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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
What is the efficiency of central tolerance calculated in mouse
5 x 10^7
26
What does stroma provide?
Micro environment for T cell development and selection
27
What are the lobules differentiated into?
Outer vortex and inner medulla filled with bone-marrow derived thymocytes
28
Cortex
Mature thymocytes that receive survival signals which make them proliferate
29
Where does central tolerance take place?
Medulla of thymocytes
30
What are the mediators of the central tolerance?
Cortical epithelial cells, dendritic cells and macrophages
31
Cortical epithelial cells
Pro-survival signals
32
What provides the signal for positive and negative selection?
Medullary epithelial cells, macrophages and dendritic cells
33
Double positive cell
Express both CD4 and CD8
34
Mature T cell receptor
Alpha and beta
35
What is the efficiency of central tolerance calculated in mouse
5 x 10^7
36
What is negative selection?
Thymocytes will recognise self-MHC molecules but will also recognise self peptides
37
Removal of useless T cells
T cell which have T cell receptor which interact very poorly with MHC molecules will be removed out of neglect
38
Positive selection
Interaction with MHC molecules gives little signal but too strong, these come out of thymus
39
Negative selection
Cells that have strong interaction with self peptides and self MHC will be deleted
40
What are positive and negative selected defined by?
Strength of interaction
41
If no interaction occurs...
Death of neglect
42
If the interaction/ affinity is too high
cells will die
43
If the interaction has intermediate affinity, what happens to the cells?
Come out of thymus
44
What does regulatory T cells have higher affinity for?
Self antigen
45
What doesn’t the thymus produce?
Thyroglobulin
46
What does the thyroid medullary epithelial cells express?
Transcription factor - autoimmune regulator (AIRE)
47
What does AIRE do?
Tell the genome of the thyroid of the epithelial cells to produce peptides
48
What else does AIRE do?
Stimulates thymic expression of many self-antigens which were thought to be resurrected to peripheral tissues
49
AIRE was one of the transcription factor known in what context?
Autoimmune disease
50
What are the consequence of AIRE mutation?
Autoimmune polyendocrinopathy with candidiasis Ectodermal dysplasia ( autoimmune polyendocrine syndrome [APS-1])
51
Why do we develop autoimmunity?
In addition to central tolerance there is peripheral tolerance
52
What happens to mature self-reactive lymphocyte that recognise self antigens in peripheral tissues?
Inactivated (anergy) Killed (deleted) Suppressed
53
What is anergy?
T cell that recognises an antigen with inappropriate costimulation (IL2 missing) or second signal isn’t sufficient or negative costimulators
54
What does missing cd28 prevent?
Prevent T cell from expressing molecules that protects them against cell death part of activation
55
What happened to T cells that don’t express protective proteins?
Die
56
Anergy in action?
Antigen recognition and naive T cells lead a signal to cd28 to become fully activated and proliferate and become effector cells
57
Anergy/deletion
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
What does the expression of CTLA-4 do ?
Interaction will lead to cell exiting the cell cycle and die
59
Why is the activation of second signal important?
Critical for the production of IL-2
60
What does the activation of IL-2 produce?
Proapoptic molecules
61
What does CD28 induce?
Anti-adoptive proteins so T cell will proliferate and survive
62
What does defects in second signal lead to?
Recognition antigen induces expression of FAS and FAS ligand
63
What happens when T cell are close together?
Molecules can interact and trigger apoptosis
64
What happens If signal occurs without signal 2?
There is no production of antipoptic proteins and T cells won’t be able to survive and die of Apoptosis
65
What are the alternative mechanism for anergy?
Ubiquitination of signalling mediators during T cell receptor activation
66
Regulatory T cells
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
Escape of T cell tolerance
Sequestration antigen hidden from immune system Privileged sites prevention by FAS and cytokines Immune regulation by regulatory T cells
68
Where does B cell development happen?
Bone Marrow
69
How is central tolerance in B cell achieved?
Cross linking of the receptors
70
What antigens induce central tolerance in B cells?
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
What are the requirements for cross-linking?
Polyvalent or membrane-bound
72
How are immature B cells deleted?
Membrane bound antigen
73
What does self reactive B cells do?
Edit their receptors to become non-reactive Die by the process of Apoptosis
74
What does B cell recognise?
Whole protein self antigen
75
Where do the B cells present the protein self antigen?
MHC class 2 complex
76
What is signal 2 for B cell?
CD40
77
What is CD40 ligand expressed by?
T helper cells which delivers second signal to the B cell to proliferate and differentiate leading to activation
78
What are required for therapy in transplants?
Anti-CD40 ligand and anti-CD40 antibodies
79
Tolerance in B lymphocyte: central tolerance
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
B cell: peripheral tolerance
Anergy Regulatory T cells
81
Central tolerance:
Apoptosis Change In receptors (receptor editing;B cells) Development of regulatory T lymphocytes (CD4+ T cells)
82
Peripheral tolerance
Anergy Apoptosis (deletion) Suppression
83
What are the potential clinical application for tolerance?
Promote tolerance to tissue graft Transplantation Control damaging immune response in hypersensivity Control damaging in autoimmune disease Limit tumour growth
84
Define tolerance
Failure to attack the body’s own proteins and other antigens

Immunology (20 decks)

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