Immune tolerence Flashcards
What is immune regulation required for?
- To avoid lymphocyte activation and tissue damage during normal protective responses against infection
- To prevent inappropriate reactions against self antigents (“tolerance”)
What is immune regulation?
Control of immune response to prevent inappropriate reactions
What is autoimmunity?
Immune response against self antigen (pathologic)
Disorders are often classed as immune-mediated inflammatory disease
My be caused by T cells or antibodies
What are examples of autoimmune diseases?
Rheumatoid arthritis Grave's disuse Addison's disease Myasthenia gravis SLE Multiple sclerosis
What are causes of autoimmune disease?
Imbalance between immune activation and control
Underlying causative factors: susceptibility genes and environmental influences
What are allergies?
Harmful immune response to non-infectious antigens that causes damage and disease
Can be mediated by:
- antibodies (IgE) and mast cells- acute anaphylactic shock or
- T cells- delayed type hypersensitivity
What is hypercytokinemia and sepsis?
Too much immune response
Often in positive feedback loop
Triggered by pathogens entering the wrong compartment (sepsis) or failure to regulate response to right level
What are the 3 stages of cell mediated immunity?
Induction -> Effector -> Memory
- Cell infection causes dendritic cell to present antigens on surface
- MHC/peptide interaction and TCR interaction
- Naive T cell becomes effector
- Effector sees MHC/peptide in infected cell and performs function
- Effector pool contracts memory
What are the 3 signals used to regulate immune response?
- Antigen recognition
- Co-stimulation
- Cytokine release
This licences the cell to respond
What is another way to regulate immune response?
make them self-limiting- naturally decline over time unless there’s continued presence of antigen to stimulate cells:
- immune response eliminated antigen that initiated response
- first signal for lymphocyte activation is eliminated
- overall decline in immune response as amount of antigen decreases
What are the 3 outcomes of an immune response?
Resolution- no tissue damage, returns to normal. Phagocytosis by macrophages
Repair- healing with scar tissue and regeneration. Fibroblasts and collagen synthesis
Chronic inflammation Active inflammation and attempts to repair damage ongoing
What is immune tolerence?
A specific response to an antigen that is caused by exposure of lymphocyte to antigen
All individuals are tolerant of their own antigens- a breakdown of self tolerance leads to autoimmunity
What is the therapeutic potential of immune tolerence?
Inducing self tolerance may be used to prevent graft rejection, treat autoimmune diseases and allergic diseases
At what points does tolerance occur?
Destruction of self T or B cells before they enter circulation (Central)
Destruction of self-reactive lymphocytes once they enter circulation (Peripheral)
What is central tolerance?
From thymus and bone marrow
Destruction of B and T cells before they enter circulation
Because there are 10^15 possible TCR and antibodies some of these will be self reactive so they need to be removed
How does central tolerance affect B cells?
If a B cell encounters an antigen in a form which can cross link their IgM, apoptosis is triggered
How does central tolerance affect T cells?
T cell selection occurs in the thymus
It’s more complex than B cell selection because of MHC-TCR interactions
Its therefor important TCRs which can recognise MHC but are not self-reactive are selected
How can T cells developing in the thymus encounter an MHC bearing peptides expressed in other parts of the body?
Specialised transcription factor allows thymus expression of genes that are expressed in other parts of the body
AIRE (Autoimmune regulator) promotes self tolerance by allowing thymus expression of genes from other tissues
Mutations in AIRE results in multi-organ autoimmunity
What is peripheral tolerance?
Destruction of any self reactive T or B cell which do enter circulation
How is tolerance broken by B cells?
Unlike T cells, B cells can change specify after they leave the bone marrow (somatic hypermutation)
This is normally good because it improves antigen quality
However exposure to self antigens or environmental antigens can create autoantibodies
What are the mechanisms of peripheral tolerance?
Regulation
Anergy- Naive T cell need co-stimulatory signals to be activated- most cells lack this and MHC II. Without the co-stimulation T cell becomes anergic
Ignorance- antigen may be too low in concentration to reach TCR trigger threshold
Deletion/ Antigen Induced Cell Death (AICD)- activation through TCR can cause apoptosis- often caused by induction of death ligand in peripheral T cells
What cells regulate immune response?
A subset of helper T cells called Treg (T regulatory cells)
They express CD4 co-receptor and CD25, a component of the high IL-2 receptor and low IL-7 receptor- they’re CD4+CD25+
They also express the nuclear transcription factor Forkhead box P3 (FoxP3)- this determines natural Treg development and function
What is the role of FoxP3?
FoxP3 is important for suppression of the immune system- mutations in it can lead to severe and fatal autoimmune disorders (Immune dysregulation, polyendocrinopathy, enteropathy, x-linked in humans and scurfy in mice)
What is the role of Treg?
Suppresses activation, proliferation and cytokine production of CD4+ and CD8+ T cells and can suppress B cells and DCs
They secrete TGF- beta and IL-10 and adenosine which are immune suppressors
They inactive DCs or responding lymphocytes
What is natural Treg?
Additional markers of natural Treg are CD152 and GITR
They develop in the thymus and require recognition of self antigen during T cell maturation
They reside in peripheral tissue to prevent harmful reactions against self antigens
What are inducible Tregs?
iTreg
Develop from mature CD4 T cells that are exposed to antigen in the periphery- no role for thymus
They may be generated in all immune responses to limit collateral damage
Whats the role of IL-10?
Key anti-inflammatory cytokine
Multi-functional (pleiotropic)
Acts in range of cells
Blocks pro-inflammatory cytokine synthesis including TNF, IL-6, IFN gamma, IL-8
What are cytokines?
Cytokines programme the immune response- they focus it for the right kind of response
They can be inflammatory or anti-inflammatory
What are chemokines?
Chemokines drive movement around the body
Act like dress labels sending things to the right place
How do T cell cytokines drive Ig class switch?
T cells produce cytokines
Cytokines programme B cells to make different classes of antibody
B cells activates a family of gene transcription meaning different variable regions are added or removed
