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POM IMMUNOLOGY > Immune Tolerance > Flashcards

Immune Tolerance Flashcards

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1
Q

What is immune regulation?

A

It is the control of the immune response to prevent inappropriate reactions

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2
Q

Why is immune regulation required?

A

Avoid excessive lymphocyte activation and tissue damage during normal protective responses against infection;
Prevent inappropriate reactions against self antigens (‘tolerance’)

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3
Q

Why is immune tolerance important?

A

To shut down an immune response after it is not needed to avoid inflammation and damage to our own tissues

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4
Q

What is autoimmunity?

A

Immune response against self(auto)-antigens= pathologic

Disorders are often classified as “immune-mediated inflammatory diseases”

Systemic or organ-specific

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5
Q

What are examples of auto-immune diseases?

A

Rheumatoid arthritis, irritable bowel disease, multiple sclerosis, psoriasis
(affects 2-5% of people)
- genetic legacy of surviving black death

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6
Q

What are the features of auto-immune diseases?

A

Fundamental problem: imbalance between immune activation and control;

Failure of control mechanisms is the underlying cause autoimmune diseases;

Underlying causative factors: susceptibility genes + environmental influences

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7
Q

What are the underlying causative factors of autoimmune diseases?

A

susceptibility genes and environmental influences

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8
Q

Are autoimmune diseases more common in women or men?

A

women

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9
Q

What is the fundamental problem in regulating immune responses?

A

The imbalance between immune activation and control

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10
Q

What is the immune mechanism of autoimmunity?

A

May result from immune responses against self antigens (autoimmunity) or microbial antigens (Crohn’s disease);

Immune response is inappropriately directed or controlled;
effector mechanisms of injury are the same as in normal responses to microbes;

May be caused by T cells and antibodies;

Many immunological diseases are chronic and self- perpetuating: because it is attacking self-antigen there is always more antigen to attack.

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11
Q

How are allergies considered an autoimmune disease?

A

An allergic response is a harmful immune response to an normally non-harmful antigen which causes tissue damage and disease

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12
Q

What mediates allergic responses?

A

Antibody (IgE) and mast cells- acute anaphylactic shock

Or T cells- delayed type hypersensitivity

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13
Q

What is hypercytokinemia?

A

A cytokine storm
- too much immune response
- often in a positive feedback loop
- triggered by pathogens entering the wrong compartment (sepsis) or failure to regulate response to correct level

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14
Q

How is hypercytokinemia linked to sepsis?

A

It is a part of sepsis

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15
Q

What are the 3 phases of cell mediated immunity?

A

Induction
Effector
Memory

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16
Q

Go into more detail about the steps of cell mediated immunity?

A
  1. cell infected, DC collects material
  2. MHC: peptide TCR interaction
  3. Naive T becomes effector
  4. Effector cell sees MHC: peptide on infected cell performs function
  5. Effector pool contracts to memory
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17
Q

What is meant by self-limitation?

A

The immune systems first response is to eliminate the antigen which initiated the response, meaning the first signal for the lymphocytes has been eliminated

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18
Q

How are self-limiting responses manifested?

A

by decline of immune responses

principle mechanism= immune response eliminates antigen that initiated the response
=> the first signal for lymphocyte activation is eliminated

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19
Q

What are the three signals required to license a cell to respond?

A

Antigen recognition
Co-Stimulation (cell to cell contact)
Cytokine release

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20
Q

How do responses against pathogens decline as the infection is eliminated?

A

Apoptosis of lymphocytes that lose their survival signals (antigens, etc.)
Memory cells are the survivors

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21
Q

What limits responses to persistent antigens?

A

Active control mechanisms may function to limit response to persistent antigens (self-antigens, possibly tumuts and some chronic infections)
- often grouped under tolerance
- basis of cancer immunotherapy

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22
Q

What are the three possible outcomes of an immune response?

