Mechanism of Tolerance Flashcards
What is Immune tolerance?
- 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
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
2 - self (on MHC-I), environmental and commensal bacterial antigens
What does self tolerance mean?
- immunes systems ability not to initiate an immune response against its own cells
- these are presented as self-antigens on MHC-I molecules
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
4 - antigen presenting cell presenting antigen to B cell and T helper cell
In order for a B cell to become active what is the basic T cell independent activation?
- 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)
In order for a B cell to become active what is the basic T cell dependent activation?
- 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
Once B cells have been activated by T cell independent and dependent pathways, what 2 things happen to the B cells?
- class switching to a different antibody, normally IgM to IgG
- clonally expand creating plasma (antigen producing) and memory B cells
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
2 - T cell binds with a MHC-I or MHC-II molecules
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
1 - T cell expresses CD28 and APC expresses B7 that bind together
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
3 - NF-KB is activated increasing cytokine transcription
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
2 - signals clonal expansion of the T cell
- can also stimulate CD8 T cells
What is the name given when the immune system becomes self reactive?
- autoimmune disease
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
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..)
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)
1 - RAG-I and RAG-II
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
3 - CD4 and CD8 double positive cell
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
2 - positive selection
- these cells will then move on in their development
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
3 - undergoes apoptosis
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
3 - undergoes apoptosis
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
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
Once a T cell has undergoing positive and negative selection, what happens next in its development?
- 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
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
- 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
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?
- 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
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
1 - FOXP3
Which part of the thalamus does negative selection occur?
1 - cortex
2 - medulla
3 - capsule
4 - corpuscle
2 - medulla
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
1 - lamda or V prepB light chain is added
- light chain is then randomly arranged using the VJ segments
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
3 - autoimmune regulator gene (AIRE)
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?
- undergo apoptosis
- called negative selection
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?
- no
- B cell tries to re-arrange the light chains on the B cell receptor
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?
- develop into mature B cells and are released into circulation
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?
- they develop into immature B cells
- process is called POSITIVE selection and occurs before negative selection
What is peripheral tolerance?
- 2nd branch of immunological tolerance, after central tolerance
- aim is to control self-reactive T and B cells which escaped central lymph tissue
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
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)
What are immune-privileged sites?
- sites that do not elicit an immune response despite presence of foreign antigens
Immune-privileged sites are sites that do not elicit an immune response despite presence of foreign antigens. What are some sites in the body?
- brain
- eyes
- testes
- uterus
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?
- blindness across both eyes
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
3 - inhibiting the 2nd stimulation required for T cell activation
- T cell binds with antigen and receives 1st stimulus
- 2nd stimulus is not received
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
2 - cytotoxic T lymphocyte associated protein 4 (CTLA-4)
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
1 - B7 preferentially binds with CTLA-4
- T cell is inactivated, fail safe mechanism of peripheral tolerance
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
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
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
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
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?
- more
- results in a weakened immune response
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
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
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
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
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
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
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
2 - dendritic cells express inhibitory ligands on their cell surface
- unable to provide co-stimulation and activate T cells
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
2 - express inhibitory ligand PD-1L on their cell surface
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?
- a fatal autoimmune disorder
- leads to dysfunctional CD4+ cells and autoimmunity