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MIIM30003 - Medical & Applied Immunology > Lecture 2 - Tolerance, B cells > Flashcards

Lecture 2 - Tolerance, B cells Flashcards

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USMLE® Step 1 flashcards
1
Q

Define Immunological Tolerance

A

The non-responsiveness to an antigen which is induced through previous exposure to that antigen

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2
Q

Define Self Tolerance

A

The non-responsiveness to self-antigens (those found in one’s own body)

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3
Q

Why do we need immunological tolerance?

A

Tolerance to:
• Self antigens
• Some foreign antigens (eg. food etc)

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4
Q

Describe the contributions to the understanding of tolerance by Peter Medawar

A

Tolerance to antigens is set up early on

Experiment:
Newborn mice injected with histo-incompatible cells and tolerated

As adults, the mice receive grafts of these histo-incompatible cells, and they are not rejected

i.e. Tolerance has been induced

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5
Q

Describe the contributions to the understanding of tolerance by Macfarlane Burnet

A

Clonal selection theory

Antigen specific clones are sensitive to toleration during their development

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6
Q

List some of the mechanisms of immunological tolerance

A

Remove:
• Deletion
• Receptor editing

Switch off:
• Anergy (cell intrinsic)
• Regulation (cell extrinsic)

Limit access:
• Immunoprivilege
• Ignorance (site or dose)

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7
Q

List some immunoprivileged sites in the body

A
  • The eye
  • The brain
  • Testes
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8
Q

What are the divisions of immunological tolerance?

A

Central
• Thymus (T cells)
• Bone marrow (B cells)

Peripheral
• Lymphoid tissue
• Organs

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9
Q

What are transgenic mice?

How are they used with respect to immunological tolerance?

A

Mice that has been bred with human genes

Process:
• Desired genes on a plasmid are injected into a single cell mouse embryo

They are very useful as an animal model for studying tolerance

Genes:
• Model antigens (e.g. BM or pancreas tissue)
• Clonal antigen receptors

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10
Q

Describe the HEL model

A

HEL: Hen egg lysozyme model

Two transgenic mice:
• Anti-HEL mouse
• HEL mouse

These two mice are crossed
By looking at the lymphocyte populations, we can learn about tolerance

HEL mouse:
• Membrane bound HEL (strongly cross linking) → Deletion of B cells
• Soluble HEL (weakly cross linking) → Anergic B cells

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11
Q

What are the main mechanisms of central B cell tolerance?

When does each occur?
What does each involve?

A 
1. Deletion
 • Immature B cell apoptosis
Occurs when:
 • High avidity ligand present
 • Strong cross-linking of BCR to antigen
Involves:
 • Pro-apoptotic molecule 'bim'
 • Reduced expression of BAFF receptor
2. Anergy
 • Cell cannot be activated
Occurs when:
 • Self antigen is soluble
 • Less receptor cross linking
Involves:
 • Cell survives to migrate into the periphery
 • Reduced surface IgM → poorly responsive
 • Most likely eventually dies
 • Unable to up regulate CD86
  1. Receptor editing
    • Can occur when strongly cross linking Ag is present in BM
    • Immature B cell undergoes more light chain rearrangement
    • If new receptor is not self-reactive, the cell lives, if not, deletion or anergy occurs
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12
Q

What sort of antigen will trigger the various mechanisms of central B cell tolerance?

A

Anergy: soluble antigen

Clonal deletion:
• Membrane bound antigen; i.e. multivalent

Receptor editing:
• Membrane bound antigen, i.e. multivalent

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13
Q

At what stage does central B cell tolerance occur?

A

Occurs at the immature B cell stage

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14
Q

Outline the stage of development of B cells

Briefly give the features of the cells at each stage

A
  1. MPP
  2. CLP
  3. Early pro-B cell
    • D-J rearranging
  4. Late pro-B cell
    • V-DJ rearranging
  5. Large pre-B cell
    • VDJ rearranged
    • Pre-BCR checkpoint
  6. Small pre-B cell
    • V-J rearranging of light chain
  7. Immature B cell
    • Heavy and light chains rearranged
    • IgM expressed on surface
  8. Mature B cell
    • IgM and IgD expressed on the surface
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15
Q

Describe the features of self-reactive B cells that make it to the periphery

A 
They will (hopefully) be: 
 • Anergic, i.e. the Ag that they are specific for is soluble

• Clonally ignorant: the Ag is soluble and present, but not cross linking

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16
Q

In which instance will B cells never reach the periphery?

A

If the Ag the B cell is specific for is strongly cross-linking and multivalent (i.e. membrane bound)

In this instance, the B cell will undergo clonal deletion and never make it to the periphery

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17
Q

Strongly cross linking Ag in BM → ?

Weakly cross linking Ag in BM → ?

A

Strongly cross linking Ag in BM → Apoptosis in BM (clonal deletion)

Weakly cross linking Ag in BM → Anergy

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18
Q

Compare IgM expression on mature B cells and anergic B cells in the periphery

A

Anergic B cells in periphery have lower expression of IgM

19
Q

What is notable about the expression of molecules on the surface of anergic B cells?

A
  • ↓ Expression of IgM
  • Fail to up regulate CD86 when they encounter Ag
  • ↓ CXCR5 expression
  • ↓ BAFF receptor expression
20
Q

What is the outcome of anergic B cells’ poor expression of CXCR5?

A

They are unable to access the B cell follicle

21
Q

What are ‘ignorant B cells’?

