Mechanism of Tolerance

Question 1

What is Immune tolerance?

Answer 1

• the ability of the immune system to be TOLERANT to self antigens
• the ability of the immune system to be TOLERANT to non dangerous antigens
• the ability of the immune system to be TOLERANT to commensal bacteria

Question 2

Immune tolerance can be defined as the immunes ability to be tolerant to antigens from oneself and foreign bodies. What are the 3 most common things that the immune system needs to be tolerant to?

1 - self (on MHC-I), environmental and pathological bacteria antigens
2 - self (on MHC-I), environmental and commensal bacterial antigens
3 - environmental, commensal bacteria and viral antigens
4 - self (on MHC-I), pathological and commensal bacteria

Answer 2

2 - self (on MHC-I), environmental and commensal bacterial antigens

Question 3

What does self tolerance mean?

Answer 3

• immunes systems ability not to initiate an immune response against its own cells
• these are presented as self-antigens on MHC-I molecules

Question 4

What 2 things are needed to activate B cells?

1 - antigen presenting cell presenting antigen to B cell and neutrophils
2 - antigen presenting cell presenting antigen to B cell and macrophage
3 - antigen presenting cell presenting antigen to B cell and cytotoxic T cell
4 - antigen presenting cell presenting antigen to B cell and T helper cell

Answer 4

4 - antigen presenting cell presenting antigen to B cell and T helper cell

Question 5

In order for a B cell to become active what is the basic T cell independent activation?

Answer 5

• B cell binds with an antigen potentially from an APC using the MHC-II = stimulation 1
• TLR provide 2nd co-stimulation
• B cell is now active and can undergo clone expansion with its original antibody (normally IgM)

Question 6

In order for a B cell to become active what is the basic T cell dependent activation?

Answer 6

• B cell has been activated by antigen presenting cell presenting foreign antigen
• T helper cell binds with MHC-II molecule on B cell using CD4 = stimulation 1
• CD40 on B cell and CD40L on T cell bind = stimulation 2
• B cell up-regulates cytokine receptors and T cell secretes them and bind = stimulation 3
• B cell is now active and cytokines determine the antibodies that will be produced by the B cell

Question 7

Once B cells have been activated by T cell independent and dependent pathways, what 2 things happen to the B cells?

Answer 7

• class switching to a different antibody, normally IgM to IgG
• clonally expand creating plasma (antigen producing) and memory B cells

Question 8

T cells require multiple steps to become active. What is the first step of the T cell activate?

1 - T cell expresses CD28 and APC expresses B7 that bind together
2 - T cell binds with a MHC-I or MHC-II molecules
3 - NF-KB is activated increasing cytokine transcription
4 - B cell binds to CD4 helper cell

Answer 8

2 - T cell binds with a MHC-I or MHC-II molecules

Question 9

T cells require multiple steps to become active. What is the 2nd step of the T cell activate?

1 - T cell expresses CD28 and APC expresses B7 that bind together
2 - T cell binds with a MHC-I or MHC-II molecules
3 - NF-KB is activated increasing cytokine transcription
4 - B cell binds to CD4 helper cell

Answer 9

1 - T cell expresses CD28 and APC expresses B7 that bind together

Question 10

T cells require multiple steps to become active. What is the 3rd step of the T cell activate?

1 - T cell expresses CD28 and APC expresses B7 that bind together
2 - T cell binds with a MHC-I or MHC-II molecules
3 - NF-KB is activated increasing cytokine transcription
4 - B cell binds to CD4 helper cell

Answer 10

3 - NF-KB is activated increasing cytokine transcription

Question 11

Once the T helper cell has been activated it up-regulates its production of cytokines and the associated receptors, specifically IL-2. What does this increase in IL-2 secretion do to the T cell?

1 - signals clonal expansion of the B cells
2 - signals clonal expansion of the T cell
3 - activates other T cells
4 - activates B cells

Answer 11

2 - signals clonal expansion of the T cell

- can also stimulate CD8 T cells

Question 12

What is the name given when the immune system becomes self reactive?

Answer 12

• autoimmune disease

Question 13

What is central tolerance?

