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Cellular and Molecular pathology > 25. Immunological Tolerance > Flashcards

25. Immunological Tolerance Flashcards

1. Understand why immunological tolerance is necessary and the damaging consequences of failed immunological tolerance. 2. Compare and contract the mechanisms of tolerance acting on the developing T cells in the thymus and mature T cells in the periphery. 3. Explain the mechanisms of tolerance which shape the B cell repertoire both in the bone marrow and in the periphery.

1
Q

What does the adaptive immune system allow for?

A
  1. Tailor made responses to specific antigens.
  2. Immunological memory
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2
Q

What is needed for the adaptive immune system to function?

A

antigen specific receptors

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3
Q

How do T cell recognise specific antigens?

A
  1. A specific T cell receptor on the cell surface.
  2. Can only recognise antigens presented on MHC complexes
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4
Q

How do B cells recognise specific antigens?

A
  1. A specific B cell receptor on the cell surface. (a membrane bound Ig)
  2. Can recognise antigens in there native form and doesn’t use MHC
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5
Q

What forms of antigen can BCRs recognise?

A
  1. Antigens on the cell
  2. Free antigens
  3. Whole antigens with their tertiary structure
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6
Q

How diverse are the antigen receptors?

A
  1. 50 trillion different antibodies
  2. 1 quintillion different T cell receptors
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7
Q

How do we create the immune diversity from a limited number of genes?

A
  1. VDJ recombination with random combinations of different gene segments.
  2. Junctional diversity with random addition or removal of nucleotides.
  3. Pairing of different light/heavy chain or different a/ß chains
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8
Q

What are the pros of antigen receptor diversity?

A

Allows us to recognise and respond to a diverse array of pathogens and stay healthy.

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9
Q

What are the cons of antigen receptor diversity?

A

They can make receptors capable of recognising harmless self-antigens are also randomly generated. This leads to potential for autoimmunity.

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10
Q

What is immunological tolerance?

A

A number of mechanisms protect the individual from self-reactive T and B cells, preventing autoimmunity by ensuring self-tolerance.

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11
Q

What is central tolerance?

A
  1. Established in immature lymphocytes during their development in the central lymphoid organs.
  2. B cells = bone marrow
  3. T cells = Thymus
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12
Q

What is Peripheral tolerance?

A

Mechanisms acting on lymphocytes in peripheral tissues

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13
Q

Why is T cell tolerance so important?

A

It impacts B cell tolerance as T cells are needed to stimulate antibody production.

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14
Q

When are most self-reactive T cells deleted?

A

During T cells development in the thymus (central tolerance)

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15
Q

Can self-reactive T cells escape central tolerance?

A

Yes and there are mechanisms to control them in the periphery.

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16
Q

What happens if T cell tolerance mechanisms fail?

A
  1. Serious autoimmune diseases.
  2. Involve B cells and T cells
  3. eg. Rheumatoid arthritis, multiple sclerosis
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17
Q

Where are T cells made?

A

They are made in the bone marrow and then migrate to the thymus for development.

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18
Q

Stages of T cell development: Double negative

A
  1. The first stage of development.
  2. CD4- and CD8-
  3. TCRaß-
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19
Q

Stages of T cell development: Double positive

A
  1. The second stage of development.
  2. CD4+ and CD8+
  3. TCRaßint
  4. At this stage they start to up regulate TCR.
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20
Q

Stages of T cell development: Positive selection and single positive

A
  1. T cell recognises MHC2 becomes a CD4 T cell.
  2. T cell recognises MHC1 becomes a CD8 T cell
  3. These are single positive T cells
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21
Q

What is positive selection?

A
  1. The process of ensuring a developing T cell expresses a TCR that recognises a self-peptide:MHC complex.
  2. Ensures the tolerance the self MHC.
  3. The T cell receives survival signals and is positively selected.
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22
Q

What is negative selection?

A
  1. Ensures a developing TCR doesn’t express a TCR that recognises a self-peptide:MHC complex with dangerously high affinity.
  2. If it does it is deleted and undergoes apoptosis.
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23
Q

What happens to a T cell with a TCR that has too low affinity?

