8- Regulation Of Lymphocyte Responses Flashcards
Why is immune regulation important?
As immune cells can kill other cells - it can kill host cells - so you don’t want too much immune activity or that could cause damage.
• Two parts of immune regulation:
Stop there being too much immune response
Prevent reactions against self antigens
• Failure of these mechanisms is the underlying cause of immune-mediated
inflammatory diseases
What are immune mediated inflammatory disease?
Definition: chronic diseases with prominent inflammation, often caused by failure of tolerance or regulation
• May result from pathogens expressing antigens that are very similar to self antigens hence causing autoimmune disease
• Can be caused by T cells and antibodies
• Can be systemic or organ-specific
Describe autoimmunity
You get a spectrum of autoimmune disease from organ-specific to systemic
Autoimmunity = immune response against self antigen
Pathogenesis is based on genetic predisposition + environmental triggers
If the MHC can recognise a broad spectrum of antigens then it could include self antigens
• Features of autoimmune disease:
FUNDAMENTAL PROBLEM: imbalance between immune activation and control
Many immunological disease are chronic
Describe allergy
Definition: harmful immune response to non-infectious agents that cause damage and disease
• Can be mediated by IgE and mast cells
• Can be mediated by T cells - DELAYED TYPE HYPERSENSITIVITY
• Allergy is, in effect, recognising benign proteins and responding to them as if
they were pathogens.
• When exposed to their antigen, mast cells degranulate and release their
histamines causing local inflammation
Describe Hypercytokinemia and Sepsis
• TOO MUCH IMMUNE RESPONSE
• Positive Feedback - by triggering inflammation you cause damage to local cells
leading to the release of more inflammatory mediators
• Hypercytokinemia - too many cytokines in the blood - this happens when the
response isn’t properly controlled and you get too much immune response
• Sepsis - when bacteria crosses from the mucosa into the blood stream -
pathogens entering the wrong compartment
• Sepsis can cause hypercytokinemia
Describe the General principles of controlling immune responses
•
Responses against pathogens decline as the infection is eliminated:
If there are lots of bugs, you get lots of T cells dealing with it
As the amount of pathogen starts to decline, you start switching off your immune response to the pathogen
This is driven by apoptosis of the lymphocytes - once they stop having antigens to bind to they lose their survival signals
• Active control mechanisms may function to limit responses to persistent antigens (self antigens, possibly tumours and some chronic infections)
Often grouped under ‘tolerance’
Chronic exposure to certain antigens switches on certain receptors which downregulates their response and leads to immunological tolerance
What is immunological tolerance?
DEFINITION: specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen (tolerogen vs immunogen)
Why is immunological tolerance important?
This is important in self-tolerance - you are tolerant against your own antigens
• Breakdown of self-tolerance leads to AUTOIMMUNITY
Therapeutic Potential - it may be possible to turn T cells from being activated to being tolerogenic - inducing tolerance by regular exposure
What are the 2 types of immunological tolerance?
Central Tolerance - destroy self-reactive T or B cells before they enter the circulation
Peripheral Tolerance - destroy any self-reactive T or B cells which do enter the circulation
- If they react with self antigens, some B cells may change their specificity (affinity hypermutation) and some T cells will turn into regulatory T cells
- If immature B cells in the bone marrow recognise an antigen in a form which can crosslink their IgM - apoptosis is triggered
What should you consider in T cell selection in the thymus?
Is it USELESS? Doesn't bind to MHC Death by neglect (apoptosis) • Is it DANGEROUS? Binds to self MHC too strongly Apoptosis is triggered - negative selection • Is it USEFUL? Binds self MHC weakly Signal to survive - positive selection
What is AIRE?
The problem with the thymus is that it’s just one organ - the cells in the thymus won’t normally produce all 25,000 gene products that your body can produce
• This means that there would be some self-peptides that aren’t made by the thymus cells and so when the T cells get out of the thymus, they discover a whole range of self-peptides, which leads to autoimmunity.
• They get around this using a specialised transcription factor - AIRE
• AIRE - allows the thymic expression of genes that are expressed in peripheral tissues - so the thymus can express all the proteins in the human body
• If all the proteins are processed and presented on MHC to the developing T cells, you are negatively selecting against the entire peptide library - thus
PROMOTING SELF-TOLERANCE
• People without AIRE or with a mutation in AIRE - Autoimmune
Polyendocrinopathy Syndrome Type 1
What are the 4 mechanisms of peripheral tolerance?
Anergy Ignorence Deletion Regulation
Describe anergy
Naïve T cells need COSTIMULATORY SIGNALS
to become activated
• If an antigen is presented in the absence of costimulation you get apoptosis or anergy
• Anergy = unresponsiveness (sort of like increasing the activation energy)
• So the context in which the DC presents the antigen can have an effect on the activation energy.
Describe ignorance
There are some immuneprivileged sites where the risk of inflammation far
outweighs the risk of infection
• At these sites, T cells CANNOT become activated because there are NO APCs
Describe deletion
Activation through the TCR can lead to APOPTOSIS of the T cell
• In peripheral T cells this is often caused by the expression of the death ligand -
Fas ligand
