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Infection and Immunity > Intro to Ab and B lymphocytes > Flashcards

Intro to Ab and B lymphocytes Flashcards

1
Q

What is the role of the immune system?

A

Responsible for recognition and elimination of pathogens

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2
Q

What are the 2 parts of the immune system?

A

Innate - rapid and non-specific
Adaptive - takes longer because must recognise specific antigens
BUT has ability to generate memory

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3
Q

What are the 2 parts of the adaptive immune system?

A

Cell mediated immunity - mediated by T - cells

Humoral immunity - Ab mediated

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4
Q

What are Ab produced by?

A

B lymphocytes

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5
Q

How do B lymphocytes generally work?

A

Bind to Ag and aid clearance of pathogen by multiple mechanisms

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6
Q

Is the specificity of Ab for B cells the same?

A

Each B cell differs in specificity for Ab

10^8 different types of B cell .˙. 10^8 Ab specificities

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7
Q

What happens upon proliferation of B cells?

A

B cells form clones of identical cells, each w/ individual specificity for Ag

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8
Q

What is the difference between a BCR and Ab?

A 
BCR = surface bound Ag
Ab = secreted form BCR
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9
Q

What is the structure of an Ab?

A

4 polypeptide chains
2 identical heavy chains = 50kDa
2 identical light chains - 25kDa

Held together by disulphide bridges

Glycosylated

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10
Q

What is the Ab binding site made up of?

A

Made up of all 4 chains = variable region

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11
Q

Where is the Ab glycosylated?

A

Highly glycosylated at the conserved regions w/in heavy chain
Post-translational mod - addition of sugars to amino acids
Important role in determining Ab effector

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12
Q

What superfamily is the Ab part of?

A

Ig superfamily

Other members include - TCR, MHC, Ab receptor

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13
Q

What is the basic structure of the Ig superfamily?

A

Each 110aa segment of Ab forms discrete, compactly folded protein domain
Domains stabilised by multiple non-covalent interactions and disulphide bridges
Each protein domain made up of beta sheets (significant aa homology) - form loops of 60-70aa = immunoglobulin fold
Proteins joined by polypeptide chain = hinge region

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14
Q

What are the domains of the Ab?

A

Constant domains make up majority of structure of Ab

Variable regions make up domain at end of Ab - Ag binding site

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15
Q

What does the Ab structure allow?

A

Allows for stable structure and multiplicity of functional variants
Flexibility for Ag binding

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16
Q

What are the 2 parts that an Ab can be split into?

A

Can be split by proteases at the hinge region into 2 identical Fab fragments
F(ab)2 - Ag binding region
And Fc region - fragment crystallisable
Comprises only of constant region of heavy chain

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17
Q

What does the Fab region determine?

A

Specificity
Affinity
Avidity
of interaction w/ Ag

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18
Q

What does the Fc region confirm?

A

Confirms functional properties of Ab

As can be recognised by Fc receptors on immune cells + can bind to complement to trigger complement cascade

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19
Q

What is the main role of an Ab?

A

To bind to Ag - can happen in multiple different ways

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20
Q

How can the Ab bind to Ag? (immune complexes)

A
  1. multiple ab bind to Ag causes formation of immune complexes
    C1q part of complement cascade - can bind to immune complexes and leads to cascade of events
    eg. pore formation in pathogen membrane and death of pathogen
  2. immune complexes can bind to Fc receptors on innate immune cells
    Most Fc receptors have low affinity for single Ab and req. immune complexes to bind and trigger intracellular signalling
    eg. opsonisation/phagocytosis
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21
Q

How can Ab bind to Ag? (ACMC)

A

Ab can bind to Ag on surface of infected cells
recognised by Fc receptors/effector cells eg. NKC
Aids in recognition and killing - Ab cell mediated cytotoxicity

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22
Q

How can Ab bind to Ag? (activation neutrophils and mast cells)

A

Binding of Ab to Ag
Then recognised by Fc receptors which causes activation neutrophils and mast cells
Enables sensitisation and ability to release preformed mediators
eg. IgE to enhance allergic sensitisation

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23
Q

How many Ab classes are there?

A

5 classes

9 subclasses

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24
Q

How are Ab classes defined?

A

Defined by heavy chain constant region
also determines effector function
Different classes are adapted to function in different parts of body

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25
Q

List the classes of Ab

A 
IgG - 4 subclasses
IgM 
IgA - 2 subclasses 
IgD
IgE
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26
Q

What is the molecular weight of an Ig molecule?

