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CMOD- Block1 > Immuno 4: Complement Cascade > Flashcards

Immuno 4: Complement Cascade Flashcards

1
Q

Name the 3 activation pathways of the complement cascade in the order that they typically act.

A
  1. Alternative
  2. Lectin
  3. Classical
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2
Q

Which activation pathways are innate, and which are an acquired immune response?

A

Alternative and lectin are innate.

Classical is acquired.

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3
Q

What is the primary opsinin created by the complement cascade activation pathways?

A

C3b

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4
Q

Anaphylatoxins are one of three end products of the complement cascade. What do they do?

A

anaphylatoxins are inflammatory mediators that activate vascular endothelium (induce vascular permeability) and recruit phagocytes to the inflammatory site

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5
Q

Opsinins are one of three end products of the complement cascade. What do they do?

A

mark pathogen surfaces for easier recognition, uptake, and destruction by phagocytes

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6
Q

The membrane-attack complex (MAC) is one of three end products of the complement cascade. What does it do?

A

MAC is responsible for direct killing of pathogen by disruption of outer envelope, forming pores that result in cell lysis

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7
Q

True or false: complement components are produced constitutively in the liver.

A

True

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8
Q

How is complement opsonization different from antibody-mediated opsonization?

A

complement opsonization is permanent because the opsins are covalently bound to the pathogen

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9
Q

Complement proteins are secreted from the liver in what form?

A

zymogen, or inactive; this is so that they’re always available but not active in the EC fluid and throughout the body

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10
Q

Regarding these proteins, some have enzymatic activity, while others serve as membrane-binding proteins and opsonins.

A

Complement component proteins

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11
Q

Complement proteins: What is the name of the complement protein that binds to antigen:antibody complexes and pathogen surfaces?

A

C1q

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12
Q

Complement proteins: What is the name of the protein that binds to mannose on bacteria?

A

MBL

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13
Q

Complement proteins: What are the names of the activating enzymes of the complement cascade?

A

C1r, C1s, C2a, Bb, D, MASP-2

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14
Q

Complement proteins: What are the names of the membrane-binding proteins and opsonins?

A

C3b, C4b

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15
Q

Complement proteins: What are the names of the peptide mediators of inflammation? Which is the most potent anaphylatoxin?

A

C5a, C3a, C4a.

C5a most potent

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16
Q

Complement proteins: What are the names of the membrane-attack proteins?

A

C5b, C6, C7, C8, C9

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17
Q

There are two versions of the C3 convertase enzyme that are responsible for cleaving component C3. Name them and the pathway that generates them.

A

C3b-Bb: alternative pathway

C4b-C2a: classical pathway predominantly, also lectin pathway

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18
Q

The importance of C3b deposition is twofold: first: C3b is a component of the ___ convertase and eventually needed for MAC formation, and two: C3b and it breakdown products are the _____ that are permanently deposited on the surface of pathogens.

A

C5; opsonins

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19
Q

The alternative activation pathway is a purely _____ pathway.

A

innate

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20
Q

Turnover of C3 protein results in formation of two C3 fragments. They are:

A

C3a, an anapylatoxin

C3b, with exposed thioester bond

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21
Q

If bound to a pathogen, C3b is a ligand for ___ __ binding, which when bound undergoes a conformational change making it susceptible to cleavage by ____ __.

A

factor B; factor D

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22
Q

Cleavage of factor B by factor D on the surface of a pathogenic cell results in what products?

A

C3b-Ba and C3b-Bb (a convertase of the alternative pathway)

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23
Q

If factor B binds to the surface of a host cell, will the alternative pathway be activated?

A

normally not; complement control proteins will prevent activation of the complement pathway

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24
Q

What component proteins compose the C5 convertase enzyme for formation of the MAC?

A

C3b-Bb+C3b=C3b2-Bb=C5 convertase

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25
Q

What is the role of the C5 convertase enzyme?

A

to cleave C5, into C5a (potent anapyloatoxin, acts on mast cells) and C5b

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26
Q

What does C5b bind to and form?

