T1 L9 Mechanisms of tolerance Flashcards
What is immunological tolerance?
Refers to mechanisms by which a lack of immunological reactivity is induced and maintained.
What is the immune system tolerant to?
Self
Harmless antigens e.g. food or environmental
Commensal microbiota
What is self-tolerance?
Differentiating between self and non-self
What happens if T-cell receptors are harmful?
They are negatively selected
What happens if T-cell receptors are useful?
They are positively selected
How many T-cells mature per day in the mouse thymus?
5x10^7
Where does T-cell development occur?
In defined thymus microenvironment
What is positive selection?
Selection of the useful
Retention of thymocytes expressing T-cell receptors that are restricted in their recognition of antigen by self MHC
As TCR is expressed, T-cells become able to recognise MHC expressed on surface of cortical epithelial cells and will survive
What is negative selection?
Selection of the harmful
Removal of thymocytes expressing T-cell receptors that recognise self-antigens presented by self MHC
What is the selection of cells in the thymus dependent on?
Strength of binding
Strong binding to self antigens causes apoptosis (negative selection)
What is AIRE (autoimmune regulator)?
Transcription factor expressed at high levels by thymus medullary epithelial cells
What is the consequence of mutations of AIRE?
Autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia
What is peripheral tolerance?
Tolerance to foreign antigens is induced and maintained in mature lymphocytes
Why is peripheral tolerance important?
Not all potential ‘self’ molecules are present in the thymus during T-cell receptor development
Don’t want to make immune responses against harmless things
Don’t want excessive lymphocyte activation and tissue damage during normal protective responses against infections
What does a breakdown of peripheral tolerance lead to?
Auto-immunity
Allergy
What are the 4 mechanisms of peripheral tolerance?
Ignorance - lymphocytes fail to recognise or respond
Clonal anergy
Clonal exhaustion
Suppression
What is clonal anergy?
Binding of antigen makes lymphocytes unresponsive
What is clonal exhaustion?
Continued stimulation by persistent antigen may ‘wear out’ responsive cells
What is suppression?
Interaction with other cells or cytokines may inhibit responsiveness
Why does clonal ignorance occur?
Self-reactive lymphocytes fail to recognise or respond to some self-antigens in the periphery - cells don’t die or become anergic
Antigens anatomically separated from immune system
Immunologically privileged sites
Describe immunologically privileged sites
Eyes, testis, uterus and placenta
Self-antigens in these sites aren’t exposed to immune system
What happens if there is trauma to the eye?
Release of sequestered intraocular protein antigens carried to lymph nodes which activate T cells
Effector T cells return via bloodstream and attack antigen in both eyes
Can cause blindness in damaged and undamaged eyes
What happens if a sequestered antigen is released?
Autoimmunity
What does CTLA-4 do and how can it be used therapeutically?
Limits immune response to tumours
Anti-CTLA-4 antibody approved for tumour immunotherapy as it enhances immune response against tumour
Describe the involvement of Treg cells in suppression
Treg suppress activation of effector responses to regulate homeostasis and tolerance to self-antigens.
What is a deficiency of Treg cells associated with?
Aggressive autoimmunity IPEX which is a fatal autoimmune disorder
What is the therapeutic role of Tregs in promoting tolerance?
Strengthen or re-establish self-tolerance in autoimmune disease
Induce tolerance to non-self antigens in organ transplantation, GVHD and allergy
Induce tumour immunity in cancer patients
How an antigen is presented to lymphocytes depends on what?
Concentration Tiiming Persistence Tissue distribution Nature of cell presenting the antigen
Describe the link between molecular weight of antigens and tolerance
Smaller, soluble, not-aggregated molecules favour tolerance
Large, aggregated, complex molecules favour immunogenicity
Describe the link between dosage of antigens and tolerance
Very small or large doses favours tolerance
Intermediate doses favours immunogenicity
How can oral tolerance be used therapeutically?
Multiple sclerosis using myelin basic or protein antigen
Rheumatoid arthritis using type II collagen antigen
Type I diabetes using insulin antigen
Describe hyposensitisation oral immunotherapy?
Using small amounts of allergens (food / pollen) to induce antigen-specific tolerance
Continuous administration of antigen promotes development and maintenance of tolerance
Oral / sublingual desensitisation immunotherapy for peanut allergy holds promise for control of allergy
