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BoD > Complement > Flashcards

Complement Flashcards

1
Q

Why is complement so named

A

It was identified as a heat-labile component of the serum that complemented the antibacterial properties of Ab

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2
Q

Are complement molecules always free

A

Some are soluble and some are membrane associated

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3
Q

In general, is fragment b bigger or smaller

A

Bigger

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4
Q

What are the 3 major functions of complement

Name some additional roles

A

Activation of inflammation
Opsonisation
Lysis of target cells

Clearance of immune complexes and apoptotic cells, stimulating adaptive responses

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5
Q

Which unusual bond in C3 is v important

A

Internal thioester bond

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6
Q

What happens when C3 is cleaved into C3a and C3b

What does this allow

A

The thioester bond in C3b is exposed and can react with hydroxyl or amino groups

Covalent linking of C3b to pathogen surface, opsonising the pathogen for phagocytosis
Also stimulates generation of more C3b

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7
Q

What does C3a do

A

It is an anaphylotoxin that stimulates local inflammation

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8
Q

Probably the most important function of complement is to facilitate the uptake and killing of pathogen is by phagocytic cells. How is this controlled?

A

Complement Receptors (CRs) that recognise proteolytic derivatives of C3

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9
Q

Which CRs are particularly important for the phagocytosis of complement tagged bacteria?

A

CR1 and CR3

CR1 binds directly to C3b

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10
Q

In the absence of an antibody, macrophages require an additional signal to C3b. What is this signal?

A

C5a and C5a receptor

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11
Q

Which blood cell highly expresses CR1

What does this mean

A

erythrocytes

It can bind C3b attached to the antibody/antigen immune complexes so they can be removed from the blood for clearance in the liver

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12
Q

What causes immune-complex disease

A

Low CR1 levels

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13
Q

What are the 3 major pathways that lead to activation of complement of

What order do they act in

A

1st - Alternative pathway
2nd - Lectin pathway
3rd- Classical pathway

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14
Q

What does the alternative pathway in complement rely on

A

Spontaneous conformational changes in C3 that expose the internal thioester group

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15
Q

What does the spontaneous exposure of the internal Thioester group in C3 lead to an aqueous environment?

What does this allow

A

Generation of C3H2O

Association with factor B

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16
Q

What can happen when C3(H2O) has associated with factor B?

What happens next?

A

It is susceptible to cleavage by the factor D

The large fragment (Bb) remains associated with C3(H2O) —-> C3(H2O)Bb

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17
Q

What type of enzyme is a factor D

A

Serine protease

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18
Q

What does C3(H2O)Bb do

What is another name for this molecule

What is its role

A

It is a protease that can cleave C3 into C3a and C3b

Aqueous/ fluid phase C3 convertase

To produce enough C3b so that some will attach to the activating surface of the pathogen

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19
Q

True or false

Microbial services are by default “activating”

A

True

They generally lack regulatory mechanisms to deactivate complement

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20
Q

What happens to C3B when attached to a surface in the alternative pathway

What is this called

A

It combined factor B and generate surface bound C3bBb

Alternative pathway C3 convertase

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21
Q

What is Alternative pathway C3 convertase able to do

What do these molecules do

A

Generate more membrane-bound C3b and soluble C3a

C3b acts as an opsonin and provides a positive feedback loop to form more C3bBb

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22
Q

What is alternative C5 convertase?

A

Instead of binding to a service, cleaved C3b can remain attached to C3bBb to form C3b2Bb

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23
Q

What does C3b2Bb do?

What is the point?

A

Cleaves C5 into C5a and C5b (C3b2Bb = Alternative C5 convertase)

To form the membrane attack complex

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24
Q

What happens in the alternative pathway when C5b is formed

A

C6 and C7 bind to C5b, allowing C7 to insert into the lipid membrane

C8 binds to C5b67 - this allows insertion into the membrane and subsequent polymerisation of C9 subunits to form a membrane pore

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25
Q

Did alternative pathway is effective against which pathogens

A

Gram negative bacteria and enveloped viruses

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26
Q

How is the Lectin pathway activated

A

Mannose binding lectin (MBL) and M-,H-, or L-ficolin

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27
Q

What kind of molecule is MBL

What is it comprised of

A

A ‘collectin’ and a PRR

Collagen and Lectin domains, hence COLL- LECTIN

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28
Q

MBL is a PRR. what does it bind

A

Close knit a raise of mannose and fructose residues that are found on microbial services of bacteria, yeast, fungi and viruses but not the host

29
Q

Are MBL molecules membrane bound

What are they associated with

A

No

They circulate in plasma in association with 2 serine proteases

30
Q

What are the 2 MBL associated serine proteases

When do they activate
What do they do

A

MBL-associated Serine Protease (MASP) 1 and 2

Upon binding the pathogen surface
Cleave C4 and C2

31
Q

Why is C4 similar to C3

A

Both have an internal thioester bond and C4b can attach to the pathogen surface

32
Q

What happens when C4b binds to the pathogen surface

A

It is joined by C2a to form C4bC2a

33
Q

What is another name for C4bC2a

A

The Classical C3 Convertase

34
Q

True or false

Complement components usually act sequentially

A

This is mostly true of C1-9 with the exception of C4

35
Q

What is unusual about C2

A

C2a > C2b

36
Q

When can the Classical Pathway be activated

A

If the surface of the pathogen can be recognised by antibody or C-reactive protein

37
Q

How does the binding of antibody to a surface help the classical pathway

A

It exposes a binding site for C1q present in the Fc region of some antibody isotypes

38
Q

What happens when a molecule of C1q binds to several Fc regions?