A

one copy each of C6 and C7; forms C5b67 complex:

C5b+C6+C7=C5b67

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27
Q

What is the function of the C5b67 complex?

A

to insert into the pathogen cell membrane, recruit C8, which then recruits 10-16 molecules of C9 which forms a pore in the membrane

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28
Q

What is it about membrane pores that cause death of the bacterium?

A

osmotic disintegrity of the cell that is formed with the addition of new pores

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29
Q

Mannose-binding protein (MBP) is associated with which complement activation pathway?

A

lectin

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30
Q

What does MBP bind to, and what does it serve as a ligand for?

A

binds to exposed mannose residues on the bacterial cell surface; then becomes ligand for Mannin-binding lectin Associated Serum Proteases (MASPs)

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31
Q

How do MASP proteins become enzymatically active, and what do they catalyze?

A

activated upon binding to MBP; cleave copies of C2 into C2a (large) and C2b (small), as well as cleave C4 into C4a (small) and C4b (large)

32
Q

The classical pathway is initiated upon what event?

A

when complement component C1 binds to an antibody that has bound to its cognate antigen; recall that C1 has affinity for the Fc portion of antibodies

33
Q

When the C1 component becomes active, ___ cleaves ___ and C1s then cleaves ___ and ___ proteins, thereby initiating the classical complement cascade.

A

C1r cleaves C1s; C2 and C4

34
Q

Which antibody isotypes are the most efficient at activating the complement cascades?

A

IgM (clear champion) and IgG3

35
Q

Why is IgM such an efficient activator of the complement cascade?

A

because it’s a pentameric antibody, the C1q stalks can bind to several Fc regions at once; this conformational change to C1 initiates cleavage of C1r which is the first step toward activation

36
Q

What is the mechanism of innate activation of the classical pathway?

A

during septic bacterial infections, liver produces and release C1 reactive protein which will bind to phosphocholine residues on the bacteria surface; this mimics an IgM molecule, so C1 binds it and the classical pathway becomes active

37
Q

What is the role of complement receptors expressed on phagocytes?

A

to facilitate recognition and phagocytosis of pathogens

38
Q

Why is complement an important component of the immune response?

A

some bacteria have learned how to avoid it, such as by developing a capsule–this encloses all surface structures of the bacteria, so phagocytes can’t see it; but the complement is a way for phagocytes to can recognize pathogens that have been labeled with C3b

39
Q

How many Fc receptors do phagocytes have for IgM?

A

zero. zilch. none.

40
Q

How do antibodies serve as opsinins?

A

if a phagocyte recognizes antibody-labeled material, it phagocytoses that material and destroys it

41
Q

CR1 is found on what immune cell?

A

phagocytes

42
Q

CR3 and CR4 recognize ____, a breakdown product of iC3, and are found on ____.

A

iC3b; phagocytes

43
Q

Erythrocytes express ____ on their surface in order to help transport small _____ _____ to liver/spleen.

A

CR1; immune complexes

44
Q

The complement cascade is a ____ feedback loop regulated by what two forms?

A

Positive; passive and active regulation

45
Q

Rapid hydrolysis of the reactive thioester bonds following cleavage of complement components is an example of what type of regulation?

A

passive

46
Q

True or false: Active regulation of the complement depends on C3 inhibitor.

A

False - depends on C1 inihibtor

47
Q

What is the mechanism of action of C1INH (C1 inhibitor)?

A

binds to C1r:C1s, forcing it to dissociate from C1q

48
Q

Is C1INH soluble or insoluble?

A

soluble

49
Q

What is the deficiency, cause, presentation, and treatment of hereditary angioneurotic edema (HANE)?

A
  • C1INH deficiency; low serum C2 and C4 levels
  • caused by overproduction of anaphylatoxins
  • presents with episodic systemic edema, most often around lips because this area is heavily vascularized
  • treated by monthly injection of C1INH
50
Q

C4-binding protein (C4BP) binds to ___ of the ____ convertase of the ____ pathway.

A

C4b; C3 convertase; classical

51
Q

How does factor H regulate?

