Lecture 16: Immune Tolerance Flashcards
What is immune regulation?
Control of immune response to prevent inappropriate reactions
What is the underlying cause of immune-mediated inflammatory diseases?
Failure of control mechanisms
What is the definition of autoimmunity?
Immune response against self (auto-) antigen = pathologic
What are the general features of autoimmunity diseases?
- Fundamental problem = imbalance between immune activation and control
- Pathogenesis: susceptibility genes and environmental triggers
- Systemic or organ specific
- immune system is inappropriately directed or controlled: effector mechanisms of injury same as in normal responses to microbes
What are the general features of allergy?
- harmful immune responses to non-infectious antigens that cause tissue damage and disease
- can be mediated by IgE and mast cells –> acute anaphylactic shock
- wheal and flare reactions
- or by T cells –> delayed type hypersensitivity
What are the general features of hypercytokinemia and sepsis?
- too much immune response
- often positive feedback loop
- triggered by pathogens entering wrong compartment (sepsis) or failure to regulate response to correct level
What 3 signals are required to licence the cell to respond?
- antigen recognition
- co-stimulation
- cytokine release
NOTE: all 3 things must happen for cell to respond
Describe how self-limitation of the immune system works.
The immune system starts clearing away the pathogen so the antigen is being eliminated, which means the first signal for lymphocyte activation is eliminated so there is a decline of immune responses.
What are the 3 phases of cell mediated immunity?
INDUCTION - cell infected, dendritic cell collects antigen fragments
EFFECTOR - MHC:peptide TCR interaction, naïve T cell becomes effector, effector cell sees MHC:peptide on infected cell + performs function
MEMORY - effector pool contracts to memory
What is meant by resolution at the end of a immune response?
No tissue damage
Returns to normal
Phagocytosis of debris by macrophages
What is meant by repair at the end of a immune response?
Healing with scar tissue and regeneration
Fibroblasts and collagen synthesis
What is meant by chronic inflammation at the end of a immune response?
Active inflammation and attempts to repair damage ongoing
Define immunological tolerance.
Specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen
What does a breakdown of self-tolerance result in?
Autoimmunity
What is the significance of immunological tolerance?
- all individuals tolerant of own antigens
- therapeutic potential –> exploited to prevent graft rejection, treat autoimmune and allergic diseases
What is the difference between central tolerance and peripheral tolerance?
Central tolerance destroys self-reactive T or B cells before they enter circulation, whilst Peripheral tolerance destroys the ones which enter the circulation
How does central tolerance control self-reactive B cells?
If immature B cells in bone marrow encounter self-antigen in form which can crosslink their IgM, apoptosis is triggered
How does central tolerance control self-reactive T cells?
It selects for T cell receptors which are capable of binding self MHC to a certain extent:
- Can’t bind to any self-MHC at all = death by neglect (apoptosis)
- NEGATIVE SELECTION: Binds self MHC too strongly (dangerous) = apoptosis triggered
- POSITIVE SELECTION: Binds self MHC weakly = signal to survive
What is the role of autoimmune regulator (AIRE)?
Transcription factor that allows developing T cells in thymus to be exposed to self-antigens/ MHC bearing peptides expressed in other parts of body by allowing thymic expression of genes from other tissues.
What can mutations in AIRE result in?
Multi-organ autoimmunity
How does anergy work in peripheral tolerance?
- naïve T cells need co-stimulatory signals to become activated
- most cells lack co-stimulatory proteins and MHC class II
- if naïve T cell sees it’s MHC/peptide ligand without appropriate co-stimulatory protein it becomes ANERGIC i.e. less likely to be stimulated in future even with co-simulation present
How does ignorance work in peripheral tolerance?
Antigen present in too low concentration to reach threshold for T cell receptor triggering - achieved by compartmentalisation of cells and fact antigen controls interactions
Where is ignorance often seen in the body?
Immunologically privileged sites e.g. eye, brain
How does antigen induced cell death work in peripheral tolerance?
- activation through T cell receptor can result in apoptosis
- influenced by nature of initial T cell activation events
- often caused by induction of expression of death ligand, Fas ligand (CD95, FasL)
- leads to apoptosis