A

150kDa

IgM/IgA - larger as can form multi-meric structure

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27
Q

Are the serum concentration of the Ab the same?

A

Differ between classes
Serum levels IgG much higher - 1 (IgG3) - 9 (IgG1) mg/ml
IgE lowest - 0.00005 mg/ml

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28
Q

Which Ab classes have a longer half life?

A

IgE & IgM

Able to persist for longer - these important for secondary immune responses

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29
Q

Which Ab class was the first to evolve?

A

IgM

major component in innate immune response

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30
Q

What is the heavy chain of IgM encoded by?

A

u gene w/ 4 Ch domains

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31
Q

What does it form when found as monomers?

A

Forms BCR on most B cells
in association with Iga and Igb chains
a - alpha
b - beta

32
Q

What percentage of the serum Ig does IgM contribute to?

A

10% serum Ig

33
Q

Describe the affinity of IgM

A

Typically low affinity receptor but when secreted form pentameric structure
Held together by disulphide bonds

34
Q

Describe the pentameric structure of an IgM

A

5 IgM associate together and stabilised by a J-chain

Increases avidity Ab

35
Q

What is the function of an IgM Ab?

A

Activate complement - (classical)

36
Q

Describe the properties of the IgM Ab

A

Mean serum conc - 1.5 mg/ml
Molecular wt - 970 kDa
1/2 life - 10 days

37
Q

Describe IgG Ab

A

Monomeric Ab
Heavy chain gamma gene
3 heavy chain conservative domains - 3Ch domains

38
Q

What percentage of serum Ig doe IgG make up?

A

70-75%

Major circulating Ab

39
Q

How many subclasses of IgG are there and what are they?

A

4 sub-classes
G1,2,3,4 (decreasing abundance)
Subclasses have different affinities to Fc receptors and have unique biological function

40
Q

What role do IgG Ab have during pregnancy?

A

IgG can cross the placenta and protect the foetus

41
Q

What is the main function of IgG Ab?

A

Have major role in activation of complement (classical) and opsonin (FcR)

42
Q

Describe IgA Ab

A

Heavy chain alpha gene and 3Ch domains

15-20% circulating Ig

43
Q

How many subclasses of IgA are there?

A

2
IgA - in serum as monomers
IgA2 - in mucous as dimers

44
Q

Describe dimeric IgAs

A

2 IgA molecules associated w/ J chains

Found in secretion eg. tears, milk, saliva, sweat or epithelia line intestines and respiratory tract

45
Q

What role do IgAs play?

A

Major role in 1st line of defence
Protection external surfaces
Can get localised mucosal response - different to systemic response
Does not activate complement - by classical pathway

46
Q

What prevents IgA enzymes from being broken down by protease?

A

Secretory component added during transport through the epithelium
Protects from degradation from proteolysis
Aids release into mucous

47
Q

How are IgA’s secreted?

A
  1. IgA dimers bind poly-Ig receptor on basolateral surface epithelial cells
  2. Complex endocytosed
  3. Carried through cytoplasm - vesicles fuse with luminal surface
  4. Ab released through proteolytic cleavage of poly-Ig receptor
  5. Dimer released attached to secretory component
    Able to bind to musins in mucous and prevent cleavage
48
Q

Describe IgD Ab

A

Heavy chain coded by delta gene
Monomer
3Ch domains

49
Q

Where are IgD Ab most likely to be expressed?

A

On surface B cells w/ monomeric IgM

.˙. <1% serum Ab

50
Q

What is the function of IgD Ab?

A

Have specific binding activity but no effector function

Instead involved in Ag triggered B cell differentiation

51
Q

What are IgD Ab sensitive to?

A

Proteolytic degradation and heat

52
Q

Describe IgE

A

heavy chain encoded by epsilon (E)

4 Ch domains - like IgM

53
Q

How abundant are IgE levels in the serum?

A

Found at trace levels
Majority IgE found bound to mast cells and basophils through high affinity FCER1 receptors
Elevated in allergic or heavy parasite infection

54
Q

What is the main function of IgE Ab?

A

Key to allergic response and parasitic infections
W/ Ag binding triggering degranulation mast cells
Very effective at killing multicellular organisms

55
Q

Why are anaphylactic responses so quick?

A

As on first exposure IgE produced - binds to mast cells

hence, on subsequent exposure, IgE is waiting and ready on mast cells

56
Q

What type of Ig is often expressed as a BCR on a B cell?

