a, and C5a (because they can trigger degranulation of mast cells)

Question 32

how does degranulation of mast cells cause anaphylaxis?

Answer 32

mast cells secrete mediators which enter the capillaries, cause contraction of the vessel and elict an anaphylaxis reaction

Question 33

what are the systemic anaphylaxis effects on the GI tract?

Answer 33

increased fluid secretion and peristalsis

Question 34

what are the systemic anaphylaxis effects on the airways?

Answer 34

constriction and increased mucus

Question 35

what are the systemic anaphylaxis effects on the bvs?

Answer 35

increased flow and permeability

Question 36

explain how complement pathways result in phagocytosis

Answer 36

- during opsonization, C3b (opsonin) binds to pathogens, and is then recognized by the complement receptor on phagocytic cells - this leads to phagocytosis od the pathogen - C3b can also bind immune complexes to modify their solubility for removal from circulation

Question 37

explain the role of complememt proteins in MAC

Answer 37

- MAC's composed of 6 unique glycoprotein macromolecules - C3b binds to the pathogen to activate the late components of the complement system, resulting in the formation of MAC - MAC results in lysis of pathogens and cells by forming a pore in the target cell membrane

Question 38

have complement deficiencies been discovered for all complement proteins?

Answer 38

almost all the ones we covered in three early/late systems yes

Question 39

what can complement deficiencies be caused by?

Answer 39

- partial or complete loss of protein synthesis in pyogenic infections caused by streptococcus pneumoniae - or due to the formation of an incomplete or abnormal protein

Question 40

less then 10% of complement disorders are diagnosed, why?

Answer 40

redundancy in the immune system

Question 41

list complement diseases and their associated outcomes (4)

Answer 41

- C1, C2, C4 deficiency - immune complex disease - MAC deficiency - increased risk of infection - C3, factor D, factor I deficiency - pyogenic infections - MBL deficiency - susceptibility to recurrent infections and decreased lung function is cystic fibrosis patients

Question 42

are homozygous deficiencies rare or more common?

Answer 42

rare

Question 43

are heterozygous deficiencies more easy or harder to detect?

Answer 43

not easily detected

Question 44

a genetic deficiency of C1-INH results in an overproduction of C2b and is the cause of:

Answer 44

hereditary angioedema

Question 45

recap: the biological functions of the complement system include: (5)

Answer 45

- opsonization - activation of inflammatory cells by anaphylaxis - cytolysis mediated by MAC formation - solubilization and clearance of immune complexes - enhancement of humoral immune responses