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Immunology year 3 > Lecture 3 Germinal Centres > Flashcards

Lecture 3 Germinal Centres Flashcards

1
Q

Innate vs adaptive response:
- Innate immune cells + Characteristics
Adaptive immune cells + characteristics

A 
Innate:
Phagocytes
Dendritic cells 
Complement
Natural Killer cells 
Natural antibodies

Characterized by:
Rapid onset
Short duration

Adaptive immune cells:
B-cells
T-Cells

Characterized by:
Delay onset
Longer duration
Lifelong protection

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2
Q 
Where do Germinal centers rise?
Where?
where are b-cells contained?
Where are T-cells contained?
Where is the germinal center?
Where do dendric cells live?
A

Secondary lymphoid organs and spleen.

The cortex contains B-cell follicle
The paracortex contains the T-cell zone
Dendritic cells live in and around the T cell zone
Germinal centers arise witin the boarder of the T/B cell zones.

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3
Q

What results do we want from a germinal center?

-2 cells and what they provide

A

Plasma cells- shorted lived. Provide large amount of soluble secreted antibodies

Memory cells - long lived, can differentiate to plasma cells upon antigen re-challenge.

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4
Q

The key players of the germinal center?

A

Dendritic cell/macrophages/APC

B-cells

T-follicular helper cells

Follicular dendritic cells

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5
Q 
What do each cell do? 
Dendritic cell?
TfH cell?
B-cell?
FDC?
A

Dendritic cells present antigen to T cells in complex with -MHC Class I (CD8 ctc) MHC class II (CD4 ThC) provide co-stimulatory signals eg: CD80/CD80L

TfH: Express the transcription factor BCL6. expresses chemokines receptor CxCR5. A subset of differentiated CD4 T cells promote B cells maturation.

B-cells: Produce antibodies. present antigen to T-cells in complex with MHC C I and MHC C II. provide co-stimulatory signals CD80/CD86

FDC: not actually a dendritic cell. non-migratory cell can retain antigen for long periods. presents antigen to B-cells in the form of immune complexes on the cell surface.

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6
Q

The germinal center overview: reaction 7 steps:

A
  1. Dendritic cell + antigen bind to naïve T-cell activating it to become a follicular T helper cell, upregulates CxCR5.
  2. the new TfH cell migrates towards the B-cell follicle and interfaces with a B-cell Activating it.
  3. The TfH cell + B-cell complex travels into the B-cell zone, seeding the germinal center.
  4. B-cell enters the darkzone and undergoes proliferation and somatic hypermutation. this expand the GC.
  5. MAture B-cells then travel to the light zone and interface with FDC for selection. This checks for a functional BCR.
  6. The successful B-cell receptor then moves to TfH cell and present antigen. If enough antigen is present on the BCR it will be released to differentiate to memory or plasma cell
  7. If the antigen is not enough the B-cell returns to step 4 to proliferate and continue somatic hypermutation to get better.

If step 5 interface with FCD fails the B-cell dies.

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7
Q

Cell-Cell interaction: the immunological synapse
- What is it?
How it forms?
Areas and proteins found?

A

The immunological synapse is where tow cells meet to communicate.

Formed by cell-cell interactions (spreading) to increase surface area

The increase surface area is followed by redistribution of proteins to enable molecular cross talk.

Areas:
cSMAC: central supra-molecular activation complex: contains TCR, MHC II, plus co-stimulatory: CD28/B7 CTLA4/CD80

pSMAC: peripheral: Adhesion molecules: LFA1, ICAM 1

dSMAC: distal: CD45, CD44, CD43

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8
Q

Signals required for TfH cell differentiation:
Signal 1 - primary and co-stimulatory
Signal 2 - ICOS
Signal 3 Autocrine

A

Signal 1: TCR + MHC C II antigen present and co-stimulatory signals CD28/B7/CD86 we need further signals to differentiate.

2 signal: Icos + ICOS L is expressed by the APC and ligates ICOS receptor expressed on T cell surface within cSMAC

3 Signal: IL-21 is secreted by existing TfH cells this ligates to IL-21 receptor at the T-cell surface causing differentiation.

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9
Q

Signals for TfH cell migration:
What ICOS & IL-21 do in cell?
this leads to?
and?

A

ICOS & IL-21 induce the express the linage defining: transcription factor BCL-6.

BCL-6 induces expression of CxCR5 a receptor for the chemokine CxCL13

CxCL13 is highly expressed at the boarder within the B-cell zone so the TfH are drawn towards the boarder between B/T cells zones.

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10
Q

How is the germinal center seeded?

A

TfH cell migrates to the B-cell boarder and cross talks with a B-cell through TCR:MHC C II ICOS/ICOS L CD40/CD40L, IL21-IL21R, PD-1/PDL-1

On successful activation of the B-cell. The B-cell/T-cell complex moves into the B-cell follicle seeding the germinal center.

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11
Q

Germinal center structure?
where are FDC?
where are T cells
Where are B-cells

A

light zone: contains FDC (stromal cells of the light zone), contains TfH cells and selecting B-cells (Centrocytes)

Dark-zone: Contains cortical reticular cells (stromal cells of the dark-zone) proliferating B-cells (centroblast)

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12
Q

B-cell proliferation in dark-zone?
B-cell under go?
mutation occur in what region?
Mutations cause?

A

GC-B-cells in the dark-zone undergo proliferation and somatic hyper mutation.