1 - process of eliminating antigen presenting cells that do no bind antigens
2 - process of eliminating any B and T cells that are self reactive
3 - immune response not responding to innate immune cells
4 - immune system not activating against CNS

Answer 13

2 - process of eliminating any B and T cells that are self reactive
- central relates to central immune sites (thymus, bone marrow, lymph nodes etc..)

Question 14

T cell receptors contain alpha and beta chains and each of these contain the following:

• alpha chain = variable and joining segments (VJ)
• beta chain = variable, diversity and joining segments (VDJ)

The variation of the above segments means that the T cell receptors can have a huge variation that is random. What 2 enzymes are able to signal to the DNA of the T cell to cause VDJ recombination and create random T cell receptors?

1 - RAG-I and RAG-II
2 - VDJ recombinase
3 - autoimmune regulator (AIRE)
4 - activation-induced cytidine deaminase (AID)

Answer 14

1 - RAG-I and RAG-II

Question 15

Once a T cell has been stimulated by RAG-I and RAG-II T cell receptors undergo VDJ recombination, producing a variety of T cell receptors. T cells are then stimulates to produce CD molecules on their surface. Do T cells only present CD4 or CD8 molecules?

1 - just CD4 single positive cell
2 - just CD8 single positive cell
3 - CD4 and CD8 double positive cell

Answer 15

3 - CD4 and CD8 double positive cell

Question 16

Once a T cell has T cell receptors and both CD4 and CD8 receptors, the autoimmune regulator gene (AIRE) is expressed in central lymphoid organs presents peptide antigens to these T cells. What is the name for when an antigen in the central lymphoid tissue is presented to the T cell and an MHC-I molecule binds with the CD8 molecule, and an MHC-II molecule binds with CD4 molecule on the T cell?

1 - negative selection
2 - positive selection
3 - VDJ recombination
4 - hypersomatic mutation

Answer 16

2 - positive selection

- these cells will then move on in their development

Question 17

Once a T cell has T cell receptors and both CD4 and CD8 receptors, the autoimmune regulator gene (AIRE) is expressed in central lymphoid organs presents peptide antigens to these T cells. If an antigen in the central lymphoid tissue is presented to the T cell and an MHC-I molecule does not binds with the CD8 molecule, and an MHC-II molecule does not bind with CD4 molecule on the T cell, what happens to this T cell?

1 - released into circulation
2 - continues to develop its receptors
3 - undergoes apoptosis

Answer 17

3 - undergoes apoptosis

Question 18

Once a T cell has T cell receptors and both CD4 and CD8 receptors, the autoimmune regulator gene (AIRE) is expressed in central lymphoid organs presents peptide antigens to these T cells. Positive selection is when an antigen in the central lymphoid tissue is presented to the T cell and an MHC-I molecule binds with the CD8 molecule, and an MHC-II molecule binds with CD4 molecule on the T cell. However, we need to see if the T cell receptor is able to bind with self antigens that are presented to the T cell. If the T cell receptor associated with the CD4 and CD8 molecules binds to the self antigen what happens to the T cell?

1 - released into circulation
2 - continues to develop its receptors
3 - undergoes apoptosis

Answer 18

3 - undergoes apoptosis

Question 19

Once a T cell has T cell receptors and both CD4 and CD8 receptors, the autoimmune regulator gene (AIRE) is expressed in central lymphoid organs presents peptide antigens to these T cells. Positive selection is when an antigen in the central lymphoid tissue is presented to the T cell and an MHC-I molecule binds with the CD8 molecule, and an MHC-II molecule binds with CD4 molecule on the T cell. However, we need to see if the T cell receptor is able to bind with self antigens that are presented to the T cell. If the T cell receptor associated with the CD4 and CD8 molecules does not bind to the self antigen what is this called and what happens to the T cell?

1 - negative selection
2 - positive selection
3 - VDJ recombination
4 - hypersomatic mutation

Answer 19

2 - positive selection

• good thing as it means the T cell receptors are not binding with self antigens
• negative selection would be if the T cell did bind to the self-antigen

Question 20

Once a T cell has undergoing positive and negative selection, what happens next in its development?

