Immune Tolerance Flashcards
What is immune regulation?
It is the control of the immune response to prevent inappropriate reactions
Why is immune regulation required?
Avoid excessive lymphocyte activation and tissue damage during normal protective responses against infection;
Prevent inappropriate reactions against self antigens (‘tolerance’)
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?
Immune response against self(auto)-antigens= pathologic
Disorders are often classified as “immune-mediated inflammatory diseases”
Systemic or organ-specific
What are examples of auto-immune diseases?
Rheumatoid arthritis, irritable bowel disease, multiple sclerosis, psoriasis
(affects 2-5% of people)
- genetic legacy of surviving black death
What are the features of auto-immune diseases?
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
What are the underlying causative factors of autoimmune diseases?
susceptibility genes and environmental influences
Are autoimmune diseases more common in women or men?
women
What is the fundamental problem in regulating immune responses?
The imbalance between immune activation and control
What is the immune mechanism of autoimmunity?
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.
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 mediates allergic responses?
Antibody (IgE) and mast cells- acute anaphylactic shock
Or T cells- delayed type hypersensitivity
What is hypercytokinemia?
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
How is hypercytokinemia linked to sepsis?
It is a part of sepsis
What are the 3 phases of cell mediated immunity?
Induction
Effector
Memory
Go into more detail about the steps of cell mediated immunity?
- cell infected, DC collects material
- MHC: peptide TCR interaction
- Naive T becomes effector
- Effector cell sees MHC: peptide on infected cell performs function
- Effector pool contracts to memory
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
How are self-limiting responses manifested?
by decline of immune responses
principle mechanism= immune response eliminates antigen that initiated the response
=> the first signal for lymphocyte activation is eliminated
What are the three signals required to license a cell to respond?
Antigen recognition
Co-Stimulation (cell to cell contact)
Cytokine release
How do responses against pathogens decline as the infection is eliminated?
Apoptosis of lymphocytes that lose their survival signals (antigens, etc.)
Memory cells are the survivors
What limits responses to persistent antigens?
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
What are the three possible outcomes of an immune response?
Resolution - no damage
Chronic Inflammation - active inflammation and attempts to repair damage ongoing
Repair - healing with scar tissue and regeneration. Fibroblasts and collagen synthesis.
What is tolerance?
specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen (tolerogen vs immunogen)
What is the significance of immune tolerance?
– 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
What is meant by self tolerance?
Self Antigens will not cause harm to us
When does tolerance occur?
Before the T or B cells ever enter the circulation (central tolerance)
Or once in the circulation (peripheral)
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 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
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
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
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
How does AIRE promote self tolerance?
by allowing the thymic expression of genes from other tissues
What does AIRE stand for?
AutoImmune REgulator
What does an AIRE deficiency lead to ?
Multi-organ autoimmunity (Autoimmune Polyendocrinopathy Syndrome type 1)
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
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
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 can happen to a B cell after antigen exposure?
- antibody production
- memory
- affinity maturation
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
What is an example of bad somatic hypermutation?
Anti-streptococcus pyogenes antibodies can cross react with heart muscle
What are the mechanisms of peripheral tolerance?
Normal T cell response
Anergy
Ignorance
Deletion/ AICD
Regulation (with a regulatory cell)
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
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
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)
What are some of the immunosuppressive cytokines that Tregs release?
TGF, IL-10
What are Tregs?
T Regulatory cells which regulate the activation of other T cells and other cells asw
What is the phenotype of regulatory T cells?
CD4, high IL-2 receptor (CD25), Foxp3 transcription factor
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
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 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)
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
When is regulation especially important?
in pregnancy
- Tregs only exist in mammals
- exposure to new antigen
- expressed in the context of foreign MHCI
What are the two types of Tregs?
Natural Tregs (nTreg) and Inducible Treg (iTreg)
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
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
What do Tregs reflect?
The Th subsets seen in T effectors
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
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
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
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 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 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
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
How does a naive CD4 + T cell become specialised CD4 cells?
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
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
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
What happens to B and T cells with different signals (Antigens, Co-stimulation, cytokines)?
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.
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