A

Resolution - no damage

Chronic Inflammation - active inflammation and attempts to repair damage ongoing

Repair - healing with scar tissue and regeneration. Fibroblasts and collagen synthesis.

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23
Q

What is tolerance?

A

specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen (tolerogen vs immunogen)

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24
Q

What is the significance of immune tolerance?

A

– All individuals are tolerant of their own antigens (self-tolerance); breakdown of self-tolerance results in autoimmunity

– Therapeutic potential: restoring tolerance may be exploited to prevent graft rejection, treat autoimmune and allergic diseases

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25
What is meant by self tolerance?
Self Antigens will not cause harm to us
26
When does tolerance occur?
Before the T or B cells ever enter the circulation (central tolerance) Or once in the circulation (peripheral)
27
What is central tolerance?
The destruction of self- reactive T and B cells in the sites of their production / maturation, before they enter circulation
28
Where does central tolerance occur?
In the bone marrow and the thymus for B and T cells
29
What happens to the cells that recognise self-antigens?
they are eliminated (deletion) or made harmless in the generative organs as part of the maturation process
30
What is the central tolerance mechanism for B cells?
if immature B cells in the bone marrow encounter any antigen which can cross link their IgM, then apoptosis is triggered
31
What is the mechanism for central tolerance for T cells?
- T cell selection occurs in the thymus - More complex than B cells, because of MHC: TCR interactions - Need to select for T cell receptors which are capable of binding self MHC/ self peptide Is T cell useless? Doesn’t bind to any self-MHC at all Death by neglect (apoptosis) Is T cell dangerous? Binds self MHC too strongly Apoptosis triggered – negative selection Is T cell useful? Binds self MHC weakly Signal to survive – positive selection
32
How can a T cell developing in the thymus encounter MHC bearing peptides that might be expressed in other parts of the body?
A specialised transcription factor allows thymic expression of genes that are expressed in peripheral tissues - so these proteins and therefore peptides can be made and presented to T cells
33
How does AIRE promote self tolerance?
by allowing the thymic expression of genes from other tissues
34
What does AIRE stand for?
AutoImmune REgulator
35
What does an AIRE deficiency lead to ?
Multi-organ autoimmunity (Autoimmune Polyendocrinopathy Syndrome type 1)
36
What is peripheral tolerance?
destroy or control any self reactive T or B cells which do enter the circulation - picks up on any escapees and also things that change
37
What determines B cell antigen specificity?
BCR which is surface bound antibody - BCR has a light and a heavy chain - Each is encoded by an individual gene, which is made by recombination of building blocks - this occurs in the bone marrow before the B cell is released
38
How does the high level of IL-2 receptors on Tregs affect peripheral tolerance?
The Tregs therefore soak up the IL-2, meaning other lymphocytes like B cells and T cells cannot get as much IL-2, and therefore are not stimulated to proliferate as much
39
What can happen to a B cell after antigen exposure?
1. antibody production 2. memory 3. affinity maturation
40
What is somatic hypermutation?
Unlike T cells, B cells can change specificity after leaving the bone marrow - This is normally good- as it improves antibody quality - Exposure to environmental antigens or self-antigens in the context of infections can alter the outcome
41
What is an example of bad somatic hypermutation?
Anti-streptococcus pyogenes antibodies can cross react with heart muscle
42
What are the mechanisms of peripheral tolerance?
Normal T cell response Anergy Ignorance Deletion/ AICD Regulation (with a regulatory cell)
43
What is peripheral tolerance Anergy?
Naive T cells need co-stimulatory signals in order to become activated Most cells lack co-stimulatory proteins and MHC class II If a naive T cell sees its MHC/peptide ligand without appropriate costimulatory protein it becomes anergic - Less likely to be stimulated in future even if co-stimulation is then present
