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2.1 Molecular Immunology > Greg - Introduction and Complement > Flashcards

Greg - Introduction and Complement Flashcards

1
Q

Define the complement system

A

The complement system is a biological cascade made up of multiple serum proteins that is part of the innate immune system

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2
Q

What is serum?

A

The liquid from clotted blood

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3
Q

What is plasma?

A

The liquid part of nonclotted blood

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4
Q

How was complement discovered?

A

Serum was taken from a patient and mixed with bacteria
It was observed that the bacteria were destroyed
However if you heat the serum and then carry out the experiment the bacteria are not destroyed, therefore it can be said that a heat-labile component in serum has the ability to lyse bacteria (complement)

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5
Q

On a electrophoresis graph, where is complement found?

A

Complement is found in the beta globulin region

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6
Q

What percentage of the globulin fraction of serum is made of complemet?

A

5%

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7
Q

What causes the levels of complement to increase?

A

An immune response i.e. infection

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8
Q

In an electrophoresis graph where are the antibodies found?

A

Found in gamma globulin region

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9
Q

What are the four main functions of complement

A

Formation of MAC

Opsonisation

Disposal of immune complexes and apoptotic cells

Activation of immune responses e.g. vascular permeability, chemotaxis for phagocytes and degranulation

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10
Q

What is the main detrimental role of complement

A

Inappropriate inflammation

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11
Q

Give an example of a disease caused by inappropriate inflammation

A

Systemic lupus is caused by an over active complement system and it causes tissue damage

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12
Q

How does complement cause lysis of pathogens?
(4)

A

Complement is deposited on the surface of pathogen

Complement forms the membrane attack complex (MAC)

This punches holes in the surface of the cell

The cell swells and bursts by osmosis

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13
Q

How do complement proteins act as opsins
(3)

A

Complement proteins bind to pathogens and mark them for phagocytosis

The phagocytes express receptors such as CR1 which allows the cell to recognise complement attached to a pathogen

When the receptor meets the complement there is a conformational change and the pathogen is phagocytosed

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14
Q

How does complement activate the inflammatory response?

A

If complement binds to the receptors found on granulocytes it causes these cells to degranulate e.g. mast cells/gatekeeper cells releasing histamine causing inflammation and vasodilation

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15
Q

How do complement proteins clear immune complexes

A

Complement marks antibody-antigen complexes for phagocytosis in the liver and spleen

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16
Q

What does CR1 stand for?

A

Complement Receptor 1

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17
Q

How many proteins make up complement?

A

30+

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18
Q

What cells make complement?

A

Hepatocytes (mostly produced here)
Epithelial cells of the gastrointestinal and genitourinary tracts
Monocytes/macrophages

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19
Q

What type of proteins are complement proteins?

A

Acute phase proteins
Zymogens

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20
Q

Complement proteins are zymogens, what does this mean?

A

Zymogens are inactive forms of enzymes
It means complement needs to be activated before working

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21
Q

How are complement proteins activated?

A

Proteolytic cleavage (the chopping off of part of the protein)

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22
Q

How are complement proteins numbered?

A

C1, C2, C3 …. C9

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23
Q

After cleavage how are the components of complement named?

A

Usually the larger component gets named B and the smaller A

e.g. C3a and C3b

However for C2, C2a is the larger piece and C2b is the smaller piece

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24
Q

What does the b part of complement proteins usually do?

A

b is usually the membrane-binding fragment

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25
Q

How do you write an activated component?

A

You overline the components

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26
Q

What are convertases?

A

Complexes with proteolytic activity e.g. C3 convertase cleaves C3 into C3a and C3b

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27
Q

How many complement pathways are there?

A

Three:
- classical pathway
- alternative pathway
- mannose-binding lectin pathway

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28
Q

What is the endpoint of all three complement pathways?

A

The formation of MAC

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29
Q

How does the classical pathway differ from the other two pathways?

A

The classical pathway is antibody dependent

30
Q

Why are antibodies needed for the classical pathway?

A

Complement fixation is needed and this only happens because there was an antibody there first and then complement came along -> in order for complement to stick to the surface of something there needs to be an antibody there first

31
Q

What antibodies initiate the classical pathway?

A

IgM and IgG

32
Q

Which subclasses of IgG initiate the pathway?

A

3/4 subclasses initiate the pathway

33
Q

Which is better at complement activation, IgG or IgM?

A

IgM is way better

34
Q

What is the first type of antibody made after an infection?

A

IgM is the first antibody secreted by plasma cells they may switch to different types such as IgG after

35
Q

What is the first molecule involved in the classical pathway?

A

C1q

36
Q

What does C1q bind with during the classical pathway?

