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MIIM30002 - Principles of Immunology > Lecture 18 - B cells - Development > Flashcards

Lecture 18 - B cells - Development Flashcards

1
Q

Where do B cells mature?
Give some features of this location

Where did they get their name?

A

Bone marrow
• Secure (encased in bone)
• Anatomically distinct compartment

Bursa of Fabricius:
• birds generate their immature B cells in this organ

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2
Q

What are so called ‘effector B cells’?

A

Plasma cells

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3
Q

Why is the bone marrow a ‘dangerous place’?

A

Prone to disease

e.g. irradiation affecting the bone marrow could lead to leukaemia

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4
Q

Until when can new B cells be produced?

A

Throughout life

NB T cells: up to 15 years

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5
Q

What is the BCR?

A

Antibodies bound to the surface of B cells

Antibody: secreted soluble BCR

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6
Q

Describe the events after antigen engagement of the BCR

A 
1. Engagement of native antigen w/ BCR
(NB do not require presentation from MHC or other molecules
2. Proliferation
3. Differentiation into plasma cells
4. Secretion of antibodies
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7
Q

Which sort of antigen are B cells really good at recognising?

Why is this good?

A
  • Higher molecular weight
  • Folded proteins in native form:
  • toxins
  • Do not require co-stimulation

This is good because it means that the B cells can recognise the antigen much more quickly; doesn’t need time for processing and presentation

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8
Q

What is the reason for the name of plasma cells?

A

Often found in the plasma

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9
Q

What are the functions of Ab?

A
  • Direct neutralisation
  • Opsonisation
  • ADCC
  • Complement activation
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10
Q

What is the life span of B cells?

Where do memory B cells reside?

A

Around 10 years

However, the memory response against a given antigen will last up to 60 years

Reside in the BM, LNs, spleen

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11
Q

Describe development of B cells

A

In BM:

  1. Pre-pro B cell
  2. Pro B cell
  3. Pre B cell
  4. Immature B cell

Periphery:

  1. Mature B cell (naïve)
    6a. Plasma cell
    6b. Memory B cell
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12
Q

At what stage is B cell development complete?

Compare the following terms:
• Naïve B cell
• Mature B cell
• Immature B cell

A

After B cells leave the BM, they are considered mature = ‘naïve’

A naïve B cell is mature

The order is:

  1. Immature (still in BM)
  2. Mature = naïve (secondary lymphoid organs, yet to experience antigen)
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13
Q

Compare pre and pro B cells

A

‘Pro’ comes before ‘pre’

Pro: progenitor
Pre: precursor

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14
Q

Describe McFarlane Burnet’s Clonal Selection Theory

A
  1. Pool of naïve B cells in lymph nodes
  2. Antigen drains into lymphatics, and into lymph nodes
  3. B cells come into contact w/ the antigen
  4. The single B cell that is specific for the Ag binds it with its BCR
  5. BCRs cluster, binding Ag, cross linking
  6. Intracellular activation signal in B cell
  7. Migration, proliferation of millions of clones (all with the same specificity)
  8. Differentiation into plasma cells, which release the Ab into the blood & tissues
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15
Q

What is the estimated number of antibodies?

A

1 x 10^6

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16
Q

What is the lineage of B cell development?

A
  1. Pluripotent Haematopoeitic stem cell (HSC)
  2. Multipotent progenitor (MPP)
  3. Common lymphoid progenitor (CLP)
  4. Pre-B cell
  5. B cell
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17
Q

What are MPPs?

A

Multipotent progenitors

  • Can not self-renew
  • Can form CLP & CMP
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18
Q

What is CLP?

What can it form?

A

Common lymphoid progenitor

Forms:
• Pre-NK cells
• Pre-B cells
• Thymocyte (goes on to form T cells)

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19
Q

Compare committed and uncommitted cells in the BM

A

Uncommited:
• HSC
• CLP
• CMP

Committed:
• B cells etc.

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20
Q

What is the default of a developing cell?

Why is this important?

A

To die

To survive, it has to receive a positive signal

It must assemble a functional B cell receptor to receive this positive signal

The B cells are only useful to the body if they have a functional B cell receptor

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21
Q

What are stromal cells?
Where are they found?

Describe their function

A

Critical for B cell development
• Often provide the critical positive signals

Located:
• Bone Marrow
• Lymph nodes

They are not white blood cells, rather tissue cells

Function:
Release of essential factors for bone development:
 • IL-7
 • CXCL12
 • FLT3 ligand
 • SCF
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22
Q

Describe the location inside the BM where B cells develop

A

Endosteum: inner lining of central sinus in long bone

Cells first develop here, then move along the stromal cell into the centre of the sinus

Endosteum → Middle of stromal cells → Central sinus → into vasculature, & circulation

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23
Q

Describe the ordered events in B cell development in the BM

A
  1. MPP attracted to BM stromal cell w/ chemokines (CXCL12)
  2. Stromal cell releases factors (IL-7, FLT3 ligand)
  3. Development into CLP; migration along stromal cells into the centre of the sinus
  4. Exposed to the next set of signals; IL-7 released by stromal cells, IL-7R expressed by CLP
  5. Developing B cells migrate further into the centre along stromal cells

NB Integrins are important for attaching the developing B cells to the stromal cells

24
Q

What is the role of IL-7R?
When is it expressed
What happens w/o its expression?

A

Receptor for IL-7

IL-7R expressed at CLP stage

IL-7 signalling through the receptor helps CLP → pro B cell

B cells don’t develop without it

25
Q

Compare:
• pro-B cells
• Large pre-B cells
• Immature B cells

A

Pro-B cell:
• No functional protein expressed
• DJ has rearranged

Large Pre-B cell:
• Expression of:
• Heavy chain + SLC
• Have pre-B cell receptor

Immature B cell:
• Expression of:
• Heavy chain + Light chain

26
Q

What is allelic exclusion?

