8 Regulation Of Lymphocyte Responses Flashcards
Q: Why is immune regulation important? (2)
A: protection from infection by pathogenic microorganisms
survival of an infected mammalian organisms
Q: What is immune regulation required to do? Failure to do this leads to?
A: avoid excessive lymphocyte activation and tissue damage
prevent inappropriate reactions to self antigens
immune-mediated inflammatory diseases
Q: What are the two types of autoimmunity on either side of the spectrum?
A: organ-specific to systemic
Q: What is autoimmunity?
A: immune response against self antigen
Q: What is pathogenesis based on?
A: genetic predisposition + environmental triggers
Q: Define immune-mediated inflammatory diseases IMID. Caused by? (2) What are the 2 types?
A: chronic diseases with prominent inflammation, often caused by failure of tolerance or regulation
Can be systemic or organ-specific
Q: What can result in immune-mediated inflammatory diseases? by? (2)
A: 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
Q: What are 3 examples for immune regulation failure?
A: autoimmunity
allergy
hypercytokinemia and sepsis
Q: What can mediate an allergy? (2) What is allergy? What causes the symptoms?
A: Can be mediated by IgE and mast cells
Can be mediated by T cells - DELAYED TYPE HYPERSENSITIVITY
Allergy is, in effect, recognising benign/non infectious proteins/agents and responding to them as if they were pathogens.
When exposed to their antigen, mast cells degranulate and release their histamines causing local inflammation
Q: What are hypercytokinemia and sepsis? What causes them? Define hypercytokinemia. Define sepsis. What is their relationship?
A: 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
Q: What are the 3 signals that licence a cell to respond (in immune system)?
A: antigen recognition
co stimulation
cytokine release
Q: What are the 2 general principles that control immune responses?
A: Responses against pathogens decline as the infection is eliminated
Active control mechanisms may function to limit responses to persistent antigens (self antigens, possibly tumours and some chronic infections)
-Often grouped under ‘tolerance’
Q: How does the response against pathogens decline as the infection is eliminated? (2) Driven by? how?
A: -If there are lots of bugs, you get lots of T cells dealing with it
- As the amount of pathogen starts to decline (antigens), 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
Q: Define immunological tolerance.
A: specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen (tolerogen vs immunogen)
Q: Why is immunological tolerance important?
A: This is important in self-tolerance - you are tolerant against your own antigens
Therapeutic Potential - inducing tolerance by regular exposure
Q: What does breakdown of self tolerance lead to?
A: autoimmunity
Q: What is therapeutic potential?
A: it may be possible to turn T cells from being activated to being tolerogenic - inducing tolerance by regular exposure
Q: What are the 2 types of tolerance?
A: 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
Q: What if immature B cells in the bone marrow recognise an antigen in a form which can crosslink their IgM?
A: apoptosis is triggered (central tolerance of B cells)
Q: What can B cells do if they react with self antigens? (2)
A: may change their specificity (affinity hypermutation) and some T cells will turn into regulatory T cells
Q: What can happen if T cell receptors TCR bind too weakly to MHC during the selection process?
A: may not be enough to allow signalling when binding to MHC presenting a foreign antigen
Q: What can happen if T cell receptors TCR bind too strongly to MHC during the selection process?
A: may allow signalling irrespective of whether a self antigen or foreign peptide is found in the groove
Q: What do you consider with T cell selection in the thymus? (3)
A: 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
Q: What is the problem with the thymus being the only organ that allows the development of T cells?
How do we get round this?
What does it promote?
A: 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
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
Q: What do mutations or absence of AIRE lead to?
A: multi-organ autoimmunity (autoimmune polyendocrinopathy syndrome type 1)
Q: What does AIRE allow?
A: the thymic expression of genes that are expressed in peripheral tissues - so the thymus can express all the proteins in the human body
Q: Which tolerance is a way of screening the newly developed T cells?
A: central tolerance
Q: What does peripheral tolerance control?
A: controls the lymphocytes which might start to react with self-antigens
Q: What are the 4 mechanisms for peripheral tolerance?
A: Anergy
Ignorence
Deletion
Regulation
Q: Explain anergy as a mechanism for peripheral tolerance. (3) Result? Definition.
A: Naïve T cells need COSTIMULATORY SIGNALS (CD) to become activated
Most cells lack costimulatory proteins and MHC class II
If a naïve T cell sees its MHC/peptide ligand without appropriate costimulatory protein = becomes anergic
ie = less likely to be stimulated in future even if co stimulation is then present
Anergy = unresponsiveness (sort of like increasing the activation energy)
Q: Explain ignorance as a mechanism for peripheral tolerance. Where does it occur? why?