A

The conformational change activates the C1r and C1s subunits

39
Q

What does C1s do

What happens to C1 next

A

It is able to cleave C4 to expose the thioester group which can covalently attach C4b to pathogen surface

Activated C1 associates with and cleaves C2, allowing C4bC2a

40
Q

What is C4bC2a

What does it do

A

The Classical C3 Convertase

Cleaves C3 to allow C3b to bind to microbial surface

This then uses the alternative pathway amplification loop by binding to factor B to generate C3bBb

41
Q

What is a classical pathway C5 convertase

A

C4bC2aC3b

Generated when C4bC2a (classical C3 Convertase) associates with C3b

42
Q

How long is the half life of C3bBb

Is this representative for the life span of complement components

A

~90 secs

Yes they are relatively unstable and quickly lose activity

43
Q

Name a positive regulator of the alternative pathway

How many positive regulators are known

A

Properdin (Factor P)

Only 1

44
Q

What does Factor P do

A

Stabilises C3bBb and increases activity 5-10 fold

Stabilises 5 convertase complex assisting in MAC complex formation

45
Q

What is Factor I

A

A soluble constitutively active serine protease

46
Q

What does Factor I degrade

Does it do this alone?

A

C3b and C4b

It requires cofactors such as MCP and Factor H

47
Q

What is MCP

Where is it expressed

What does it do

A

Membrane Cofactors Protein

Host cell membranes

Induces dissociation of C4bC2a and C3bBb, and cleavage of C3b and C4b by Factor I

48
Q

True or false

MCP has decay accelerating capacity but not factor I cofactor activity

A

False

It has both decay accelerating capacity and factor I cofactor activity

49
Q

Which Complement Receptor acts in a similar way to MCP

A

CR1

50
Q

What is the main control factor responsible for regulating complement activation in solution

A

Factor H

51
Q

What is factor H

A

A soluble cofactor for Factor I that attaches sialic acid present on host membranes

52
Q

What does Factor H attach to

Where is this found

A

Sialic acid

Host membranes but is absent in most bacteria

53
Q

What does Factor H induce

A

Dissociation of C3bBb complexes and makes C3b susceptible to cleavage by Factor I

54
Q

What is DAF

Where is it found

What does it do

A

Decay accelerating factor

On the surface of host cells

Dissociates the classical (C4bC2a) and alternative (C3bBb) C3 convertases

55
Q

What is protectin

A

A host cell surface protein that binds the MAC intermediate C5b678 and prevents its insertion into membranes

Also interacts with C9 and prevents its recruitment to the MAC complex

56
Q

How do early components of complement pathways facilitate clearance of soluble immune complexes?

Components of Which pathway is responsible for this

A

Coating them with C4b and C3b

Classical pathway

57
Q

Who suffers from immune complex disease

A

Individuals with defects in C1-4 as they cannot clear immune complexes from the blood

58
Q

What does defects in C3 result in

Why is this

What else can lead to the same result

A

Susceptibility to pyogenic infections (ie pus forming infections such as staphylococcus and streptococcus)

It is an important opsonin assisting in phagocytosis of bacteria

Defects in activating C3

59
Q

What is the most effective defence against Neisseria

Who would suffer from recurrent Neisseria infections

A

Complement mediated lysis

Individuals with deficiencies in membrane attack components C5-9

60
Q

Control of which kind of bacteria relies heavily on opsonisation

A

Encapsulated bacteria

61
Q

Defects in generation of which complement components result in susceptibility pyogenic infection

A

C3b

Factor D and properdin

62
Q

What can lead to C3 depletion

What does this result in

A

Uncontrolled alternative pathway activation

Factor I and Factor H deficiency
And leads to susceptibility to pyogenic infection

63
Q

Why does a reduced GPI synthesis lead to reduced DAF and protectin on RBCs

What does this cause

A

DAF and protectin are GPI-anchored proteins

Paroxysmal Nocturnal Hemoglobinuria

64
Q

What is PHN?

A

Paroxysmal Nocturnal Hemoglobinuria

Complement mediated lysis of RBCs because of reduced expression of DAF and protectin on erythrocytes

65
Q

Name 4 complement evasion strategies

A

Interference of antibody-complement interactions

Binding and inactivation of complement components

Destruction of complement components by proteases

Mimicry of inhibitory regulators or recruitment of host inhibitors

66
Q

Which pathogen is a good example of complement evasion

A

Staphylococcus aureus

67
Q

How does staphylococcus aureus avoid complement (6)

A

The cell wall is protected by a polysaccharide capsule to prevent opsonisation

Secretes proteins that bind or degrade C3

Staphylococcal Protein A binds the Fc region of IgG blocking complement recruitment

Clumping factor A recruits Factor I to the bacterial surface

Chemotaxis Inhibitory Protein blocks C5a chemotactic receptor on neutrophils

Neutrophil extravasation is interfered with

68
Q

What happens if C3 Convertase does manage to assemble at the site of staphylococcus aureus infection

A

C3 Convertase is bound and inactivated by Staphylococcus Complement Inhibitor (SCIN) preventing generation of opsonins (eg C3b)

BoD (11 decks)

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