Immune Tolerance Flashcards
Define Immune regualtion
Control of the immune response to prevent inappropriate immune reactions
Why is immune regulation important?
Prevents:
Responses against self
Tissue damage
Excessive lymphocyte activation
What does failure in control result in?
Autoimmunity
Allergy
Hypercytokinemia and Sepsis
Define autoimmunity
Immune response against self-antigen
Often classified under ‘immune-mediated inflammatory diseases’
What are the two principles of autoimmunity?
Susceptibility genes and environmental trigger
Systemic or organ-specific
What are the main features of autoimmune disease?
Imbalance between immune activation and control
Immune response is inappropriately directed/ controlled
Many are chronic and self-perpetuating
What are the main features of immune-mediate inflammatory disease?
Chronic with prominent inflammation Can be autoimmune or response against microbial antigen (Crohn's) May be caused by T-cells and antibodies May be systemic or organ specific
What are examples of immune-mediate inflammatory disease?
Rheumatoid arthritis
IBS
MS
Psoriasis
What is Allergy?
Harmful response to non-infectious antigens that cause tissue damage and disease
Can be mediated by IgE and mast cells (acute anaphylactic shock)
Or mediated by T-cells- delayed type hypersensitivity
What is Hypercytokinemia and Sepsis?
Too much immune response
Often in a positive feedback loop
Triggered by pathogen entering the wrong compartment (sepsis) or failure to regulate response to the correct level
How is a response licensed?
3 required signal model
- Antigen recognition
- Co-stimulation: cell-cell contact
- Cytokine release
What is self-limiting response?
Cardinal feature of all immune responses: SELF LIMITATION
Manifested by decline of immune response
Principle mechanism: immune responses eliminated antigen that initiated responses
First signal for lymphocyte removed
What are the three phases of cell mediated immunity?
Induction
Effector
Memory
What are the three options for the end of response?
Resolution
Repair
Chronic Inflammation
What is resolution?
No tissue damage, returns to normal.
Phagocytosis of debris by macrophages
What is repair?
Healing with scar tissue and regeneration
Fibroblast and collagen synthesis
What is chronic inflammation?
Active inflammation and attempts to repair damage ongoing
What is tolerance?
Specific unresponsiveness to an antigen that is induces by exposure to that antigen
Why is tolerance important?
Therapeutic potential- inducing tolerance may be exploited to prevent graft rejection, treat allergy and auto-immune diseases
What is Central tolerance?
Destroys self-reactive T or B cells before they enter the circulation
What is Peripheral tolerance?
Destroy or control any self-reactive T or B cells which do enter the circulation
How does central tolerance happen with B-cells?
If immature B cells in bone marrow encounter antigen in a form which can crosslink their IgM
Apoptosis is triggers
How does central tolerance happen with T-cells?
Need to select for T cell receptors which are capable of binding self MHC
Removed if useless or too dangerous
What is AIRE?
AutoImmune REgulator
Transcription factor that allows expression of all human proteins
Enables self deselection
What do mutations in AIRE result in?
Multi-organ autoimmunity
How does peripheral tolerance work?
Removal of self-reactive cells already in circulation
What is anergy?
Mechanism of peripheral tolerance
Naive T-cells need co-stimulatory signals in order to become activated
Most cells lack these proteins and MHC class II
If naive T-cell sees MHC without appropriate co-stimulatory protein it becomes anergic
What does anergic mean?
Less likely to be stimulate in future
Even is co-stimulation is then present
What is ignorance?
Mechanism of peripheral tolerance
Antigen may be present in too low a concentration to reach the threshold for T-cell receptor triggering
Immunologically privileged sites e.g. eye
Compartmentalisation of the cells and antigen control interactions
What us antigen induced cell death?
Mechanism of peripheral tolerance
Activation through the T-cell receptor can result in apoptosis
What are the three mechanism of peripheral tolerance?
Anergy
Ignorance
Antigen induces cell death
What are the 5 types of T-helper cells?
T-helper 1 cells T-helper 2 cells Follicular helper T cells Th17 cells T-reg
What do T helper 1 cells do?
Produce interferon gamma
Boost intracellular immune response
What do T-helper 2 cells do?
Produce IL-4,5,13
Boost anti-multicellular organism réponse
What do follicular helper T cells do?
Produce IL-21
Essential for generation of isotope-switched antibodies
What do Th17 cells do?
Secrete IL-17 in autoimmune diseases such as arthritis
Important for the control of bacteria
What do T-reg cells do?
Regulate the activation of effector functions of other T-cells
Inhibit other T-cells
Necessary to maintain tolerance to self-antigen
Make FoxP3 transcription factor
How are T-helpers defined?
Cytokines they release
Transcription factors they use
Why is regulation key in pregnancy?
Pregnancy can be seen as a parasitic infection
Exposure to new antigen
How can tolerance be lost?
Exposure to environmental antigens or self-antigens in the context of infection can alter the outcome
What is IL-10?
Key anti-inflammatory cytokine
Multi functional
Acts on a range of cells
Blocks pro-inflammatory cytokine synthesis
