Lecture 10:Immune Tolerance Flashcards

1
Q

What are self-peptide?

A

Peptide of antigen that belong to our own body

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2
Q

What do immune system respond to?

A

Foreign antigens but not to self-antigens

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3
Q

How are T lymphocytes that produce self antigens eliminated?

A

Thymic development called central tolerance

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4
Q

Why must self-reactive lymphocytes be selected against?

A

To prevent autoimmunity

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5
Q

define immunological tolerance

A

Specific unresponsiveness/inability to respond to antigen that is induced by exposure of lymphocyte to that antigen

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6
Q

What does breakdown of self-tolerance lead to ?

A

Autoimmunity

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7
Q

Define autoimmune disease

A

Active immune response against self-antigens

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8
Q

What are the therapeutic potential of immune tolerance

A

Graft rejection treat autoimmune and allergic diseases Prevent autoimmune response in gene therapy Stem cell transplantation Break tolerance in cancer

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9
Q

Why is a mechanism for T/B cell repertoire selection needed?

A

Many of thymocyte will recognise self antigen Certain type of thymocytes harmful in the thymus

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10
Q

How is T cell receptor generated?

A

Recombination during transcription of TCR gene alpha and beta chains

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11
Q

What are the different sites?

A

Variable (V) Diversity (D) Joints (J) Constant region (R)

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12
Q

When thyroid cells are inflamed, what can they express?

A

MHC class molecules

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13
Q

What level does immune system act on?

A

Central and peripheral tolerance

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14
Q

Thymus

A

Multiple checkpoints at which T cells are maturing in it and selected

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15
Q

What structure does thymus have?

A

Lobulated structure with a stroma of epithelial cells and connective tissue

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16
Q

What does stroma provide?

A

Micro environment for T cell development and selection

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17
Q

What are the lobules differentiated into?

A

Outer vortex and inner medulla filled with bone-marrow derived thymocytes

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18
Q

Cortex

A

Mature thymocytes that receive survival signals which make them proliferate

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19
Q

Where does central tolerance take place?

A

Medulla of thymocytes

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20
Q

What are the mediators of the central tolerance?

A

Cortical epithelial cells, dendritic cells and macrophages

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21
Q

Cortical epithelial cells

A

Pro-survival signals

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22
Q

What provides the signal for positive and negative selection?

A

Medullary epithelial cells, macrophages and dendritic cells

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23
Q

Double positive cell

A

Express both CD4 and CD8

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24
Q

Mature T cell receptor

A

Alpha and beta

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25
Q

What is the efficiency of central tolerance calculated in mouse

A

5 x 10^7

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26
Q

What does stroma provide?

A

Micro environment for T cell development and selection

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27
Q

What are the lobules differentiated into?

A

Outer vortex and inner medulla filled with bone-marrow derived thymocytes

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28
Q

Cortex

A

Mature thymocytes that receive survival signals which make them proliferate

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29
Q

Where does central tolerance take place?

A

Medulla of thymocytes

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30
Q

What are the mediators of the central tolerance?

A

Cortical epithelial cells, dendritic cells and macrophages

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31
Q

Cortical epithelial cells

A

Pro-survival signals

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32
Q

What provides the signal for positive and negative selection?

A

Medullary epithelial cells, macrophages and dendritic cells

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33
Q

Double positive cell

A

Express both CD4 and CD8

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34
Q

Mature T cell receptor

A

Alpha and beta

35
Q

What is the efficiency of central tolerance calculated in mouse

A

5 x 10^7

36
Q

What is negative selection?

A

Thymocytes will recognise self-MHC molecules but will also recognise self peptides

37
Q

Removal of useless T cells

A

T cell which have T cell receptor which interact very poorly with MHC molecules will be removed out of neglect

38
Q

Positive selection

A

Interaction with MHC molecules gives little signal but too strong, these come out of thymus

39
Q

Negative selection

A

Cells that have strong interaction with self peptides and self MHC will be deleted

40
Q

What are positive and negative selected defined by?

A

Strength of interaction

41
Q

If no interaction occurs…

A

Death of neglect

42
Q

If the interaction/ affinity is too high

A

cells will die

43
Q

If the interaction has intermediate affinity, what happens to the cells?

A

Come out of thymus

44
Q

What does regulatory T cells have higher affinity for?

A

Self antigen

45
Q

What doesn’t the thymus produce?

A

Thyroglobulin

46
Q

What does the thyroid medullary epithelial cells express?

A

Transcription factor - autoimmune regulator (AIRE)

47
Q

What does AIRE do?

