Immune Tolerance Flashcards
Why is immune tolerance important?
To shut down an immune response after it is not needed to avoid inflammation and damage to our own tissues
What is autoimmunity?
System of immune responses in an organism against its own cells and tissues, mediated by self antigens
What is the fundamental problem in regulating immune responses?
The imbalance between immune activation and control
How are allergies considered an autoimmune disease?
An allergic response is a harmful immune response to an normally non-harmful antigen which causes tissue damage and disease
What is hypercytokinemia?
A cytokine storm
What is meant by self-limitation?
The immune systems first response is to eliminate the antigen which initiated the response, meaning the first signal for the lymphocytes has been eliminated
What are the three mechanisms which license a cell to respond?
Antigen recognition
Co-Stimulation
Cytokine release
What are the three possible outcomes of an immune response?
Resolution - no damage
Chronic Inflammation - active inflammation and attempts to repair damage
Repair - healing with scar tissue and regeneration
What is meant by self tolerance?
Self Antigens will not cause harm to us
Inducing tolerance may be exploited to prevent…
Graft rejection, treat autoimmune conditions and allergic diseases
What is central tolerance?
The destruction of self- reactive T and B cells in the sites of their production / maturation, before they enter circulation
Where does central tolerance occur?
In the bone marrow and the thymus for B and T cells
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 death of that cell is triggered via apoptosis
What is the mechanism for central tolerance for T cells?
If the T cells binds MHC too strong = apoptosis (negative selection)
If the T cell doesn’t bind any MHC = apoptosis
If the T cell binds MHC too weakly, kept
How can a T cell developing in the thymus encounter MHC bearing peptides that might be expressed in other parts of the body?
AIRE is a specialised transcription factor which allows for the expression of genes that are normally expressed in peripheral tissues, so these proteins and therefore peptides can be made and presented to T cells
What does an AIRE deficiency lead to ?
Multi-organ autoimmunity
What is peripheral tolerance?
Ensures that self reactive T and B cells which escaped central tolerance do not cause autoimmunity
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
What are some of the immunosuppresive cytokines that Tregs release?
TGF, IL-10
What are Tregs?
T Regulatory cells which regulate the activation of other T cells
What affect does IL-10 have?
Causes cells to express more death ligands
What affect do Tregs have on DC’s?
They inhibit dendritic cells
What are the two types of Tregs?
Natural Tregs (nTreg) and Inducible Treg (iTreg)
What is the Fas ligand?
a death ligand
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
What is ignorance in relation to peripheral tolerance?
When the antigen concentrations are too low to trigger a T cell response
If you have an antigen, by no co-stimulation, what happens to the cell?
it becomes anergic
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
What three things can happen to a B cell after it is exposed to an antigen?
- Antibody production
- Becomes a memory cell
- Affinity maturation
What is affinity maturation?
A further round of differentation taken by the B cell so that it can bind to antigen better - this change occurs through somatic hypermutation
What can affinity maturation sometimes lead to?
The production of self reactive B cells
Where does somatic hypermutation occur?
In the germinal centers of lymph nodes and spleen
What is Ig class switching?
When a b cell goes from producing one type of immunoglobulin to another
During class switching, what is happening to the genome of the antibody?
Somatic hypermutation
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
Which enzyme is upregulated by cytokines to allow for class switching?
AID - allows cuts to be made in the DNA, thus producing VDJ rearrangement
What three signals do immune cells need to be activated?
- Antigen
- Co-stimulation
- Cytokines
What is FoxP3?
Protein which is important in the development and regulation of Treg, T cells which limit the immune response
What do mutations in FoxP3 lead to?
Severe autoimmune diseases like IPEX and Tregs are not produced properly
What does IL-10 do?
Blocks pro-inflammatory cytokine synthesis including TNF, IL-6, IL-8, IFN-gamma and down regulates macrophage functions
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
Where does immunological ignorance occur?
In the eyes or brain as they are immunologically privileged
What type of animal are Tregs found in?
Mammals
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
Which Treg type develops in the thymus?
Natural Treg
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
How do T cells shape the immune response for different pathogens?
Through the use of cytokines
Which T Helper cell is involved in controlling bacterial and fungal infections?
Th17
What cytokines do TfH release?
IL-21
where are T follicular helper cells located?
Tfh are located in secondary lymphoid organs (SLOs), including the tonsil, spleen and lymph nodes.
What structures do TfH play a particular role in?
The development of germinal centers
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
Which T cell Cytokines drives Ig class switching?
IL-4, IL-5, TGF-Beta, IFN-gamma
What is the definition of tolerance?
specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen (tolerogen vs immunogen)
Why is it necessary to delete cells before they enter into circulation?
Approximately 1015 possible TCR and 1015 possible antibodies generated at random
Some of these will be self-reactive
Therefore need to be removed
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
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
Where does ignorance as a peripheral tolerance mechanism occur?
in immunologically privileged sites
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
