T1 L7: Mechanisms of tolerance Flashcards
What is meant by immunological tolerance?
When lack of immunological reactivity is induced and maintained
Where is tolerance to self-antigens induced?
In the lymphoid organs and then maintained in the periphery
What are the mechanisms of B-cell self-tolerance in the bone marrow?
- Deletion of the cell by apoptosis
- Anergy (paralysis of function)
- Receptor editing to alter the specificity
What is Di-George syndrome?
When there is a lack of mature T-cells
By what age is degradation of the thymus complete?
30 years
What is immunosenescence?
Progressive deterioration of the immune responses mainly associated with age
What is the microenvironment for T-cell development?
In the thymic stroma (epithelial cells and connective tissue) create the microenvironment
What is positive selection?
Retention of thymocytes expressing TcR that are restricted in their recognition of antigen by self MHC
(Selection of the useful)
What is negative selection?
Removal of thymocytes expressing TcR that recognise self antigens presented by self MHC
(Selection of the harmful because they bind too much)
What is the function of AIRE?
It’s an autoimmune regulator that regulates gene transcription and stimulates the expression of self antigens normally restricted in peripheral tissues
What conditions do mutations of AIRE lead to?
Autoimmune polyendicrinopathy with candidiasis and ectodermal dysplasia (APECED) also known as autoimmune polyendocrine syndrome (APS-1)
AIRE mutations lead to failure to express self antigens in the thymus
What impact does tolerance have on allergies?
It’s caused by a breakdown in peripheral tolerance
What are unresponsive (helpless) B-cells?
An auto-reactive B-cell that can be present without being able to be activated if there is no help available
What is split tolerance?
Tolerance in certain compartments of the body but not others
What are the 4 mechanisms of peripheral tolerance?
- Ignorance: Lymphocytes fail to recognise or respond
- Clonal anergy: Binding to an antigen makes the lymphocyte unresponsive
- Suppression: Interaction with a suppressor cell or cytokine to inhibit lymphocyte responsiveness
- Clonal exhaustion: Continued stimulation by persistent antigen wears out responsive cells
What are immunologically privileged sites?
Sites where even foreign antigens accessing these tissues do not trigger immune responses
Eg. Eye, Testes, uterus/placenta
If these sequestered antibodies are released, it can result in autoimmunity Eg. anti-sperm antibodies after a vasectomy
What is sympathetic ophthalmia?
When there is physical trauma to the eye that initiates an autoimmune response because T-cells are now released. It causes blindness is the damaged and undamaged eye
What is the function of CTLA-4?
It stops cells from killing each other including cancer cells. It stops the action of CD28
Blocking CTLA-4 promotes tumour rejection
What us the function of CD28?
It’s the major co-stimulation pathway for naive T-cell activation. CTLA-4 blocks the pathway
What is the function of Treg (T regulatory cells)?
They supress activation of of effector responses and are critical for regulating homeostasis and tolerance of self-antigens
What happens if there is an absence of Treg?
Associated with aggressive autoimmunity
What is the function of FOXP3?
It’s the Forkhead/winged helix transcription factor critical for Treg activity and development
What do mutations in FOXP3 gene cause?
It causes IPEX: Immunodysregulation, Polyendocrinopathy, and Enteropathy Xlinked syndrome
It’s a fatal autoimmune disorder characterised by systemic autoimmunity in the first year of life
What is activated-induced cell death (AICD)?
When repeated stimulation of T-cells by persistent antigens results in apoptosis of the activated cell
