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IMIN 371 > Germinal centres, B cell differentiation, and regulation > Flashcards

Germinal centres, B cell differentiation, and regulation Flashcards

1
Q

Where does a B cell contact its Ag in the LN and where does it move to?

A
  • contact Ag in follicle
  • moves to paracortex (T cell zone) after contact
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2
Q

Where do B cells receive their second signal (co stimualtion)?

A

Receive costimulation from activated Th cells

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3
Q

Describe how B cells present Ag to T cells to get help

A
  1. B cells edocytose Ag bound to BCR (RME)
  2. peptides from internalized Ag.s are very efficiently present in MHC-ll
  3. cell-cell complex formed when MHC-II+Ag is recognized by activated Th cells
  4. allows B cells to receive costimulatory signals
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4
Q

What are the conditions that have to be met for a B cell presenting Ag to a Th cell?

A
  • B cells receive help from T cells that recognize the same Ag
  • epitope recognized by BCR does not have to be the same as that recognized by the TCR (linked recognition)
  • B cells can also act as APCs and present Ag to naive T cells
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5
Q

What is the importance of linked recognition?

A

prevent auto-Ab production

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6
Q

What type of T cells do B cells present Ag to? What signals do they receive?

A
  • B cells present to Th2 and TFH cells
  • cotimulatory signal = CD40/CD40L
  • cytokines = IL-4 and 21
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7
Q

When do T cells express CD40L?

A

Upregulated upon activation

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8
Q

What are the roles of Th2 cells in the context of B cell activation? (is it the primary activator subtype, how this subtype created, what does it do for B cells)

A
  • not the primary B cell activator subtype
  • naive T cells differentiate to Th2 in the presence of IL-4
  • Th2 help limited to some B cell activation and induce class switch to IgE
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9
Q

What are the roles of TFH cells in the context of B cell activation? (is it the primary activator subtype, how this subtype created, what does it do for B cells)

A
  • primary B cell activator subtype
  • differentiate into TFH in the presence of IL-6 and 21
  • TFH express Bcl-6 (master transcriptional regulator)
  • migrate to B cell zone and are required to form germinal centres
  • high CXCR5 and low CCR7 expression (attracts and retains TFH to B cell follicle)
  • produce IL-21 to support differentiation of B cells
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10
Q

What are the effects of CD40L and cytokines (IL-2, 4, 5, 6 and 21) on B cells?

A

CD40L:
- transmembr protein expressed on the surface of activated Th2 and TFH cells
- signal required for affinity maturation, isotype switching, and memory

cytokines:
- secreted by Th cells to promote B cell proliferation and differentiation
- influences class switching

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11
Q

What is X-linked hyper-IgM syndrome? (what causes it, what are the effects)

A
  1. due to LOF mutations in CD40L
  2. effects
    - impaired humoral immune response to TD Ag.s
    - also have some defects in cell-mediated immunity
    - don’t form germinal centres –> lack B cell memory, fail to make high affinity Ab.s, no class switching –> elevated serum levels of IgM
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12
Q

Why in X-linked hyper-IgM syndrome is cell-mediated immunity affected?

A

naive CD8+ T cells require CD40L stimulation

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13
Q

What are the three fates of B cells receiving T cell help?

A
  1. entry into germinal center
  2. IgM-bearing memory cells from primary response
  3. primary focus
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14
Q

What determines if a B cell will go into a germinal centre or primary focus?

A

High IRF-4 and BLIMP-1 expression –> inhibit Pax-5 and Bcl-6 (germinal center fate factors) –> plasma cell fate –> Ab secretion

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15
Q

What happens to B cells that go into primary focus?

A
  • requires high IRF-4 and BLIMP-1
  • formed at the T/B cell border in LN
  • rapid production of IgM Ab.s
  • can class switch to IgG
  • low Ag affinity
  • most die by apoptosis
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16
Q

What is blimp-1?

A

TS repressor critical for plasma cell differentiation, down regulates genes involved in:
- BCR signaling
- Ag presentation
- proliferation

17
Q

What happened when Blimp-1 was knocked out in B cells?