A

Often monomeric IgM/IgD on surface

Both have same Ag specificity on an individual B cell

57
Q

What is the frequency of other types of Ig being expressed as a BCR?

A

10% Circulating B cells express IgG, IgA, IgE

Some tissue bias eg. mucosal B cells express IgA

58
Q

What is the purpose of the intracytoplasmic tail?

A

Short tail anchors the surface bound BCR to membrane

59
Q

Why do BCRs need to associate with a accessory molecule?

A 
As the intracytoplasmic tail is short
Accessory molecule aids intracellular signalling 
Ig alpha - CD79a
Ig beta - CD79b
carry out signalling fn of BCR
60
Q

What are ITAM molecules and how are they phosphorylated?

A

Immunoreceptor Tyrosine based activation motifs

Ligation BCR causes phosphorylation of ITAM

61
Q

What is the effect of ITAM phosphorylation?

A

Downstream effects - differentiation into plasma cells and Ab production

62
Q

What is the effect of BCR ligation?

A

Clonal expansion
Following Ag recognition by BCR
B cells activated to proliferate

63
Q

What is clonal expansion?

A

When one B cell gets activated it becomes a clone

64
Q

What occurs after clonal expansion and describe the properties of these cells?

A

Majority of cells become effector cells/ plasma cells
Endoplasmic reticulum - plasma cells have multiple as it’s site of Ab production
Mitochondria - have lots of as require lots of energy to produce Ab

65
Q

Describe the lifespan of plasma cells

A

Limited lifespan - die within few days (apoptosis)

Small proportion cells remain as long lived memory B cells - able to respond rapidly upon reinfection

66
Q

What triggers class switching?

A

Triggered by Ag interaction w/ B cells

67
Q

What is the primary Ab response?

A

IgM

68
Q

What occurs upon activation? (secondary response)

A

B cell changes Ab production to other classes Ab - esp IgG

Can also be IgA, IgE - depends on functional requirement

69
Q

What can occur during class switching?

A

Somatic hypermutation can occur
Point mutation into variable region gene sequence
Produced closely related clones with slight difference Ag specificity and affinity

70
Q

What occurs during somatic hypermutation?

A

Mutations that improve Ag affinity are selected for and expanded in affinity maturation
Requires T cell help

71
Q

How can Ab be used in clinic?

A

Ab can be raised against any organic substance

Can do this by injecting Ag into animals (mice) - produce Ab against Ag

72
Q

How can Ab be produced for clinical use? (more detail)

A

Take Ab producing B cells from mice and fuse w/ B cell of tumour line eg. myeloma cells

Produces hybridoma cells which can undergo continuous proliferation

Hybridoma cells screened for desired Ab clone
Clones are grown and produce large amount identical Ab - can be harvested for use

73
Q

What are the issues with Ab produced from mice?

A

Constant region heterogeneity = Mice Ab have different constant region and so recognised by human immune system as foreign

Illicits prod. of anti - antibodies -> formation of immune complexes + inflammation

74
Q

How were issues with mice Ab overcome?

A

Engineering Ab

75
Q

What are the different types of engineered Ab?

A

Chimeric Ab - made by fusing murine variable region (responsible for Ag binding) w/ human Fc constant domains
= less immunogenic Ab and Fc region can interact w/ human effector cells to generate immune response

Humanised Ab - murine hyper-variable region w/ fully human Ab
Even less immunogenic but still possibility as hyper-variable region foreign

Fully human monoclonal Ab - phage display libraries (in vitro McAb) or humanised mice

76
Q

How can the different types of engineered Ab be differentiated?

A

Type of Ab identified by suffix that’s used

Chimeric - iximab
eg. infliximab - treats rheumatoid arthritis, Crohn’s disease and ulcerative colitis
inhibits TNF - alpha

Humanised - zumab
eg. alemtuzumab - treats B cell leukaemia
targets Ag CD52 on T + B lymphocytes

Fully human Ab - umab
eg. adalimumab - treats rheumatoid arthritis, Crohn’s disease and ulcerative colitis
inhibits TNF - alpha

77
Q

What are checkpoint inhibitors?

A 
New class monoclonal Ab
Interfere w/ inhibitory signals that regulate lymphocytes

eg. Ipilimumab - anti - CTLA4
Nivolumab - anti - PDI
Revolutionised cancer therapy

Blocking above checkpoints = T cells can become activated + prod. responses against tumours

Infection and Immunity (8 decks)

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