44
What is meant by peripheral tolerance Ignorance?
Antigen may be present in too low a concentration to reach the threshold for T cell receptor triggering Immunologically privileged sites e.g. eye, (brain) Compartmentalisation of cells and antigen controls interactions
45
What is peripheral tolerance AICD?
Antigen Induced Cell Death Activation through the T-cell receptor can result in apoptosis Influenced by the nature of the initial T-cell activation events In peripheral T cells is often caused by the induction of expression of the death ligand, Fas ligand (CD95 ligand, FasL)
46
What are some of the immunosuppressive cytokines that Tregs release?
TGF, IL-10
47
What are Tregs?
T Regulatory cells which regulate the activation of other T cells and other cells asw
48
What is the phenotype of regulatory T cells?
CD4, high IL-2 receptor (CD25), Foxp3 transcription factor
49
What are the mechanisms of action for T regulatory cells?
– Secretion of immune- suppressive cytokines (TGF-beta, IL-10, IL-35), – Inactivation of dendritic cells or responding lymphocytes
50
What affect does IL-10 have?
Causes cells to express more death ligands
51
What affect do Tregs have on DC's?
They inhibit dendritic cells
52
What happens if there is a mutation in factor FoxP3?
Mutation in FoxP3 leads to severe and fatal autoimmune disorder - Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome. Mice had similar condition called scurfy – was associated with mutations in FoxP3 (Forkhead box Protein 3)
53
What is IL-10?
Key anti-inflammatory cytokine Multi-functional (pleiotropic) Acts on a range of cells Blocks pro-inflammatory cytokine synthesis including TNF, IL-6, IL-8, IFNγ Downregulates Macrophage functions Viral mimics
54
When is regulation especially important?
in pregnancy - Tregs only exist in mammals - exposure to new antigen - expressed in the context of foreign MHCI
55
What are the two types of Tregs?
Natural Tregs (nTreg) and Inducible Treg (iTreg)
56
What are natural regulatory T cells (nTreg)?
Development (in thymus) requires recognition of self antigen during T cell maturation Reside in peripheral tissues to prevent harmful reactions against self
57
What are inducible regulatory T cells (iTreg)?
Develop from mature CD4 T cells that are exposed to antigen in the periphery; no role for thymus Maybe generated in all immune responses, to limit collateral damage
58
What do Tregs reflect?
The Th subsets seen in T effectors
59
What are the specialized subset of cells of CD4 T helper cells?
Tfh= Pro-antibody= IL-21 Th17= control bacterial and fungal infection= IL-17a, IL-17f Th2= anti-multicellular organisms= IL-4, IL-13 Treg (Th0)= anti-inflammatory= IL-10, IL-35, TGFB Th1= boost cellular immune response= IFN-y
60
What are cytokines?
Cytokines program the immune response They can focus it for the right kind of response They can be inflammatory (increase the response) Or anti-inflammatory (decrease the response) Examples include: Interferon gamma, Interleukin 2, IL-10
61
What are chemokines?
Chemokines drive movement around the body Act like address labels sending stuff to the right place Chemokine receptor profiles change with activation state of the cells
62
What is the Fas ligand?
a death ligand
63
How does the Fas ligand result in antigen induced cell death?
As an immune response progresses, Fas protein expression is upregulated When Fas is ligated by FasL on CD8 T killer cells, it triggers apoptosis of the cell
64
What is ignorance in relation to peripheral tolerance?
When the antigen concentrations are too low to trigger a T cell response
65
If you have an antigen, by no co-stimulation, what happens to the cell?
it becomes anergic
66
How can cells become anergic due to the effect of Tregs?
Anergy occurs when there is no co-stimulation (CD28 on T cell to B7 on B cell). Treg cytokines cause B7 expression to decrease meaning less co-stimulation, leading to the cells becoming anergic
67
What can affinity maturation sometimes lead to?
The production of self reactive B cells
68
Where does somatic hypermutation occur?
In the germinal centers of lymph nodes and spleen
69