A

binds C3b, making susceptible to factor I cleavage (inactivates C3b and C4b)

52
Q

How does factor I inactivate C3b and C4b?

A

it’s a protease that cleaves the proteins once Factor H/MCP/CR1 (for C3b) or C4BP (for C4b) has made them susceptible:
C3b–>iC3b (opsinin for use elsewhere, not in complement activation)
C4b–>inactive

53
Q

Deficiency of factor I results in what?

A

extended C3 convertase activity and up-production, eventually leading to depletion of C3 which prevents activation of complement cascades when needed

54
Q

What are the 3 membrane-bound proteins that serve to protect host cells by way of deactivating the C3 convertase?

A

DAF - decay accelerating factor
MCP - membrane co-factor protein
CR1 - complement receptor 1

55
Q

What is the function of DAF?

A

dissociates C3 convertase

56
Q

What is the function of MCP?

A

binds C3b/C4b making them susceptible to cleavage by factor I

57
Q

What is the function of CR1?

A

binds C3b/C4b making them susceptible to cleavage by factor I

58
Q

What is CD59 and what does it do?

A

aka protectin; binds to the C5b-6-7-8 complex and prevents polymerization of C9; located on host cell membranes to prevent MAC pore formation

59
Q

Deficiency of the phosphoinositol glycolipid tail that anchors DAF and CD59 to host cell membranes results in what?

A

clinical disease where patients suffer from episodes of intravascular RBC lysis, aka paroxymal nocturnal hemoglobinuria

60
Q

What is the function of factor P?

A

stabilizes alternative C3 convertase

61
Q

List the 3 primary products of the complement cascade.

A

C3b (most important)
Membrane Attack Complex
Anaphylatoxin

62
Q

What is the last of the membrane attack complex complements to coalesce?

A

C9

63
Q

What Complement molecules are included in the membrane attack complex?

A

C5b-C9

64
Q

In the classical complement pathway, the C1 molecule is made up of:

A

6 stalks of C1q and small C1r and C1s subunits

65
Q

Inherited deficiency of mannose-binding lectin would result in the greatest reduction in C3b deposition through which pathway of complement activation?

A

Lectin Pathway

66
Q

Inherited deficiency of factor D would result in the greatest reduction in C3b deposition through which pathway(s) of complement activation?

A

Alternative Pathway

67
Q

Inherited deficiency of C2 would result in the greatest reduction in C3b deposition through which pathway(s) of complement activation?

A

Classical and Lectin Pathways

68
Q

C1r and C1s catalyze the cleavage of what two complement proteins for the classical pathway?

A

C2 & C4

69
Q

What are the multiple roles of the products of C5 cleavage?

A

C5b is a component of the membrane attack complex in the alternative pathway.
C5a goes on to become an anaphylatoxin and a chemotaxin in the classical pathway.

70
Q

Inherited deficiency of which component would result in the inability to activate the classical complement cascade (in an acquired manner) while leaving the alternative and lectin pathways in tact?

A

C1 - recall that it mediates cleavage of C4 and C2 for use in making the C3 convertase

71
Q

Genus Neisseria is especially sensitive to which product of the complement cascade?

A

Membrane attack complex

72
Q

Would you expect gram-positive and gram negative bacteria to be equally susceptible to killing by membrane attack complex?

A

No, gram-positive bacteria would be more resistant because of their thicker cell wall.

73
Q

Which host cells are most susceptible to damage in patients that have a deficiency of C4BP, factor H, factor I, DAF, or MCP?

A

erythrocytes, because they have high surface area and no nucleus to alter gene expression for membrane repair or anything like that

74
Q

Deficiency of c-reactive protein results in decreased deposition of complement C3 protein through which pathway?

A

Classical pathway

75
Q

Deficiency of MAC components results in heightened susceptibility to only one pathogen. What is it?

A

Neisseria - this is weird because for most pathogens, the C3 attack process is the most significant killer

76
Q

Would you expect Gram-negative or Gram-positive to be more resistant to attack by the MAC?

A

Gram-positive, because they have a thicker cell wall presenting a greater challenge for the MAC to permeate the cell

CMOD- Block1 (36 decks)

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