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KN-Immunology Block 1 > L9: B cell-Mediated Immunity II The Compliment System > Flashcards

L9: B cell-Mediated Immunity II The Compliment System Flashcards

1
Q

What is the classical complement pathway activated by?

A

antigen:antibody complexes

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2
Q

What is the lectin pathway activated by?

A

lectin binding to pathogen surfaces

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3
Q

What is the alternative complement pathway activated by?

A

pathogen surface

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4
Q

What is the first complement pathway to act? Second? Last?

A

First is alternative pathway. Then lectin, then classical.

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5
Q

What is the first step for all complement pathways after activation?

A

Cleavage of C3 to form C3a and C3b.

C3b covalently binds to surface components of pathogen

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6
Q

Which is the larger fragment: C3a or C3b? Which one binds to the pathogen surface?

A

C3b for both

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7
Q

What does C3a do?

A

it is an anaphylatoxin (inflammatory mediator)

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8
Q

What are anaphylatoxins?

A

They are small chemotactic molecules that induce vascular permeability and induce inflammatory response

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9
Q

What forms the C3 convertase enzyme in the classical cascade?

A

cleavage of C2 and C4. The big fragment of C4 (C4b) binds to the small fragment of C2 (C2a)

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10
Q

What forms the C3 convertase enzyme in the alternative cascade?

A

C3 is cleaved and the larger C3b part binds to a bacterium. Factor B then binds to the C3b on the bacterium. Factor D then come and cleaves B to form Ba and Bb. Bb remains attached to C3b and they form the active convertase enzyme, which will in turn rapidly cleave more C3 molecules.

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11
Q

What other role does C3b play besides forming C3 convertase and fixation of complement?

A

It is a component of the C5 convertase enzyme that is required for activation of the membrane attack complex

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12
Q

Is the alternative complement pathway innate or adaptive immunity?

A

it is purely innate

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13
Q

What is formed if a C3b factor binds to a C3b that is already bound to a Bb?

A

it forms a C5 convertase (C3b2,Bb)

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14
Q

What does C3b2,Bb do?

A

It is also known as C5 convertase. It cleaves C5 into C5a and C5b. C5b is the initiator of the membrane attack complex.

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15
Q

What happens after cleaving C5 forms C5a and C5b?

A

C5b will bind to C6 and C7 to form C5b67 complex, which can bind to membranes via C7. C8 will then bind to the complex and insert itself into the membrane. C9 then binds to complex and polymerizes. C10-16 then bind to form a pore in the bacteria membrane.

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16
Q

What specific bacterial family will cause severe problems in patients who have a defect in C8 and C10 complement factors?

A

C5b and C6-16 are necessary for the membrane attack complex in the complement cascade. The only known bacterium that causes severe problems when it is defective is Neisseria

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17
Q

What is MBP and what does it do?

A

MBP is mannose-binding protein and it binds to terminal mannose residues on the surface of bacteria. These are unique to bacteria and do not exist in host cells. After binding to microbial surface, they have affinity for MASP-1 and MASP-2 (mannan-binding lectin-associated serum proteases)

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18
Q

What do MASPs do?

A

They bind to MBP after it has bound to a mannose on the surface of microbes. They then cleave C4 and C2 to form C4a, C4b, C2a, and C2b.
C2b and C4b bind to the pathogen surface and together form the active C3 convertase, which cleaves C3 to C3a and C3b

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19
Q

What is the adaptive component of the complement cascade?

A

the classical pathway

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20
Q

What initiates the classical pathway?

A

When complement componenet C1 binds to the Fc region of an antibody that is bound to its specific antigen. This is mediated by C1q (a part of C1). When C1q binds to the antibody, C1r is activated and cleaves C1s, which then cleaves C2 and C4.

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21
Q

How many IgM molecules does it take to bind C1q?

A

only one since IgM is pentameric and can bind in 5 places.

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22
Q

How many IgG molelcules are needed to bind C1q?

A

at least 2

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23
Q

Besides IgG and IgM, what other Ig can activate the classical complement cascade?

A

IgA. It is less efficient, but can activate it by binding C1q.

