Immune Tolerance Flashcards
What is immune regulation?
Control of the immune response to prevent inappropriate reactions
What is immune regulation required to do?
Avoid excessive lymphocyte activation and tissue damage
Prevent inappropriate reactions against self antigens
What is autoimmunity?
Immune response against self antigens or microbial antigens
What causes autoimmunity?
Imbalance between immune activation and control —> failure of control mechanisms
Susceptibility genes + environmental influences
Why are many immunological diseases chronic and self-perpetuating?
Attacking self-antigen there is always more antigen to attack
What is allergy?
Harmful immune responses to non-infectious antigens that cause tissue damage and disease
What can allergy be mediated by?
Antibody (IgE) and mast cells —> acute anaphylactic shock
T cells —> delayed type hypersensitivity
What is hypercytokinemia and sepsis?
Too much immune response
Often in a positive feedback loop
What is hypercytokinemia and sepsis triggered by?
Pathogens entering the wrong compartments (sepsis)
Failure to regulate response to correct level
What are the 3 phases of cell mediated immunity?
Induction
Effector
Memory
What happens in the induction stage in cell mediated immunity?
Cell infected
Dendritic cell (DC) collects material
Loads it onto MHC
Moves into lymph nodes
What happens in the effector stage of cell mediated immunity?
Present antigen through MHC to T cells —> recognise specific MHC complex
Get activated and expand clonally
Effector T cells return to site of infection —> elicit response
What happens in the memory stage of cell mediated immunity?
Infected cells cleared —> T cells move into contraction phase —> shut down immune response
How is the immune response self-limiting?
Decline of immune response due to the response of the eliminating agent that initiated the response
What 3 signals are required to license a response?
Antigen recognition
Co-stimulation
Cytokine release
How are the responses against pathogens declined as the infection is eliminated?
Apoptosis of lymphocytes that lose their survival signals
Memory cells are the survivors
How are responses to persistent antigens limited?
Active control mechanisms —> ‘tolerance’
What are the 3 possible end responses of an infection?
Resolution —> no tissue damage, return to normal, phagocytosis of debris my macrophages
Repair —> healing with scar tissue and regeneration
Chronic inflammation —> active inflammation and attempts to repair damage ongoing
What is tolerance?
Specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen
What is the significance of immunological tolerance?
All individuals are tolerant of their own antigens —> breakdown results in autoimmunity
Therapeutic potential —> restoring tolerance may be exploited to prevent graft rejection, treat autoimmune and allergic diseases
At what two times does tolerance occur?
Before T or B cells ever enter the circulation —> central
Once in the circulation —> peripheral
What happens in central tolerance?
Lymphocytes that recognise self antigens are eliminated or made harmless in the generative organs as part of the maturation process
Why delete cells before circulation?
Function of the way the immune restore is generated
How are B cells centrally tolerated?
If immature B cells in borne marrow encounter antigen in a form which can cross link their IgM —> apoptosis is triggered
How are T cells centrally tolerated?
T cell selection occurs in the thymus
Need to select for T cell receptor that’s capable of binding self MHC
T cell receptor don’t bind to any self-MHC —> death by apoptosis
T cell binds too strongly to self-MHC —> apoptosis triggered - negative selection
T cell bins=do weakly to self-MHC —> signal to survive - positive selection
What is AIRE?
Autoimmune regulator
A specialised transcription factor that allows thymidine expression of genes tat are expressed in peripheral tissues
—> promotes elf tolerance by allowing the tunic expression of genes from other tissues
What happens in peripheral tolerance?
Destroy or control any self reactive T or B cells which enter the circulation
What are the 3 pathways activated B cells can undergo?
Antibody production
Memory
Affinity maturation —> recognise antigen and change shape of antibody to better bind to it
How can affinity maturation cause autoimmunity?
Normally good but exposure to environmental antigens or self antigens in context of infections can alter the outcome
Mechanism of peripheral tolerance - what is anergy?
Naive T cells need co-stimulatory signals in order to become activated
Most cells lack co-stimulatory proteins and MHC class II
If naive T cells sees firs MHC w/out appropriate costimulatory protein —> becomes anergic —> deactivated
Less likely to be stimulated in future
Mechanism of peripheral tolerance - what is ignorance?
Antigen may be present in too low a conc. to reach the threshold for T cell receptor triggering
Happens in immunologically privileged sites —> T cells never sees antigen so can ‘ignore’ it
Also happens in compartmentalisation of cells and antigens —> T cell never encounters antigen so never becomes reactive
Mechanisms of peripheral tolerance - antigen induced cell death
Activated through the T cell receptor can result in apoptosis
Influenced by the nature if the initial T cell activation events
In peripheral T cells —> often caused by induction of expression of the death ligand —> Fas ligand
What are Treg cells?
Sunset of helper T cells that inhibit other T cells and other cells
What are some of the defining features of Treg cells?
CD4
High IL-2 receptor (CD25)
Foxp3 transcription factors
What are some mechanics of Treg cells?
Secretion of immune-suppressive cytokines
Inactivation of dendritic cells or responding lymphocytes
What do mutations in FoxP3 lead to?
Severe and fatal autoimmune disorder -immune dysregulaton, Polyendocrinopathy, Enteropathy X linked (IPEX) syndrome
What does the IL-10 cytokine do?
Key anti-inflammatory cytokine
Multi-functional —> acts on a range of cells
Block pro-inflammatory cytokine synthesis
Downregulates macrophage functions
Viral mimics
Who do Tregs only exist in mammals?
Critical when mother is exposed to antigens often expressed in context of MHC I in baby —> half of baby’s from dad so foreign
What is ‘natural’ regulatory T cells?
Development in thymus requires recognition of self antigen during T cell maturation
Residues in peripheral tissues to prevent armful rations against self
What are inducing regulatory T cells?
Develop from mature CD4 T cells that are exposed to antigen in periphery —> no role for thymus
May be generated in all immune responses to limit collateral damage
What are cytokines?
They program immune response —> focus it for the right kind of response
Can be inflammatory or anti-inflammatory
What are chemokines?
Drive movement around the body
Act like address labels sending stuff to the right place
Receptor profile change with activation state of the cells
What is cross regulation in regards to T cells?
T helper type is defined by transcription factors —> Cytokines shape transcription factor pathways
Cross regulation is where cytokine response from 1 type of Th cell will shutdown the response of other Th cell types
How do T cells help[ improve the function of antibodies?
Different antibody classes have different constant regions which is important for their functions
Difference in function reflect the different types of response required to clear pathogens
There are a number of gene cassettes that can be swapped in and out
T cell produce cytokines which programme B cells to activate gene factors to switch Ig classes