A
  • impaired Ig signaling
  • lack of plasma cells
18
Q

How can we discern plasma cells from other B cells?

A

plasma cells have low levels of B220 and high levels of syndecan-1

19
Q

What cells are found in germinal centres?

A
  • germinal centre B cells (specific)
  • FDCs
  • non-specific IgD+ B cells
  • macrophages
  • TFH cells
20
Q

What are the three important functions of germinal centres?

A
  1. site of affinity maturation and SMH
  2. isotype switching/CSR
  3. memory B cell formation

note: all these features distinguish TD from TI Ag.s

21
Q

Describe the germinal centre reaction

A

T cell zone:
1. naive B cell is activated by TD Ag
2. migrates to germinal centre

Germinal centre (Dark zone)
1. activated B cell enters dark zone
2. B cell begins to proliferate and go under SHM
3. B cell moves to light zone

Germinal centre (light zone)
1. selection of high affinity, mutated, receptor-bearing B cells
2. those that are selected against go under apoptosis
3. those that are selected for can differentiate into plasma cells or memory cells OR can undergo CSR
4. B cells that have class switched can go under light zone dark zone re-circulation

22
Q

What is affinity maturation?

A

production of Abs with high affinity for Ag

23
Q

What mutations occur in SHM and where do they occur?

A
  • type = point muts, insertions, dels
  • occur = VDJ exons and VJ exons
24
Q

What enzyme does SHM require, what does it do?

A

AID (activation induced cytidine deaminase):
- deaminates cytosine into uridine

25
Q

How can a U/G mismatch be repaired?

A
  1. different NTs subsitituted for modified base
  2. bases around modified base can also be modified
  3. modifies sequence of V regions of heavy and light chains
26
Q

Where do FDCs present Ag to centrocytes (mutated BCR)?

A

in the light zone

27
Q

Describe the competition for Ag that occurs in the light zone

A
  1. centrocytes with highest affinity for Ab can compete for limited Ag and are selected to survive (receive survival signals from TFHs and FDCs)
    - high affinity BCRs internalize Ag and present it to TFH cells and receive additional signals to promote cell survival and further differentiation
  2. centrocytes with no or little affinity undergo apoptosis
28
Q

Describe what switch regions are, where they are located in genes, and what they facilitate

A
  • switch regions are upstream of each isotype constant region except for delta
  • switch regions are introns
  • isotype switching involves DNA recombination between switch regions (switch recombination)
29
Q

Describe switch recombination

A
  1. switch regions contain targeting sites for AID
  2. AID initiates DSBs in s(mu) and s(gamma) regions/whatever constant region it will switch to
  3. excision circle (interfering DNA) is created and lost
30
Q

What proteins help in ending the B cell response?

A
  • CD22 = B cell co-inhibitory R
  • -ve regulation by Fc(gamma)Rllb
31
Q

Describe the structure of CD22, where is it expressed?

A
  • expressed on the surface of B cells, associated with BCR
  • intraceullar tail is phosphorylated by Lyn when BCR is activated
  • intracellular tail has 3 ITIMS
  • phosphorylated ITIMs recruit SHP-1
32
Q

What is SHP-1 and what is it’s role in BCR signaling? What happens if SHP-1 is not expressed?

A
  • SHP-1 is a hematopoietic cell specific tyr phosphotase that has two SH2 domains
  • both SH2 domains are required to interact with phosphorylated ITIMs in order to get stable binding of SHP-1 to CD22
  • SHP-1 limits the magnitude and duration of BCR signaling by de-phosphorylating tyr-phosphorylated proteins
  • mic deficient in SHP-1 or CD22 develop autoimmune disease
33
Q

Describe negative regulation of B cells by Fc(gamma)RIIb

A
  1. circulating Ag-IgG complexes bind to Fc(gamma)RIIb on B cell surface
  2. cross linking of bound Ag between BCR and Fc(gamma)RIIb brings Fc(gamma)RIIb close to activated Src kinases (e.g. Lyn)
  3. Lyn phosphorylates ITIMs of Fc(gamma)RIIb
  4. attracts phosphotases that reverse activating signals

IMIN 371 (20 decks)

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