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24
Q

What happens after an Ig such as IgM or IgG binds to C1q in the classical cascade?

A

C1r cleaves C1s, which can then cleave C2 and C4, which then form C4b,C2a, which can cleave C3 and deposit C3b on the microbial membrane surface for opsinization or membrane attack complex

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25
Q

What is the most important function of the complement cascade?

A

C3b deposition (opsonization)

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26
Q

What effect does the alternative pathway have on the classical pathway?

A

it amplifies it

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27
Q

Describe innate activation of the classical pathway.

A

C-reactive protein (CRP) that is produced during the acute phase response (inflammatory) binds to phosphocholine on pathogen surfaces. CRP is a binding site for C1q. This activates C1r which will cleave C1s, which will cleave C2 and C4

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28
Q

How do follicular dendritic cells use complement receptors?

A

They express an array of complement receptors that can bind to antigens that have the C3b and other complements on them. THey then present those antigens to B cells in secondary lymphoid tissue

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29
Q

What is CR2?

A

It is a co-receptor for the B cell receptor and a receptor on FDCs.
It binds to C3d, C3dg, iC3b and Epstein-Barr virus. It is necessary if C3b on pathogen surfaces is cleaved (forming iC3b, C3d, or C3dg fragments).
FDHs use it to bind and retain these fragments for B cell stimulation.

30
Q

Antibody binding is only temporary. Is the same true of complement binding for C3b opsonization?

A

No. C3 opsonization is a permanent reaction

31
Q

What is C5a receptor?

A

It binds C5a and activates G protein on endothelial cells, mast cells and phagocytes. It can cause mast cell degranulation.

32
Q

What does CR1 do?

A

Stimulates phagocytosis by binding to C3b and C4b. Found on macs, neutros, B cells and FDCs.
Also commonly found on erythrocytes it promotes C3b and C4b decay.
Erythrocyte transport of immune complexes

33
Q

What role do erythrocytes play in immune response?

A

they remove immune complexes when CR1 on their surface binds to a C3b-covered immune complex.

34
Q

How are the complement pathways passively regulated?

A

following cleavage of factors like C3, thioester bonds are rapidly hydrolyzed. If it doesn’t bind to something quickly, it will become inert.

35
Q

Why is complement cascade regulation so important?

A

it is a positive feedback loop. If it is not regulated, host would be damaged

36
Q

What are the active controls of the complement cascade?

A

There are host proteins that dampen the complement cascade in the plasm and on the cell-surface.

37
Q

What does C1INH do?

A

C1 inhibitor. binds to activated C1r:C1s and forces them to dissociate from C1q, which limitsx spontaneous activation of C1

38
Q

What happens in a patient with C1INH deficiency?

A

HANE (hereditary angioneurotic edema) serious illness with systemic edema due to overproduction of anaphylatoxins. Treated with injections of C1INH

39
Q

What is C4BP (C4-binding protein)?

A

a plasma regulator protein that binds to C4b of the C3 convertase of the classical pathway. The C2a is displaced and the C4b gets cleaved by factor I.

40
Q

What is factor H?

A

plasma protein that binds to C3b and allows it to be cleaved by factor I

41
Q

what is factor I?

A

plasma protein that inactivates C3b and C4b

42
Q

What does factor I deficiency lead to?

A

depletion of C3. It also prevents formation of iC3b, which is a critical opsonin in the absence of antibody and critical for alternate pathway.

43
Q

What is DAF?

A

Decay accelerating factor. Dissociates C3 convertases and shuts them down.

44
Q

What is MCP?

A

membrane co-factor protein. Binds to C3b and C4b, making them susceptible to factor I cleavage

45
Q

What is CR1?

A

complement receptor 1. Binds to C3b and C4b to make them susceptible to factor I cleavage.

46
Q

What is protectin?

A

aka - CD59.
binds to the C5b, C6, C7, C8 complex to prevent polymerization of C9.
This prevents formation of membrane attack complex on host cells, but does not inhibit MAC formation on antigen

47
Q

What is CD59?

A

protectin. It prevents membrane attack complex on host cells.

48
Q

How is CD59 anchored to cell membranes?

A

phosphoinositol glycolipid tail

49
Q

What will a deficiency in phosphoinositol glycolipid cause?