A

Mature B cells in the periphery that are specific for self-Ag, but do not respond because:
• Self-Ag is non-cross linking, or
• Only expressed outside the BM

They are unaware of their self-antigen at the time of development

22
Q

Describe how breaks down in tolerance can lead to kidney damage

A

Molecular mimicry:

Ignorant naïve T cells in the periphery

Infection with a microbe that shares epitopes with a tissue specific self Ag

B cell response launched against microbe epitope

Now B cells are activated, they can move into the periphery, where they encounter the self-Ag for which they are specific

Formation of immune complexes, which are deposited in the organs that filter blood, e.g. kidney, joints

Activation of the C’ cascade

23
Q

List some immune-mediated disease with a proposed role of molecular mimicry

A
  • Acute rheumatic fever
  • Chagas’ disease
  • Guillain-Barré syndrome
  • Herpetic keratitis
  • Insulin-dependent DM (T1DM)
  • Lyme arthritis
  • Multiple sclerosis
24
Q

What is the microbe or Ag responsible for triggering molecular mimicry in the following diseases:
• Acute rheumatic fever
• Guillain-Barré syndrome
• Glomerulonephritis?

A

ACF: Group A strep

G-B syndrome: Campylobacter

Glomerulonephritis: Group A strep

25
Q

What are the target host-Ag in the following diseases caused by molecular mimicry:
• ARF
• G-B syndrome?

A

ARF: multiple cardiac glycoproteins

G-B syndrome: Peripheral nerve gangliosides

26
Q

Describe the mechanism of peripheral B cell tolerance

Where does it occur?

A

Occurs in 2° lymphoid tissues (i.e. B cell encounters Ag once mature)

Mechanism:
• Self-reactive B cells migrate from blood into LNs
• B cells don’t experience T cell help
• B cells die

Also:
• Anergic B cells struggle to get into follicle

When B cells recognise Ag, but do not receive T cell help, they die

27
Q

Describe the signals required by B cells to respond to antigen

A

Need two signals:
• Antigen
• T cell help (CD40L, cytokines)

28
Q

What happens to B cells in the absence of T cell help?

A

They die

In the sole presence of signal 1, B cells eventually die

29
Q

Describe the structure of a LN

A
  • Afferent & efferent lymphatics
  • Blood vessels
  • 1° lymphoid follicle (B cell zone)
  • 2° lymphoid follicle (containing germinal centres)
  • Paracortex (T cell zone)
  • HEV (in paracortex)
30
Q

Describe how naïve lymphocytes enter LNs

A

Through HEVs

31
Q

Describe how the structure of LNs is set up and maintained

A

1°LF:
• FDCs produce CXCL13
• Mature B cells express CXCR5
• B cells migrate into the follicle

Paracortex:
• FRC make CCL19/21
• Naïve T cells express CCR7
• T cells migrate to paracortex

32
Q

Where are HEV located?

A

In paracortex

33
Q

Describe the events that occur when B cells experience Ag

A
  1. Naïve (mature) B cell experiences Ag
  2. B cell upregulated CCR7 and migrates to the boundary between the follicle and the paracortex
  3. B cell and TFH interact and form the primary focus
  4. B cell migrates back into the follicle to form a GC
  5. SHM, affinity maturation and CSR occur in GC
34
Q

What are the fates of auto-reactive B cells in the periphery?

A
  • Deletion
  • Anergy
  • Survival
35
Q

If mature naïve lymphocytes are anergised or deleted when they experience their antigen in the periphery, how can lymphocytes ever be activated against foreign antigen?

A
  1. Infection with a microbe triggers inflammation
  2. Inflammation results in the up-regulation of co-stimulatory molecules on the APCs such as DCs, and the production of cytokines which activate the lymphocytes
36
Q

What happens when DCs present Ag to naive lymphocytes in the absence of infection or inflammation?

A

The interaction with the lymphocyte will be tolerogenic: i.e. tolerance inducing

37
Q

Describe the important receptors / molecules in B cells that are clonally deleted in central tolerance

A

Increased bim

Decreased BAFF receptor

38
Q

What is bim?

A

Pro-apoptotic molecule

Removes Bcl-2 from Bax/Bak, resulting in the triggering of apoptosis

39
Q

What is BAFF receptor?

A

Detects the survival signal in B cells

40
Q

What is happening in receptor editing?

A

They light chain is rearranged again

NB the heavy chain cannot be edited at this point

41
Q

Where does CCLR19/21 come from?

A

FRCs (Fibro-reticular cells) in the paracortex

42
Q

Describe the apoptotic pathway in B cells

A
  1. Bcl-2 normally keeping Bax and Bak separate
  2. Bim binds Bcl-2
  3. Bcl-2 removed from Bax and Bak
  4. Bax and Bak unite to form a pore in the membrane of the mitochondria
  5. Cytochrome c moves out of the mitochondria through this pore
  6. Formation of apoptosome, activation of caspases
  7. Apoptosis
43
Q

Compare cell surface molecule expression of anergic and ignorant B cells

A

Ignorant B cells express the same surface molecules are normal naïve B cells (i.e. they are fully able to respond to Ag)

Anergic B cells:
↓ IgM, ↓ BAFF, ↓CXCR5, ↓CD86

44
Q

In which situations will B cells in the periphery die?

A

If they fail to get into the B cell follicle

If they do not receive T cell help after becoming activated

MIIM30003 - Medical & Applied Immunology (30 decks)

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