Answer 20

• CD4 and CD8 receptors on T cell will continue to bind with antigens
• which ever has the stronger binding, either CD4 or CD8 the cells DNA will down regulate the other
• the T cell will then become a CD4+ or CD8+ cell, associated with MHC-II and MHC-I, respectively

Question 21

What are regulatory T cells (Tregs)?

1 - B cell subtype
2 -cytotoxic T cell subtype
3 - T helper cell subtype
4 - specialised subpopulation of T cells

Answer 21

• specialised subpopulation of T cells
• act to suppress immune response and maintain homeostasis and self-tolerance
• Tregs can also inhibit T cell proliferation and cytokine production and play a critical role in preventing autoimmunity

Question 22

T cells (Tregs) are specialised subpopulation of T cells that act to suppress immune response and maintain homeostasis and self-tolerance. Tregs can also inhibit T cell proliferation and cytokine production and play a critical role in preventing autoimmunity. What T cells do the Tregs develop from and which tissue does this occur in?

Answer 22

• develop from CD4+ T helper cells in the medulla of the thymus
• come from central lymphoid tissue
• T cells suspected to bind self antigens, but not enough to undergo apoptosis then up-regulate FoxP3 and become Treg cells

Question 23

T cells (Tregs) are specialised subpopulation of T cells that develop from CD4+ T helper cells in the thymus. Tregs act to suppress immune response and maintain homeostasis and self-tolerance. Tregs can also inhibit T cell proliferation and cytokine production and play a critical role in preventing autoimmunity. What transcription factor to Tregs possess that is crucial for their role in regulating the immune system and and preventing autoimmunity?

1 - FOXP3
2 - TNF-a
3 - IL-6
4 - NF-KB

Answer 23

1 - FOXP3

Question 24

Which part of the thalamus does negative selection occur?

1 - cortex
2 - medulla
3 - capsule
4 - corpuscle

Answer 24

2 - medulla

Question 25

Once the heavy chain has been arranged on the B cell receptors, how is the light chain created? 1 - lamda or V prepB light chain is added 2 - VJ segments are re-arranged 3 - light chain copies the heavy chain variable region

Answer 25

1 - lamda or V prepB light chain is added | - light chain is then randomly arranged using the VJ segments

Question 26

Once the heavy and light chain has been arranged on the B cell receptors, the central lymphoid tissue contains a gene that is able to test self antigens on the developing B cells. What is this enzyme called? 1 - phosphokinase 2 - lactate dehydrogenase 3 - autoimmune regulator gene (AIRE) 4 - C reactive protein

Answer 26

3 - autoimmune regulator gene (AIRE)

Question 27

Once the heavy and light chain has been arranged on the B cell receptors, the central lymphoid tissue contains a gene that is able to test self antigens on the developing B cells called autoimmune regulator gene (AIRE). What happens to the B cells that bind to self antigens and what is this process called?

Answer 27

- undergo apoptosis | - called negative selection

Question 28

Once the heavy and light chain has been arranged on the B cell receptors, the central lymphoid tissue contains a gene that is able to test self antigens on the developing B cells called autoimmune regulator gene (AIRE). If the B cell binds with a self antigen, is it always killed off?

Answer 28

- no | - B cell tries to re-arrange the light chains on the B cell receptor

Question 29

Once the heavy and light chain has been arranged on the B cell receptors, the central lymphoid tissue contains a gene that is able to test self antigens on the developing B cells called autoimmune regulator gene (AIRE). What happens to the B cells that do not bind to self antigens?

Answer 29

- develop into mature B cells and are released into circulation

Question 30

Once the heavy and light chain has been arranged on the B cell receptors, the central lymphoid tissue contains a gene that is able to test self antigens on the developing B cells called autoimmune regulator gene (AIRE). What happens to the B cells that do not bind to self antigens and are able to bind with foreign antigens?

Answer 30

- they develop into immature B cells | - process is called POSITIVE selection and occurs before negative selection

Question 31

What is peripheral tolerance?