A

CD59 uses it to anchor to host cell membranes and protect them. They suffer from intravascular RBC lysis due to CD59 and DAF deficiency

50
Q

What will a deficiency in phosphoinositol glycolipid cause?

A

CD59 uses it to anchor to host cell membranes and protect them. They suffer from intravascular RBC lysis due to CD59 and DAF deficiency

51
Q

What complement factor is the most powerful chemotactic factor for neutrophils?

A

C5a

52
Q

What do the smaller fragments of complement protein cleavage usually do?

A

They are usually anaphylatoxins that have inflammatory effects. Usually the ‘a’ part.

53
Q

What does C3b do? Why is it so important?

A

serves as a potent opsonin, facilitating uptake and destruction of the pathogen. It is the most abundant of the complement proteins. All 3 pathways rely on formation of C3 convertatse, which cleaves C3 into C3a and C3b.

54
Q

What does MBP do?

A

Mannose binding protein, is a complement component that binds to terminal mannose residues on bacterial surfaces. It then interacts with MASP-1 and MASP-2

55
Q

What do MASP-1 and MASP-2 do?

A

they bind to MBP that has bound to mannose residues on bacterial surface. They then are activated and cleave C2 to produce C2a nd C2b, and C4 to produce C4a and C4b.

56
Q

After MASP-1 and MASP-2 cleave C2 and C4, how does the lectin pathway differ from the classical pathway?

A

It is identical to the classical pathway after the production of C2a,C2b, C4a and C4b.

57
Q

What activates the classical complement cascade?

A

complement component C1 binds to Fc region of antibody that is bound to the surface of a pathogen. (usually IgM, IgG1, or IgG3).

58
Q

What is C1?

A

a complex of C1q, C1r and C1s.
C1q will bind to antigen:antibody comlexes and then cleave C1r, which will cleave C1s.
C1s will then cleave C2 and C4.

59
Q

What prevents C2a and C4b from marking self cells as destruction targets? What stops C3b?

A

They are rapidly hydrolyzed and can only bind to cells immediately adjacent to the antibody.
C3b is not broken down as fast so it does make it to other cells, but host cells have control proteins that rapidly deactivate it.

60
Q

What two complement fragments make up C3 convertase?

A

Lectin and Classical: C4b,C2a (C2a is one of the few where the ‘a’ fragment is larger than the ‘b’)
Alternative: C3b,Bb

61
Q

What does deposited C3b on pathogen cell surfaces bind to on phagocytes?

A

CR1 (complement receptor 1). This triggers phagocytosis. Can also trigger mast cell degranulation.

62
Q

What pathways will factor B deficiency affect?

A

total lack of alternative pathway because C3 convertase (C3b,Bb) will no longer be there.
Also reduction of lectin and classical as well because C3b deposition from lectin and classical will be greatly reduced.

63
Q

Which complement pathways are purely innate?

A

alternative and lectin.

The classical pathway is a bridging between acquired and innate

64
Q

What does C3b do in the alternative pathway?

A

It binds to pathogens then serves as a binding site for factor B. Factor D will then come cleave that

65
Q

What does factor B do?

A

Factor B binds to C3b in the alternative pathway. It is then cleaved by Factor D to form Bb and Ba. Bb binds to C3b to form C3b,Bb (alternative C3 convertase)

66
Q

What does Factor D do?

A

cleaves factor B so it can form Bb and Ba, which then combines with C3b to form C3 convertase

67
Q

What does CR3 and CR4 do?

A

bind to CRb and iC3b, but they are not sufficient to activate phagocytosis.

68
Q

How do RBC’s carrry immune complexes to spleen and other lymphoid tissues?

A

using CR1 to bind to C3b on the pathogen complex. Macros in these sites will then remove and digest the complexes.

69
Q

What is a podocyte?

A

specialized epithelial cell that uses CR1 to bind to immune complexes. They are are found in capillaries within kidney glomeruli.

70
Q

What complement protein fragments form C5 convertase?

A

Classical: C4b,2a,3b
Alternative: C3b(2),Bb

KN-Immunology Block 1 (12 decks)

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