Regulation of T-lymphocyte response Flashcards
Why do we regulate the immune system?
- Stop there being too much of a response
- Prevent reactions against self antigens
- Failure means immune mediated inflammatory disease
What are autoimmune diseases?
- spectrum of organ specific, systemic, immune response against self antigen
- pathogenesis based on genetic predispositions and environmental triggers
Why do autoimmune diseases occur?
- If MHC can recognize broad antigen spectrum may include self antigens
- imbalance between immune activation and control,
○ Chronic diseases with prominent inflammation
Define allergy:
harmful immune response to non infectious agents
Why do allergies occur?
- IgE and mast cells (acute anaphylactic shock) or T cells (delayed type sensitivity)
- When exposed to their antigen mast cells degranulate and release histamines
What happens when there is too much of an immune response?
- Positive feedback triggering inflammation, causing damage to local cells leading to release of more inflammatory mediators
What is hypercytokinema?
- cytokine storm: too many cytokines in blood
- pathogens enter wrong compartment e.g bloodstream
- Or failure to regulate response to correct level
How is the immune response controlled?
- Response declines as infection is eliminated, driven by apoptosis of lymphocytes (once stop having antigens to bind they lose survival signal
- Active control mechanisms may function to limit responses to persistent antigens
- Chronic exposure to antigens switches on certain receptors which downregulate their response
What is the result of immunological control?
- immunological tolerance: specific unresponsiveness to an antigen induced by exposure of lymphocytes to that antigen
- everyone tolerant of own antigens (breakdown=autoimmunity)
What happens during central tolerance?
- destroy self reactive T/B cells before they enter circulation
What stops lymphocytes attacking self proteins?
- Autoimmune regulators (AIRE) is a TF allowing thymic expression of genes expressing peripheral tissue
- If all proteins processed and presented on MHC you negatively select against entire peptide library so promote self tolerance
- So sees every protein body can make so doesn’t just see thymus tissue
What is peripheral tolerance?
- control lymphocytes which may start to react with self antigen
What are the 4 main mechanisms of peripheral tolerance?
- Anergy: unresponsiveness
- if antigen presented to T cell in absence of costimulatory signal leads to DC signaling anergy or apoptosis
- Ignorance: no APC
- Antigen present in too low concentration to reach threshold for triggered
- Immunologically privileged site e.g eye, brain
- Deletion: activation through TCR can lead to apoptosis
- Antigen induced cell death
- Regulation: by Treg cells producing cytokines IL-10 inhibiting other self reactive T cells
What is the structure of Regulatory T cells:
- Type of CD4 Th
- IL-2 receptor
- Low IL7 level
How do Tregs work?
- Mechanism: secrete immunosuppressive cytokines (IL10)
- IL10 shuts down DC more likely to present antigen as anergenic or apoptotic say it’s safe
What is breaking tolerance?
- exposure to environmental antigens/self antigens in context of infection may alter outcome
What is self limitation?
- Once one response becomes dominant shuts down the others
- Decline in immune response
- Lymphocyte activation is eliminated
What is the importance of IL10?
- Key inflammatory cytokine
- Blocks pro inflammatory cytokine synthesis
- Downregulates macrophages
What drives Treg?
driven by transcription factor FoxP3, produce canonical cytokine IL-10