A
  1. not strong enough interactions with MHC
  2. not rescued by positive selection survival signals.
  3. “death by neglect” = apoptosis
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24
Q

What happens to T cells with a TCR with low affinity?

A

They survive positive selection and mature to become naive T cells.

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25
Q

What happens to T cells with a TCR with too high affinity?

A
  1. Very strong interactions with self MHC molecules.
  2. Dangerously self reactive.
  3. Deleted by central tolerance in negative selection
26
Q

What proportion of T cells are eliminated in the thymus?

27
Q

What could happen if high affinity self reactive T cells escape negative selection?

A

autoimmune disease

28
Q

What is the reality of T cell central tolerance?

A
  1. Allows only self-MHC restricted, self-tolerant T cells to leave the thymus.
  2. not 100% effective
  3. Weakly self reactive T cells can escape negative selection
29
Q

Why do some T cells escape negative selection?

A

not all self antigens are expressed in the thymus

30
Q

What controls weakly self-reactive T cells?

A

peripheral tolerance

31
Q

What are the different mechanisms of peripheral tolerance?

A
  1. Regulatory T cells
  2. Antigen sequestration
  3. Anergy
  4. Activation induced cell death
  5. immune privileged sites
32
Q

What is antigen sequestration?

A
  1. Antigens are hidden from T cells.
  2. Physically behind a barrier where the T cells are separated (eg the blood brain barrier)
  3. Functionally so no APC are present to activate the T cells.
33
Q

Why does antigen sequestration work?

A

If self reactive T cells never encounter the self antigen they will not be activated and not cause autoimmunity.

34
Q

What 3 signals do T cells need to activate?

A
  1. TCR interaction with peptide:MHC complex for activation.
  2. Co-stimulatory signals like CD28 for survival.
  3. cytokine signalling for differentiation.
35
Q

What is T cell Anergy?

A
  1. TCR engagement without co-stimulation can induce anergy.
  2. A state of unresponsiveness characterised by a lack of proliferation and IL-2 secretion in response to an antigen.
  3. Functional inactivation of self-reactive T cells.
36
Q

What is activation induced cell death?

A
  1. After self-antigen recognition a brief period of activation is followed by apoptosis.
  2. Apoptosis is induced by the Fas pathway.
  3. T cells will express the death receptor Fas and when the T cell is activated FasL is induced.
  4. Fas:FasL interaction induces apoptosis by suicide or fratricide.
37
Q

What are immune privileged sites?

A
  1. Tissues in the body that are too precious and damage would be bad.
  2. They are not subject to normal immune response.
  3. Brain, Eye, Testis, Uterus
38
Q

What is the immune status of immune privileges sites?

A
  1. Tissue barrier that exclude naive lymphocytes.
  2. They lack normal lymphatic drainage so you don’t get APC there.
  3. soluble factors are locally produced to suppress the immune response.
  4. FasL is expressed to trigger apoptosis in lymphocytes that do access the site.
39
Q

What are often targets for autoimmune disease?

A

self-antigens in immune privileged sites

40
Q

What are regulatory T cells?

A
  1. Most are CD4 T cells.
  2. Suppress the immune response.
  3. Thymically derived regulatory T cells (tTreg) arise during T cell development.
  4. Patients without tTreg have catastrophic failures in peripheral tolerance.
41
Q

What different about tTreg cells?

A
  1. They are allowed to exit the thymus despite having a self-reactive TCR
  2. Their self reactivity falls between the threshold for positive and negative selection.
42
Q

What is the function of tTreg cells?

A

They actively prevent autoimmunity when they encounter a self antigen.
They do this by not secreting IL-2 and suppressing neighbouring cells.

43
Q

What is Foxp3?

A

A transcription factor essential for the regulatory function of tTreg cells.

44
Q

What does the expression of Foxp3 do?

A

It causes naive CD4+ T cell to become regulatory cells.

45
Q

What can the loss of Foxp3 function cause?