A: antigen may be present in too low a concentration to reach the threshold for T cell receptor triggering
immunologically privileged sites eg eye, brain
At these sites, T cells CANNOT become activated because there are NO APCs
Q: Explain deletion as a mechanism for peripheral tolerance. Often caused by? when?
A: = Antigen Induced Cell Death
-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
Q: Explain regulation as a mechanism for peripheral tolerance. (2)
A: Regulated by T regulatory cells (Treg) - subset of helper T cells
Treg produces cytokines (IL-10) which inhibits other self-reactive T cells
Q: What transcription factor is expressed by Treg? What do mutations of this lead to? examples (3).
A: FoxP3
mutations lead to severe and fatal autoimmune disorder: IPEX = immune dysregulation, Polyendocrinopathy, Enteropathy X-linked syndrome)
Q: What are regulatory T cells? Phenotype. (3)
A: type of CD4 T helper cell
Phenotype: CD4, IL-2 receptor, FoxP3
Q: What’s a T regulatory cell’s mechanism of action? (4) What happens to individuals who can’t make Treg? (2)
A: Secrete immunosuppressive cytokines (TGFb, IL-10 and IL-35)
They engage other effector T cells and turn them off
IL-10 also has a role in shutting down dendritic cells
It switches the DCs from saying ‘this is dangerous’ to ‘this is safe’
have broad spectrum autoimmune conditions - it is a failure of peripheral tolerance
Q: What are the 2 types of Treg? Describe (2,1).
A: Natural (nTreg)
Develop in the Thymus
Reside in peripheral tissues to prevent harmful reactions against self
Inducible (iTreg)
When they are exposed to APCs they turn from being a T helper activator function to a Treg function
Q: What is peripheral tolerance largely driven by? reason?
A: Tregs
Tregs produce IL-10 which shuts down other immune responses
Q: Why is immune regulation key in pregnancy?
A: Pregnancy is like a parasitic infection
To allow successful pregnancies, the body needs to immunosuppress
Q: Define resolution. What’s involved?
A: NO tissue damage, returns to normal.
Phagocytosis of debris by macrophages.
Q: Define repair. What’s involved?
A: healing with scar tissue and regeneration
Fibroblasts and collagen synthesis
Q: What is chronic inflammation? due to? characterised by? (4)
A: long lasting inflammation (weeks or months) due to persistent aggressive stimuli and is characterised by: active inflammation with mononuclear cells, tissue destruction and repair
Q: Explain breaking tolerance. (2) Example.
A: Exposure to environmental/self antigens in the context of infection/Inflammation = can alter the outcome and trigger a lack of tolerance
EXAMPLE: Streptococcus pyogenes can produce an antigen which looks like heart muscle antigen
Q: What is self limitation? (3)
A: Self-Limitation = a feature of all immune responses
PRINCIPLE MECHANISM: the immune response eliminates the antigen that initiated the response
-So, the first signal for lymphocyte action was eliminated
The immune response shuts down
Q: Describe cross regulation by T cell cytokines.
A: T helper cells produce cytokines= have a diverse actions on a wide range of cells -> influence the outcome of the immune response
Q: What family do cytokines belong to?
A: inflammatory mediators
Q: What is IL-10? Function? (3) Which cell does it act on?
A: key inflammatory cytokine
multifunctional
- blocks pro inflammatory cytokine synthesis including TNF, IL-6, IL-8
- downregulates macrophages
- viral mimics
acts on a range of cells
Q: What induces regulatory macrophage phenotype?
A: Interaction of resident macrophages with Tregs or with a B cell subset
Q: What is a regulatory macrophage’s function? therefore? What do they produce? level?
A: NORMAL FUNCTION: reduce inflammatory immune response and thereby limit tissue damage
Produce high levels of IL-10
Q: What can suppress T cells? explain. Where has this been seen? (3)
A: amino acid starvation-
removing essential amino acids which leads to downregulation of responses
cancer, pregnancy, infectious disease- HIV
Q: Summarise T and B lymphocyte collaboration. What interaction has bidirectional effects? What are T cells induced to do? result? (2) What do T cell derived cytokines drive? What do cytokines direct?
A: Specific interaction of antigen-binding B cell with the T cell has bidirectional effects
T cells are induced to express B cell costimulatory molecule CD40 which binds to CD40 on B cells, and secrete cytokines.
T cell derived cytokines drive proliferation and differentiation of B cells into antibody secreting plasma cells
The cytokines direct immunoglobulin class-switching