What is Ig class switching?
When a b cell goes from producing one type of immunoglobulin to another
70
During class switching, what is happening to the genome of the antibody?
Somatic hypermutation
71
During class switching which part of the BCR changes?
The constant region of the heavy chain, not the variable region - this is so the antigen specificity is not affected
72
Which enzyme is upregulated by cytokines to allow for class switching?
AID - allows cuts to be made in the DNA, thus producing VDJ rearrangement
73
What is FoxP3?
Protein which is important in the development and regulation of Treg, T cells which limit the immune response
74
What do mutations in FoxP3 lead to?
Severe autoimmune diseases like IPEX and Tregs are not produced properly
75
What does IL-10 do?
Blocks pro-inflammatory cytokine synthesis including TNF, IL-6, IL-8, IFN-gamma and down regulates macrophage functions
76
What is an immune privileged area?
A site which can tolerance the introduction of new antigens without eliciting an immune response eg eyes and brain
77
Where does immunological ignorance occur?
In the eyes or brain as they are immunologically privileged
78
What type of animal are Tregs found in?
Mammals
79
Why are Tregs only found in mammals?
They are critical in pregnancy, as you get half MHC from mum and half MHC from dad, which may be seen as foreign antigens so tolerance is critical
80
Which Treg type develops in the thymus?
Natural Treg
81
Where do inducible Treg's come from?
Develop from mature CD4 T cells that are exposed to antigen in the periphery; no role for thymus
82
How do T cells shape the immune response for different pathogens?
Through the use of cytokines
83
Which T Helper cell is involved in controlling bacterial and fungal infections?
Th17
84
What cytokines do TfH release?
IL-21
85
How would you describe T cell help?
it is cross regulated T helper type defined by transcription factors Cytokines shape transcription factor pathways Cross-regulation
86
How does a naive CD4 + T cell become specialised CD4 cells?
87
where are T follicular helper cells located?
Tfh are located in secondary lymphoid organs (SLOs), including the tonsil, spleen and lymph nodes.
88
What structures do TfH play a particular role in?
The development of germinal centers
89
what co-stimulation and cytokines do TfH use to help B cells proliferate?
Co-stimulation = have CD40 which interacts with CD40L on B cell Cytokine = produces IL-21
90
Which T cell Cytokines drives Ig class switching?
IL-4, IL-5, TGF-Beta, IFN-gamma
91
Why is it necessary to delete cells before they enter into circulation?
Approximately 10^15 possible TCR and 10^15 possible antibodies generated at random Some of these will be self-reactive Therefore need to be removed
92
What is meant by anergy as a mechanism for peripheral toleance?
Naive T cells need antigen and CO-STIMULATION in order to be activated When a T cell sees an antigen on MHC of APC, and bind, however does not have appropriate co-stimulation - becomes ANERGIC (unresponsive) and is therefore even less likely to stimulate a response in the future
93
What is meant by ignorance as a mechanism of peripheral tolerance?
When the antigen is not in high enough concentration for the naive T cell to become activating - leading to the T cell to become unresponsive
94
Where does ignorance as a peripheral tolerance mechanism occur?
in immunologically privileged sites
95
What is AICD as a mechanism for peripheral tolerance
When the APC presents an antigen with Fas (death ligand) as its co-stimulatory molecules, drives the cell to apoptosis
96
What happens to B and T cells with different signals (Antigens, Co-stimulation, cytokines)?
97
Do T cells shape the antibody response?
Yes, The constant region (the stem of the antibody) is important in the function. Different antibody classes have different constant regions. The differences in function reflect the different types of response required to clear pathogens. There are a number of gene cassettes that can be swapped in and out.
98
What drives Ig class switch?
T cells cytokine - the cytokine depends on the type of T helper cell IFNy, Il-4, TGF-B, IFNy, IL-4, TGF-B

POM IMMUNOLOGY (13 decks)

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