A

2x C1r and 2x C1s to form C1qrs

37
Q

Where is C1q found?

A

It is found floating around in circulation

38
Q

What are the two fragments of antibodies?

A

Fab (fragment with antigen binding) and Fc (fragment that is crystallisable) fragments

39
Q

How many Fc fragments does C1qrs have to bind to?

A

C1qrs has to bind to two Fc fragments on antibodies (this is why the classical pathway is complement dependent)

40
Q

What is the evolutionary point of the classical pathway needing two Fc fragments to bind to on antibodies?

A

This prevents C1qrs activating in circulation when it accidently bumps into an antibody
It prevents unwanted inflammation

41
Q

What happens after C1qrs binds to two Fc fragments?

A

There is a conformational change in shape and one of the C1r’s is activated -> this then activates the other C1r -> this activates both of the C1s s

42
Q

Where exactly on the Fc fragment does complement bind?

A

The Ch2 domain

43
Q

Why is IgM much better at activated C1qrs than IgG?

A

IgM is a pentamer while IgG is a monomer

44
Q

What happens after C1s s are activated?

A

C1s can now cleave C4 and C2 to give C4a, C4b, C2a and C2b

45
Q

What does C4b do?

A

It sticks down on to the surface of the pathogen

46
Q

What does C2a do?

A

It sticks down to the surface of the pathogen along with C4b to form C42a

47
Q

What happens after C4b2a is formed?

A

C4b2a is a C3 convertase
=> C3 is cleaved into C3a and C3b

48
Q

What happens after C3 is cleaved

A

C3a floats away
C3b sticks to the pathogen surface
C4b2a3b is formed

49
Q

What happens after C4b2a3b is formed?

A

C4b2a3b is a c5 convertase
=> c5 is split into C5a and C5b
C5b binds to C6

50
Q

What happens when C5b binds to C6

A

This initiates the formation of the membrane attack complex

51
Q

How is the MAC formed

A

C5b, C6 and C7 bind together to form C5b67
C8 then joins to form C5b678
Many C9 molecules then join to create a pore and form C5b6789

52
Q

How does the Mannose binding lectin pathway work?

A

MBL attaches to mannose/frucose containing polysaccharides on bacteria
MBL is then bound by MASP-1 and MASP-2

53
Q

What does MASP stand for?

A

MBL associated serine proteases

54
Q

How many subunits are there to MBL?

A

6

55
Q

When can the MBL pathway begin?

A

Day one of infection

56
Q

How does the alternative pathway work?

A

C3 can spontaneously split

57
Q

Write a note on the MAC

A

Membrane attack complex
Best at killing gram negative bacteria - low peptidoglycan
Gram positive are generally resistant to the MAC

58
Q

What do the Ca s do after they have been released?

A

They are anaphylatoxins (pro inflammatory molecules)

59
Q

What do anaphylotoxins do?

A

Activate basophils and mast cells to degranulate resulting in increased vascular permeability and contraction of smooth muscle cells

60
Q

What is C3bs function outside of pathway activation?

A

it acts as an opsonin

61
Q

What is C4bs function outside of pathway activation?

A

It acts as an opsonin

62
Q

List the anaphylatoxins

A

C5a
C4a
C3a

63
Q

What are the functions of anaphylatoxins
(4)

A

Degranulation of mast cells
Smooth muscle contraction
Increased vascular permeability
C5a causes chemotaxis of leukocytes

64
Q

Write a note on C3 deficiency

A

Most severe clinical manifestations of complement deficiency

Recurrent bacterial infection and immune complex diseases

65
Q

Give two examples of conditions that are caused by regulatory protein deficiencies

A

Hereditary angioedema

Paroxysmal nocturnal haemoglobinuria

66
Q

Write a note on hereditary angioedema
(3)

A

Caused by mutations in the C1 inhibitor

Patients experience intermittent episodes of oedema

Oedema can be life threatening if airway becomes blocked

67
Q

How does C1 inhibitor work?

A

C1 inhibitor causes the dissociation of C1r and C1s from C1q

This prevents the classical pathway

68
Q

Write a note on paroxysmal nocturnal haemoglobinuria
(2)

A

An acquired disorder where a defect in PIGA results in a deficiency in GPI-anchored proteins including CD59

Without this RBCs are unprotected from lysis by complement

69
Q

How is paroxysmal nocturnal haemoglobinuria treated?

A

The monoclonal antibody Eculizumab is used

Eculizumab binds C5 and halts the complement cascade

70
Q

What is the CH50 assay used for?

A

It demonstrates the ability of serum complement to lyse sheep RBCs coated with antibody

71
Q

What does a high CH50 mean?

A

A poor complement activation

2.1 Molecular Immunology (19 decks)

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