A

Tell the genome of the thyroid of the epithelial cells to produce peptides

48
Q

What else does AIRE do?

A

Stimulates thymic expression of many self-antigens which were thought to be resurrected to peripheral tissues

49
Q

AIRE was one of the transcription factor known in what context?

A

Autoimmune disease

50
Q

What are the consequence of AIRE mutation?

A

Autoimmune polyendocrinopathy with candidiasis Ectodermal dysplasia ( autoimmune polyendocrine syndrome [APS-1])

51
Q

Why do we develop autoimmunity?

A

In addition to central tolerance there is peripheral tolerance

52
Q

What happens to mature self-reactive lymphocyte that recognise self antigens in peripheral tissues?

A

Inactivated (anergy) Killed (deleted) Suppressed

53
Q

What is anergy?

A

T cell that recognises an antigen with inappropriate costimulation (IL2 missing) or second signal isn’t sufficient or negative costimulators

54
Q

What does missing cd28 prevent?

A

Prevent T cell from expressing molecules that protects them against cell death part of activation

55
Q

What happened to T cells that don’t express protective proteins?

A

Die

56
Q

Anergy in action?

A

Antigen recognition and naive T cells lead a signal to cd28 to become fully activated and proliferate and become effector cells

57
Q

Anergy/deletion

A

Naive T cells on epithelial cells or on APC don’t become mature T cells will only receive signal 1 that means cells can produce IL2 - cannot proliferate - won’t become protected against apoptosis - deleted

58
Q

What does the expression of CTLA-4 do ?

A

Interaction will lead to cell exiting the cell cycle and die

59
Q

Why is the activation of second signal important?

A

Critical for the production of IL-2

60
Q

What does the activation of IL-2 produce?

A

Proapoptic molecules

61
Q

What does CD28 induce?

A

Anti-adoptive proteins so T cell will proliferate and survive

62
Q

What does defects in second signal lead to?

A

Recognition antigen induces expression of FAS and FAS ligand

63
Q

What happens when T cell are close together?

A

Molecules can interact and trigger apoptosis

64
Q

What happens If signal occurs without signal 2?

A

There is no production of antipoptic proteins and T cells won’t be able to survive and die of Apoptosis

65
Q

What are the alternative mechanism for anergy?

A

Ubiquitination of signalling mediators during T cell receptor activation

66
Q

Regulatory T cells

A

Inducible Arise when there is anti-inflammatory in presence of cytokines (IL-10) Recognises self on APC Prevent proliferation, activation and effector functions of T cells Characterised by FOXp3

67
Q

Escape of T cell tolerance

A

Sequestration antigen hidden from immune system Privileged sites prevention by FAS and cytokines Immune regulation by regulatory T cells

68
Q

Where does B cell development happen?

A

Bone Marrow

69
Q

How is central tolerance in B cell achieved?

A

Cross linking of the receptors

70
Q

What antigens induce central tolerance in B cells?

A

Antigens that are in high concentration in blood (ligate many receptors at the same time) Antigens that immobilise on the membrane of cells because they will ligate more than 1 receptor

71
Q

What are the requirements for cross-linking?

A

Polyvalent or membrane-bound

72
Q

How are immature B cells deleted?

A

Membrane bound antigen

73
Q

What does self reactive B cells do?

A

Edit their receptors to become non-reactive Die by the process of Apoptosis

74
Q

What does B cell recognise?

A

Whole protein self antigen

75
Q

Where do the B cells present the protein self antigen?

A

MHC class 2 complex

76
Q

What is signal 2 for B cell?

A

CD40

77
Q

What is CD40 ligand expressed by?

A

T helper cells which delivers second signal to the B cell to proliferate and differentiate leading to activation

78
Q

What are required for therapy in transplants?

A

Anti-CD40 ligand and anti-CD40 antibodies

79
Q

Tolerance in B lymphocyte: central tolerance

A

Deletion of immature cells by high-affinity antigen Recognition in the bone marrow - some immature cells may change their antigen receptors when they encounter antigens in the vine marrow

80
Q

B cell: peripheral tolerance

A

Anergy Regulatory T cells

81
Q

Central tolerance:

A

Apoptosis Change In receptors (receptor editing;B cells) Development of regulatory T lymphocytes (CD4+ T cells)

82
Q

Peripheral tolerance

A

Anergy Apoptosis (deletion) Suppression

83
Q

What are the potential clinical application for tolerance?

A

Promote tolerance to tissue graft Transplantation Control damaging immune response in hypersensivity Control damaging in autoimmune disease Limit tumour growth

84
Q

Define tolerance

A

Failure to attack the body’s own proteins and other antigens