16 Regulation of lymphocytes Flashcards
What is immune regulation?
Control of the immune response to prevent inappropriate reactions
Why is immune regulation required?
- To avoid excessive lymphocyte activation and tissue damage
- To prevent inappropriate reactions against self antigens (tolerance)
What is the underlying cause of immune-mediated inflammatory diseases?
Failure of control mechanisms
What is autoimmunity?
Immune response against self antigen
What is organ specific autoimmunity
Immune response only recognises an antigen present in one organ (e.g. Graves’ - eyes)
What is systemic autoimmunity?
Throughout the whole body
What are the underlying principles of autoimmunity?
- Genetic susceptibility (self antigens presented in different ways)
- Environmental receptors (trigger)
Why are many immunological diseases chronic and self-perpetuating?
More of the affected protein is being synthesised and thus immune cells continue to be activated
What is Crohn’s disease?
Inflammation of the gut
Failure of tolerance/regulation can also cause
Chronic diseases with prominent inflammation
Examples of chronic diseases with prominent inflammation
- Rheumatoid arthritis
- Irritable bowel disease
- MS
- Psoriasis
What is allergy?
Harmful immune response to non-infectious antigens causing tissue damage and disease
Allergies can be mediated by
- IgE and mast cells (type I)
- T cells (delayed, type IV)
What is hypercytokinemia?
Too much immune response (often +ve feedback loop)
What triggers hypercytokinemia?
- Pathogens entering the wrong compartment (sepsis)
- Failure to regulated response to correct level
What is the 3 signal, licensing model?
- Antigen recognition (activation)
- Co-stimulation (e.g. TCR + DC)
- Cytokine release
What is self-limitation?
Decline of immune response due to elimination of initiating antigen
What are the 3 phases of cell mediated immunity?
- Induction
- Effector
- Memory
What happens in induction?
Cell infected DC collects material
What happens in the effector phase?
- MHC peptide and TCR interact
- Naïve T becomes effector
- Effector cells sees MHC peptide on infected cell and functions
What happens in the memory phase?
Effector pool contracts to memory
What is resolution?
- No tissue damage
- Return to normal
- Phagocytosis of debris by macrophages
What is repair?
- Healing with scar tissue and regeneration
- Fibroblasts and collagen synthesis
What is chronic inflammation?
Active inflammation and attempts to repair damage ongoing
Why do responses against pathogens decline as the infection is eliminated?
- Apoptosis of lymphocytes that lose their survival signals
memory cells left as survivors
How are responses to persistent antigens (tumours, self, chronic) limited?
Active control mechanisms (grouped under tolerance)
T cells become inert
What is the basis of cancer immunotherapy?
Reactivation of T cells, reversing inertness
What is PD-L1?
An inhibitory marker made by T cells making the cells inert over time
What is immunological tolerance?
Specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen
What is the importance of tolerance?
- All individuals are tolerant of their own antigens (self-tolerance)
- Inducing tolerance may prevent graft-rejection, treat autoimmune and allergic diseases
What is central tolerance?
Destruction of self-reactive T or B cells before they enter circulation
What is peripheral tolerance?
Destruction/control of any self reactive T or B cells entering circulation
Central tolerance of B-cells
If immature B cells in bone marrow encounter a cognate antigen cross-linking their IgM, apoptosis is triggered
How does tolerance work with T cells?
Need to select for TCRs which are able to bind to self MHC
What is a useless T cell?
Doesn’t bind to any self MHC at all (apoptosis)
What is a dangerous T cell
Binds self MHC too strongly causing activation (apoptosis - negative selection)
What are useful T cells?
Bind to self MHC weakly (signal to survive - positive selection)
What is Autoimmune Regulator (AIRE)?
A specialised transcription factor allowing thymic expression of genes expressed in peripheral tissues
What does AIRE do?
Promotes self tolerance (allows thymic expression of genes from other tissues)
What can happen if there are mutation in AIRE?
Multi-organ autoimmunity
What is a potential benefit of mutated AIRE?
May not be affected by several pathogens as viruses have evolved to have similar proteins to self
What are the 4 mechanisms of peripheral tolerance?
- Anergy
- Ignorance
- Deletion
- Regulation
What is anergy?
- Naive T cells need co-stimulatory signals to be activated
- If the T cells sees the MHC peptide ligand without appropriate costimulatory protein, it becomes anergic
What does anergic mean?
Less likely to be stimulated in future, even if co-stimulation is then present
What is ignorance?
- Antigen may be present in too low a concentration to reach T cell activation threshold
What is an immunologically privileged site?
Where T are cells unable enter (e.g. eyes, nerves , brain)
What is antigen induced cell death (AICD)?
- Activation through T-cell receptor can result in apoptosis
- Often caused by expression of death ligand Fas (CD95 ligand, FasL)
What does Th1 do?
- Produce interferon gamma
- Boos intracellular response
(viral infection)
What does Th2 do?
- Produce Il-4, Il-5, Il-13
- Boost anti-multicellular organism response
(parasite/worm)
What do follicular helper cells do (Tfh)?
- Produce IL-21, reside in B cell follicles
- Essential for generation of isotype-switching antibodies
(communicate + activate B cells)
What does Th17 do?
- Secrete IL-17 in autoimmune diseases such as arthritis
- Control of bacteria, activate neutrophils, macrophages
- Pro-inflammatory
What do Treg cells do (Th0)?
- Regulate the activation or effector functions of other T cells
- Maintain tolerance to self antigens
- IL-10, TGFB
How are T helper cells defined?
- Cytokines they produce
- Transrciption factors they use
What is cross regulation?
If one type of cytokine is being produced, other pathways are shutdown
- Cannot have 2 types of CD4 responses at the same time
How do Treg cells inhibit other cells?
They produce the cytokine IL-10 which is anti-flammatory making the immune response less aggressive
What other important molecule is encoded by Treg cells?
Foxp3 - transcription factor drives IL-10 production
Specifies how T cell responds
What does a mutation in Foxp3 lead to?
Broad systemic autoimmunity
What is scurfy?
A condition in mice associated with Foxp3
What is IPEX syndrome?
- Immune dysregulation
- Polyendocrinopathy
- Enteropathy
- X-linked
What are natural Treg cells (nTreg)?
- Develop in thymus
- Require recognition of self antigen during T cell maturation
- Reside in peripheral tissues
What are inducible Treg cells (iTreg)?
- Develop from mature CD4 cells exposed to antigen in periphery
- May be generated in all immune responses
Why is regulation critical in pregnancy?
- Exposure to new antigen (paternal antigens)
- Expressed in the context of foreign MHC I
- T regs only exist in mammals
How can tolerance be lost?
Exposure to environmental antigens or self antigens in infections
Example of tolerance being lost
Post strep pyogenes
- B cells made against bacteria
- Antibodies cross react with auto-antigen
- React with heart muscle
What is IL-10?
- Key anti-inflammatory cytokine that acts on a range of cell
What does IL-10 do?
- Blocks pro-inflammatory cytokine synthesis (TNF, IL-6, IL-8, IFNy)
- Down-regulates macrophages
Co-stimulation - T cells
- Express CD40L to activate B
- Express CD28 to be activated
Co-stimulation - B cell
- Express CD40 to be activated by T
- Express B7 to activated T
What shapes the B cell response?
Production of cytokines by T cells
What is class switching?
- Variable region remains same
- Antibody type changes
- Depends on type of T helper cell