Answer 31

- 2nd branch of immunological tolerance, after central tolerance - aim is to control self-reactive T and B cells which escaped central lymph tissue

Question 32

Ignorance is a part of peripheral tolerance. What is ignorance? 1 - primary lymphoid tissue fails to recognise self reactive B and T cells 2 - secondary lymphoid tissue fails to recognise self reactive B and T cells 3 - self reactive B and T cells released simply do not react with self antigens 4 - innate immune system does not respond to B and T cells

Answer 32

3 - self reactive B and T cells released simply do not react with self antigens - they do not die or become anergic (lymphocytes fail to give certain responses)

Question 33

What are immune-privileged sites?

Answer 33

- sites that do not elicit an immune response despite presence of foreign antigens

Question 34

Immune-privileged sites are sites that do not elicit an immune response despite presence of foreign antigens. What are some sites in the body?

Answer 34

- brain - eyes - testes - uterus

Question 35

The eye is an immune-privileged site. However, if there is trauma to the eye this can initiate an autoimmune response in the eyes. What can this cause if left untreated?

Answer 35

- blindness across both eyes

Question 36

For a T cell to become activated it needs 3 stimulus: ``` 1st = antigen on MHC-II from professional antigen presenting (PAP) cell binds with T cells CD4+ 2nd = CD28 on T cell binds with B7 on the PAP 3rd = NFKB up-regulates secreting cytokines, such as IL-2 ``` What is anergy? 1 - Treg cells inhibit T cells 2 - inhibiting APC from presenting antigens on MHC-II to T cells 3 - inhibiting the 2nd stimulation required for T cell activation 4 - inducing apoptosis of T cells

Answer 36

3 - inhibiting the 2nd stimulation required for T cell activation - T cell binds with antigen and receives 1st stimulus - 2nd stimulus is not received

Question 37

Anergy is when T cell binds with an antigen and receive their 1st stimulus (MHC-II and CD4+), but they do not receive their 2nd stimulus (CD28 and B7). In addition to this, T cells begin expressing an inhibitory molecule on their surface that will go on to inhibit the T cell further from expressing CD28. What is this inhibitory molecule called? 1 - CD86 2 - cytotoxic T lymphocyte associated protein 4 (CTLA-4) 3 - CD80 4 - IL-6

Answer 37

2 - cytotoxic T lymphocyte associated protein 4 (CTLA-4)

Question 38

Anergy is when T cell binds with an antigen and receive their 1st stimulus (MHC-II and CD4+), but they do not receive their 2nd stimulus (CD28 and B7). In addition to this, T cells begin expressing an inhibitory molecule on their surface that will go on to inhibit the T cell further, called cytotoxic T lymphocyte associated protein 4 (CTLA-4). Why is the production of CTLA-4 so important? 1 - B7 preferentially binds with CTLA-4 2 - B7 preferentially binds with CD40 3 - B7 preferentially binds with CD28 4 - B7 preferentially binds with CD40L

Answer 38

1 - B7 preferentially binds with CTLA-4 | - T cell is inactivated, fail safe mechanism of peripheral tolerance

Question 39

Anergy is when T cell binds with an antigen and receive their 1st stimulus (MHC-II and CD4+), but they do not receive their 2nd stimulus (CD28 and B7). In addition to this, T cells begin expressing an inhibitory molecule on their surface that will go on to inhibit the T cell further, called cytotoxic T lymphocyte associated protein 4 (CTLA-4). How can anti-CTLA-4 be useful as a cancer therapy? 1 - anti-CTLA-4 can induce T cell proliferation 2 - anti-CTLA-4 can stop T cell from being inhibited 3 - anti-CTLA-4 can induce cytotoxic T cells to proliferation 4 - anti-CTLA-4 can induce B cell proliferation

Answer 39

2 - anti-CTLA-4 can stop T cell from being inhibited | - T cells are switched off in cancer, the anti-CTLA-4 would stop this

Question 40

Clonal exhaustion is a part of peripheral tolerance. What is clonal exhaustion? 1 - mature T cells present PD-1 receptors recognised by PD-L1 receptors on APC 2 - naive T cells present PD-1 receptors recognised by PD-L1 receptors on APC 3 - mature T helper cells present PD-1 receptors recognised by PD-L1 receptors on APC 4 - mature cytotoxic T cells present PD-1 receptors recognised by PD-L1 receptors on APC ``` PD-1 = programmed cell death receptor PD-L1 = programmed cell death receptor ligand APC = antigen presenting cell ```