A

Only one of the heavy chain alleles is rearranged

NB we have two alleles; one on each chromosome

The other allele remains in germ line configuration

27
Q

What is the heavy μ-chain?

A

Successfully rearranged heavy chain for IgM (i.e. the first heavy chain made)

28
Q

Describe the pre-B cell checkpoint

A

It is important to check that the rearrangement of the heavy chain is successful before we progress on to rearrangement of the light chain

Surrogate light chain binds to the heavy chain

If the heavy chain can form a complex with the SLC, a success signal will be transmitted (with Igα and Igβ)

This also finalises allelic exclusion.
If the pre-B cell receptor is not signalling, we still have the other allele, which will then undergo arrangement

29
Q

Which genes are important for the expression of the surrogate light chain?

A

E2A+EBF

30
Q

What is the important thing about pre-BCR engagement?

A

It is antigen independent

Do not need antigen for the receptor to be engaged

31
Q

When do we call it a pre-B cell?

A

Once it has passed the pre-B cell checkpoint

32
Q

How many potential alleles of the light chain before rearrangement?

A

4; two of each κ and Lambda

33
Q

Why does it take 3 months for Bruton’s XLA to emerge?

A

IgG from the mother cross the placenta and provide protection for the first three months

34
Q

What is isotopic exclusion?

A

Only one of κ and lambda is expressed

35
Q

Describe the expression pattern of RAG

A

Two peaks:
• Pre-pro B cell & Pro B cell: heavy chain rearrangement
• Small Pre B cell: light chain rearrangement

36
Q

What is PAX5?

When is it important?

A

Transcription factor, vital for B cell development

Expressed around the pre B cell, immature B cell stage

Elimination of PAX5 from B cell, development of B cells from pro- to pre- can be reversed

37
Q

Who is Sir Gustav Nossal?

A

PhD student of McFarlane Burnet

• Confirmed clonal selection theory, through proving allelic exclusion, i.e.

One cell produces only one antibody

His experiment:
• Two different rabbits
• Made a chimera mouse by irradiating it, then giving it a bone marrow transplant from two different types of rabbits.
• Two different types of B cells in mouse
• However, there was only ever one type of Ab produced; either Ab from one of the donors, or from the other
• This proves that one B cell only makes one antibody

38
Q

Describe the process of selection

A

Negative selection:
• If the B cell encounters a strongly cross-linking antigen in the BM

→ Clonal deletion
→ Receptor editing

39
Q

List the checkpoints of B cell deveopment

A
  • V-DJ rearrangement (heavy chain)

* V-J rearrangement (light chain)

40
Q

What is µ:κ?

A

Ig that has used the kappa chain

41
Q

What is the result of the spurt of proliferation that occurs after successful rearrangement of the heavy chain?

A

Multiple clones have the same heavy chain.
Each clone then goes on to rearrange the light chain differently.
They do not end up with the same iodiotype

42
Q

How does allelic exclusion occur?

A

Not known at the moment

43
Q

What is E2A important for?

At what stage is it expressed?

A

Surrogate light chain expression

Expressed at CLP stage
Forms a complex with EBF, which is vital at the pre B cell stage

44
Q

When is FLT3 expressed?

What is its role?

A

Expressed at the MPP stage of B cell development

Induces expression IL-7R at the CLP phase

45
Q

Compare the Immunoglobulin expressed on the surface of immature and mature B cells

A

Immature: IgM+

Mature: IgD+, IgM+

46
Q

What releases IL-7?

A

Bone marrow stromal cells

47
Q

What effect does IL-7 bring about?

A

Growth factor for all cells of the lymphoid lineage (B cells, T cells, NK cells)

48
Q

What is the B cell equivalent of naïve T cells?

What are the features of these?

A

Naïve T cells = Immature B cells

They have both completed their development and moved out into the periphery.
Neither have yet experienced their antigen

49
Q

At which stages of development do B cells express IL-7R?

A

Up until the immature B cell stage

50
Q

At which stage does the following occur:
• V(L)-J(L)
• V(H) - DJ(H)
• D(H) - J(H)

A

V(L)-J(L): small pre B cell

V(H) - DJ(H): pro B cell

D(H) - J(H): Pre-pro B cell

51
Q

At which stage is the heavy chain rearrangement complete?

A

Large pre B cell

52
Q

At which stage is the light chain rearrangement complete?

A

Immature B cell

53
Q

At which stage do B cells leave the BM?

A

Once they are immature (i.e. heavy and light chains rearranged)

54
Q

When is IgD expressed?

Describe the process

A

Mature B cells (i.e. naïve B cells)

  1. Light chain is rearranged and expressed as IgM
  2. No strongly binding antigen encountered
  3. Delta heavy chain expressed
  4. IgD expressed on cell surface
55
Q

Which factors do BM stromal cells release that are vital for B cell development?

What are some other factors vital for B cell development?

A
  • IL-7
  • CXCL12
  • FLT3 ligand
  • SCF
  • IL-7R expression
  • RAG
  • E2A+EBF (SLC expression)
56
Q

Describe Receptor editing

A
  • RAG is still active after light chain rearrangement
  • It can rescue cells form clonal deletion:
  • Continuing light chain rearrangement
  • New receptor specificity is now expressed
  • If receptor is still self-reactive, the B cell is deleted

MIIM30002 - Principles of Immunology (30 decks)

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