Mutations are introduced into the hypervariable region CDRs within the V region of the antibody heavy and light chain.

  • changes in amino acid substitution
  • this is done by enzyme activation induced cytidine deaminase (AICD) which cut the DNA to cause SMH & class switching.
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13
Q

Mutations = change in BCR affinity:
What mutations causes?
occurs at random but what is the desired effect?
Explain affinity maturation?

A

Mutations in the CDRs leads to structural and charge alterations in the BCR antigen binding site.

Mutations are at random and can lead to an increase or decrease in affinity of the binding site.

Through somatic hypermutation in the dark-zone and selection in the light zone. Antibody affinity slowly rises over the course of the germinal center response = affinity maturation.

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14
Q

Migration of B-cells to the light-zone for selection:
After proliferation and SHM they downregulate what meaning?

Cortical reticular cells secrete? that causes?
FDC Secrete? that causes?
Centrocyte vs Centroblast expression?

A

Once B-cells have undergone proliferation & SMH they downregulate CxCR4 this causes migration towards the light-zone via CxCR5.

Cortical reticular cells secrete CxCL12 which is at high concentrations in the dark-zone. CxCL12 binds CxCR4

FDC secrete CxCL13: high concentrations in light zone. CxCL13 binds CxCR5 so when the B-cells loose CxCR4 they move to the light zone.

Centroblast: Centrocyte:

  • CxCR 5 + - CxCr5+
  • CxCR4 + - CxCR 4 -
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15
Q

Light zone selection:
FDC
B-cell sipping antigen

A

FDC are key antigen source in the light zone but they dont express MHC CII.
FDC retain and cycle antigen in an intact form bound to complement receptor (CR2) - means many epitopes retained on a single antigen.

B-cells with new BCR test their affinity against the FDC antigens.
-little/no affinity b-cells are signaled to die by apoptosis,

-Any more B-cell captures antigen and carry it away. B-cells receive survival signals.

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16
Q

Centrocyte:FDC interactions are a key checkpoint.

A

Recruitment by CxCL13.

Survival signals BAFF secreted by FDC binds to BAFF-R

Immunocomplexes: Complement receptor 1 (CR1) to capture antigen.

Removal (pro-death signals) secrete MFG8e binds to receptor on B-cell surface signaling apoptosis.

17
Q 
2nd selection the second test: 
B cell TfH interactions
-antigen presentation? 
-Signal & co-stimulatory signals
-Amount of antigen?
A

B-cells (centrocytes) process and present captured antigen in complex with MHC C II to TfH cells in the light zone. -forms immunological synapse. MHC C II/TCR and co-stimulatory: CD28/CD80/CD86

in addition survival signals are needed CD40/CD40L

TfH cells need maintenance signals ICOSL to ICOS.

The amount of antigen is key in this step: The more antigen the better the antibody.
The less antigen the lower the antibodies affinity.

18
Q

TfH-centrocyte interaction: use of PDL-1 and PD-1?

A

B-cells can influence the TfH cells.

PDL-1 : PD-1R Signals prevent TfH cell upregulating CxCR3 and holds them in the light zone.

Concentrates the TfH cell in the GC.

Maintains the BCL-6 phenotype.

19
Q

TfH centrocyte interactions continued:

  • IL21 uses, effects in B-cell and TfH?
  • Centrocytes next steps?
A

IL-21 is crucial, IL-21R is expressed on both TfH and B-cells.

IL-21 only produced by TfH cell on successful interactions.

IL-21 for B-cells provides proliferation signals (i.e go and proliferate to improve BCR)

For TfH reinforces BCL-6 expression and promotes their activity inducing co receptor expression on B-cell (CD86)

This means B-cells re-express CxCR4 and travel back to the dark-zone to do another round = increased affinity for the BCR.

20
Q 
TfH mediated class switching: 
what enzyme causes class switching?
by what process?
signals that lead to class switch?
A

Activated induced cytidine deaminase AICD is the enzyme required.

From IgM & IgD (low affinity) to IgA, IgE, IgG (high affinity).

AICD excises DNA segments encoding their class to leave the class of choice.

Cytokines from the TfH instruct class switch: CD40/CD40L is crucial. Lacking in CD40 leads to hyper IgM syndrome.

See notes for cytokine break down.

21
Q

GC end point- plasma/memory cells

  • Memory cell properties?
  • Plasma cell properties?
A

Memory cells are long lived:

  • Enter circulation as patrolling cells or reside in lymphoid tissue or target organs.
  • Spleen is a major reservoir of memory cells.

Plasma cells:

  • once matured leave the GC.
  • secrete large amounts of antibody that increase serum titres.
  • Small proportion traffic to bone marrow and are retained for long periods.
22
Q

Commitment to plasma/memory is unclear but:

Common signals?
plasma cells?
Memory B-cells?

A

Common signals:

  • strength of the TCR ligation of TfH- amount of antigen.
  • CD40/CD40L and co-stimulatory signals

Plasma cell signals:

  • IL-21 upregulates plasma cell gene program.
  • BLIMP-1, BCL-6, IRF4
  • IRF-4 knockout mice lack plasma cells

Memory cells:

  • IL-24 inhibits differentiation to plasma cells
  • BACH-2 & IRF 8 upregulation
  • BACH-2 knockout mice lack memory cells.

Immunology year 3 (3 decks)

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