Answer 40

1 - mature T cells present PD-1 receptors recognised by PD-L1 receptors on APC - binding between PD-L1 and PD-1 triggers T cell to shut down

Question 41

Clonal exhaustion is a part of peripheral tolerance. Clonal exhaustion is when T cells that have been active for a long time express programmed cell death receptor (PD-1) on their surface. Profession antigen presenting cells (PAPs) contain PD-L1 and bind with PD-1, triggering the T cell to shut down. In chronic infections and cancer, do they have more or less than normal T cells expressing PD-1?

Answer 41

- more | - results in a weakened immune response

Question 42

Clonal deletion is a part of peripheral tolerance. What is clonal deletion? 1 - self reactive T cells do not receive 2nd stimulus and APC cells induce apoptosis 2 - self reactive T cells do not receive 2nd stimulus and cytotoxic T cells induce apoptosis 3 - self reactive T cells do not receive 2nd stimulus and up-regulate Fas 4 - self reactive T cells do not receive 1st or 2nd stimulus for activation

Answer 42

3 - self reactive T cells do not receive 2nd stimulus and up-regulate Fas - Fas is a ligand that can induce apoptosis in T cells as the immune response is reducing

Question 43

Clonal deletion is a part of peripheral tolerance. Clonal deletion is the death of clonally expanded T cell as the immune response is reducing. How do clonal T cells initiate the apoptosis of clonal T cells? 1 - up-regulation of FOXP3 that induce cell apoptosis 2 - up-regulation of PD-1 that induce cell apoptosis 3 - up-regulation of Fas ligand that induce cell apoptosis 4 - up-regulation of CTLA-4 that induce cell apoptosis

Answer 43

3 - up-regulation of Fas - Fas ligand on CD8+ cytotoxic T cell or NK cell bind with Fas - caspase enzymes are released, triggering apoptosis of clonal T cells

Question 44

T regulatory T cells (Tregs) are a form of T cell that is able to modulate the immune system and inhibit T cell proliferation. What 2 things do Tregs soak up in order to secrete anti-inflammatory cytokines? 1 - IL-1 and triphosphate 2 - IL-2 and triphosphate 3 - IL-1 and adenosine 4 - IL-2 and adenosine

Answer 44

4 - IL-2 and adenosine - normally help T cells proliferate and bind with professional antigen presenting cells - but if Tregs take it all away then no signal for T cell clonal expansion

Question 45

T regulatory T cells (Tregs) are a form of T cell that is able to modulate the immune system and inhibit T cell proliferation. They are able to absorb IL-2 and adenosine whilst secreting anti-inflammatory cytokines. What effect to the anti-inflammatory cytokines have on dendritic cells? 1 - dendritic cells secrete anti-inflammatory cytokines 2 - dendritic cells express inhibitory ligands on their cell surface 3 - dendritic cells stop presenting antigens 4 - causes dendritic apoptosis

Answer 45

2 - dendritic cells express inhibitory ligands on their cell surface - unable to provide co-stimulation and activate T cells

Question 46

T regulatory T cells (Tregs) are a form of T cell that is able to modulate the immune system and inhibit T cell proliferation. They are able to absorb IL-2 and adenosine whilst secreting anti-inflammatory cytokines, causing dendritic cells to express inhibitory ligands on their cell surface and inhibit their ability to provide co-stimulation and activate T cells. What else do Tregs do to professional antigen presenting cells? 1 - secrete anti-inflammatory cytokines 2 - express inhibitory ligand PD-1L on their cell surface 3 - stop them from presenting antigens 4 - causes apoptosis

Answer 46

2 - express inhibitory ligand PD-1L on their cell surface

Question 47

Patients who have congenital mutations in the FOXP3 gene, meaning the do not have normal functioning T regulatory cells (Tregs) can suffer with Immunodysregulation polyendocrinopathy enteropathy X-linked (or IPEX) syndrome. What is this syndrome?

Answer 47

- a fatal autoimmune disorder | - leads to dysfunctional CD4+ cells and autoimmunity