4.6 Immune Tolerance Flashcards
What are the reasons for having immune regulation (2)?
Avoid excessive inflammation and tissue damage during normal protective responses
Prevent inappropriate reactions against self-antigens
What is autoimmunity?
Systemic or organ specific immune response against self-antigens
What are allergies?
Harmful immune responses to non-infectious antigens that cause tissue damage and disease
What 2 things can mediate allergic responses?
IgE and mast cells – acute anaphylactic shock
T cells – delayed type hypersensitivity
What do hypercytokinemia and sepsis lead to?
Positive feedback loop
Too much immune response leads to cytokine production and damage
What are the 3 phases of cell mediated immunity, and explain each phase?
Induction phase – DCs load antigens onto MHC, migrate to lymph nodes and present antigens to lymphocytes
Effector phase – effector T cells migrate to sites of infection and elicit response
Memory phase – once all infected cells cleared, T cells move into contraction phase and immune response is shut down
What is meant by self-limitation?
The immune response declines once it has cleared the initial antigen
How do responses against pathogens decline as infection is cleared?
Apoptosis of lymphocytes as they lose their survival signals (the antigen)
Memory cells survive
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
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
What is the central tolerance mechanism for B cells?
If immature B cells encounter antigens which cross link their IgM, apoptosis is triggered
What is the mechanism for central tolerance for T cells?
If the T cell binds self-MHC strongly, apoptosis
Doesn’t bind self-MHC, apoptosis
Binds self-MHC weakly, survives
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 transcription factor allowing for the thymic expression of genes normally expressed in peripheral tissues
Thus these MHC bearing 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 reduce the availability of IL-2 for other B cells and T cells
Thus they are not stimulated to proliferate
What are some of the immunosuppresive cytokines that Tregs release?
TGF, IL-10
What do Tregs do?
Inhibit other immune cells
What affect does IL-10 have?
Causes cells to express more death receptors and 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 happens when DCs present any antigen to naive T cells?
Partial activation
What happens when DCs present specifically a foreign antigen to T cells?
Stimulates B7 expression on APC which binds CD28 on T cell, leading to full activation
What happens when a self-antigen binds a naive T cell?
Upregulation of FOXP3 transcription factor
Causes differentiation into T-reg
How do T-reg cells cause anergy?
Fully developed T-regs express cytotoxic T lymphocyte associated antigen 4 (CTLA-4)
CTLA-4 binds B7 protein on APCs, preventing co-stimulation of other T cells, leading to incomplete activation
How do T-reg cells inhibit the proliferation of other T cells?
Express adenosine and IL-2 receptors to decrease availability for other T cells
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 differentiation for B cells so they can bind to antigens better
Change occurs due to 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?
Activation induced cytidine deaminase
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 do mutations in FoxP3 lead to?
T-reg cells not produced properly
Severe autoimmune diseases, like immune polyendocrinopathy enteropathy X-linked syndrome (IPEX)
What does IL-10 do?
Blocks pro-inflammatory cytokine synthesis including TNF, IL-6, IL-8, IFN-gamma and downregulates 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
Why are T-regs 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
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?
Secondary lymphoid organs (tonsils, spleen, 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
Why is it necessary to delete cells before they enter into circulation?
Approximately 10^15 possible TCRs and 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?
When an APC presents a self-antigen to a T cell, there is no B7 expression on the APC and thus no co-stimulation
Thus TCRs cannot send activating signals and T cells express CTLA-4 which further reduces B7 availability, causing inactivation
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 activated, thus the T cell becomes anergic
How does ignorance as a mechanism of peripheral tolerance occur?
Compartmentalisation and anti-inflammatory cytokines prevent migration of T cells out of 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 is antigen-induced cell death as a mechanism of peripheral tolerance?
When T cells repeatedly recognise self antigens and lack co-stimulation, this causes:
Decreased IL2 and anti-apoptotic protein expression
Increased pro-apoptotic protein expression, causing apoptosis
Increased Fas and Fas ligands, causing apoptosis
How does the Fas ligand result in antigen induced cell death?
When Fas is ligated by FasL on CD8 T killer cells, it triggers apoptosis of the cell