A
  1. The loss of tTreg cells
  2. hyper responsive T cells
  3. fatal autoimmunity in IPEX patients
46
Q

How does Foxp3+ tTreg cells help maintain peripheral tolerance?

A
  1. Granzymes are released to induce death in T cells and APC.
  2. suppressive cytokines are produced to inhibit other cells.
  3. Expression of CD25 allows tTreg to compete for IL-2
  4. Altering dendritic cells function to indirectly reduce T cell activation.
47
Q

What are the stages of B cell development?

A

In the bone marrow:
1. pro-B-cell
2. Pre-B-cell
3. Immature B cell

48
Q

When does VDJ recombination in B cell development occur?

A

at the pro-B cell stage

49
Q

What interactions are essential for B cell development?

A

Bone marrow stromal cells expressing:
1. Adhesion molecules
2. stem cell factors
3. IL-7

50
Q

What is productive rearrangement?

A

The expression of IgM on the surface of immature B cells

51
Q

What is B cell central tolerance?

A
  1. Occurs before the immature B cells leave the bone marrow.
  2. The surface IgM associates with other transmembrane signalling molecules to form the BCR.
  3. BCR interacts with ligands in the bone marrow stroma.
  4. Signals delivered via the BCR determine the fate of the B cell.
  5. Immature B cells that have no strong reactivity to self-antigens mature and migrate to the periphery.
52
Q

What is the ideal BCR?

A

One that has no interaction between self-antigens and the BCR.

53
Q

What are the 4 fates of self-reactive B cells in the bone marrow?

A
  1. Deletion
  2. Receptor editing
  3. Anergy
  4. Ignorance of its antigen
54
Q

B cell central tolerance fates: deletion

A
  1. Encounters a strongly self-reactive antigen.
  2. Development is arrested.
  3. Deletion by apoptosis
55
Q

B cell central tolerance fates: receptor editing

A
  1. Encounters a strongly self-reactive antigen.
  2. Development is arrested.
  3. Further rearrangement of the Ig light chain to replace the self reactive receptor
  4. New BCR.
56
Q

What are the 2 fates of B cell receptor editing?

A
  1. The new receptor is still self reactive and the B cell undergoes apoptosis.
  2. The new receptor is no self-reactive so the B cell undergoes normal development.
57
Q

What is the evidence for receptor editing in B cells?

A
  1. 1 transgenic mouse expressing HEL as a self antigen.
  2. 1 transgenic mouse expressing anti-HEL on B cells.
  3. Breed them.
  4. Most B cells are negatively selected in the bone marrow and are deleted.
  5. Some B cells escape deletion through receptor editing.
58
Q

B cell central tolerance fates: Anergy

A
  1. Caused by soluble antigens
  2. A state of unresponsiveness to the self-antigen.
59
Q

B cell central tolerance fates: Immunological ignorance

A
  1. The concentrations of the self-antigen are too low to stimulate a B cell response so they remain ignorant.
  2. The antigen may be inaccessible to the B cell.
  3. The antigen may have a very low affinity for the BCR
60
Q

Why does B cell tolerance need to be maintained in the periphery?

A
  1. When B cells leave the bone marrow they are not fully mature.
  2. These transitional B cells undergo further development in the periphery.
  3. So some self-reactive B cells encounter their antigen for the first time in the spleen.
  4. These B cells that encounter self-antigens in the periphery undergo peripheral tolerance mechanisms.
61
Q

What are the B cell peripheral tolerance mechanisms?

A
  1. Deletion by apoptosis.
  2. induction of anergy
  3. B cell ignorance
  4. Survival and maturation
62
Q

How can B cell tolerance be affected by T cells?

A
  1. B cells depend on T cells for production of high affinity, class switched antibodies.
  2. If the T cell repertoire lacks T cells with self-reactive TCR, the B cell with that self reactive BCR won’t receive signals necessary for high affinity autoantibody production.
  3. However the reverse is also true. Failures in T cell tolerance can cause generation of self-reactive antibodies.

Cellular and Molecular pathology (25 decks)

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