Immunology 8 - Regulation of lymphocyte responses Flashcards
Why is immune regulation important?
- To avoid excessive lymphocyte activation and tissue damage during normal protective responses against infections
- To prevent inappropriate reactions against self antigens (‘tolerance’)
Define autoimmunity
Immune response against self (auto-) antigen = pathologic
What are the general principles of the autoimmune response?
- Pathogenesis: Susceptibility genes + environmental triggers
- Systemic (relating to a system) or organ-specific
What can cause an immune-mediated inflammatory disease?
- Immune responses against self antigens (autoimmunity) or microbial antigens (Crohn’s disease?)
- T cells and antibodies
What is allergy?
Harmful immune responses to non-infectious antigens that cause tissue damage and disease
What is allergy mediated by?
- Antibody (IgE)
- Mast cells (acute anaphylactic shock)
- T cells (delayed type hypersensitivity)
What cases hypercytokinemia and sepsis?
- Too much immune response
- Often in a positive feedback loop
- Triggered by pathogens entering the wrong compartment (sepsis) or failure to regulate response to correct level
How does self limitation occur in regard to immune responses?
There is a decline of the immune response as the antigen is eliminated, meaning the signal for lymphocyte action is eliminated.
What occurs to lymphocytes when the infection is eliminated?
- There is apoptosis of lymphocytes that lose their survival signals
- Memory cells are the survivors
Define immunological tolerance.
Specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen (tolerogen vs immunogen)
What is the significance of immunological tolerance?
- All individuals are tolerant of their own antigens (self-tolerance); breakdown of self-tolerance results in autoimmunity
- Therapeutic potential: Inducing tolerance may be exploited to prevent graft rejection, treat autoimmune and allergic diseases
What are the two types of tolerance
- Central tolerance
- Peripheral tolerance
What is central tolerance?
Destroying 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
What happens in central tolerance to suppress the immune response?
- Apoptosis
- Editing of B cell receptors
- Development of regulatory lymphocytes (only in CD4+ T cells)
What happens in peripheral tolerance to suppress the immune response?
- Anergy (lymphocyte doesnt react to their antigen)
- Apoptosis
- Suppression
How is apoptosis of B cells triggered in the bone marrow?
When immature B cells in bone marrow encounter antigen in a form which can crosslink their IgM.
How are T cells selected in the thymus?
- If the t cell cant bind to any self-MHC there is death by neglect (apoptosis)
- If the T cell binds to self MHC too strongly, there is negative selection (apotosis)
- If the T cells binds to MHC weaky there is a signal to survive (positive selection)
How do T cells in the thymus encounter MHCs with petides expressed in other parts of the body?
- A specialised transcription factor (AIRE) allows thymic expression of genes that are expressed in peripheral tissues
- Promotes self tolerance by allowing the thymic expression of genes from other tissues
What do mutations in AIRE cause?
Multi-organ autoimmunity
What are the 4 possible outcomes in peripheral tolerance when there is an abnormal T cell response?
- Anergy
- Ignorance
- Deletion
- Regulation
Describe the process of anergy
- When naive T cells are activated there are costimulatory signals
- If a naive T cells sees an MHC without the right costimulatory protein it will be less likely to be stimulated in the future
- This is true even when costimulation is present
Describe the process of ignorance in T cells
- The antigen is present in such a low concentration the threshold is not reached for T cell activation
- Occurs in the brain and eyes, where infection is unlikely
- Can occur by compartmentalisation of cells
Describe the process of antigen induced cell death in T cells
- Activation through the T cell receptor results in apoptosis
- In peripheral cells this is caused by Fas ligand (FasL)
Describe the process of regulation in T cells
- T regulatory cells (Treg) inhibit other cells
- Secrete immune-supressive cytokines
- Inactivate dendric cells/responding lymphocytes
What are the types of Treg cells?
- Natural regulatory T cells (nTreg)
- Inducible regilatory T cells (iTreg)
How do nTreg cells develop and where do they reside?
- Development requires recognition of self antigens during T cell maturation
- Reside in peripheral tissues to prevent harmful reactions against self.
How do iTreg cells develop and when are they generated?
- Develop from mature CD4 T cells that are exposed to antigen in the periphery; no role for thymus
- May be generated in all immune responses, to limit collateral damage
Why is regulation important in pregnancy?
- Pregnancy is like a parasitic infection
- Half of the antigens present are from the husband, so are non-self
- Therefore, there is foreign MHC I
What is resolution after the immune response?
Where there is no tissue damage, everything returns to normal
What is repair after the immune response?
Healing with scar tissue and regeneration - involving fibroblasts and collagen synthesis.
What is chronic inflammation after the immune response?
Active inflammation and attempts to repair damage ongoing.
What can cause tolerance to end?
- Exposure to environmental antigens or self antigens in the context of infections can alter the outcome
- Antibodies can cross react with heart muscle
- Exposure in the wrong place - e.g. peanut oil onto broken skin can induce inflammation
- Exposure + inflammation may trigger lack of tolerance
How does cross regulation of T cells occur?
- The T helper cell that is dominating the immune response produces cytokines to inhibit the other T helper cell types.
- This focuses the immune response so that unnecessary responses don’t occur (eg. you don’t want a fungal response to a virus)
Why is IL-10 reffered to as the master regulator?
- Key anti-inflammatory cytokine
- Multi-functional (pleiotropic)
- Acts on a range of cells
- Blocks pro-inflammatory cytokine synthesis
- Downregulates Macrophages
- Mimicked by some viruses
Summarise T and B cell collaboration and the mechanisms governing the generation of antibody classes
- B cells are selected for by T cells which bind to processed antibodies on their cell surface
- T cells then produce cytokines to activate the B cells
- B cells can bind to soluble antigens¬ T cells cant.
- T cells cause the Ig class switch by different classes producing different types of cytokines.
