Mechanisms of tolerance Flashcards
Immunological tolerance
Immune system is tolerant to self
Immune system is tolerant to harmless antigens such as food or environmental ag
Immune system is tolerant to commensal microbiota
Thymic involution
The human thymus is fully developed before birth and increases in size during puberty
Thymus is most active in the young and atrophies markedly with age
Progressively shrinks
Degeneration is complete by the age of 30, residual thymic activity persists until advanced age
Reduced production of T cells does not completely impair immunity
Why is a mechanism for repertoire selection and self tolerance needed?
Generation of the TcR repertoire involves many random mechanisms to allow diversity
Specificity of TcR in the immature repertoire is also random and will include cells with receptors that are
- harmful (negatively select)
- useless (neglect)
- useful (positively select)
Which cells complete their maturation and form the peripheral T cell pool?
Only cells that bear antigen receptor with appropriate affinity for the peptide presented in self MHC complexes
- naive T cells
- self MHC restricted
- self tolerant
T cells in thymus
Mature in the thymus
Most die there
98% of cells die in the thymus without inducing any inflammation or any change in the size of the thymus
Thymic macrophages phagocytose apoptic thymocytes
T cell development in microenvironment
Thymic stroma (epithelial cells and connective tissue) provides the microenvironment for T cell development and selection
Thymocytes
Intimately associated with epithelial cells as they develop in the thymus
Positive selection
Retention of thymocytes expressing TcR that are restricted in their recognition of antigen by self MHC
e.g. selection of the useful
Negative selection
Removal of thymocytes expressing TcR that either recognise self antigens presented by self MHC
e.g. selection of the harmful
Autoimmune regulator
Transcription factor expressed at high levels by thymic medullary epithelial cells
Mutations of AIRE lead to autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia, also called autoimmune polyendocrine syndrome
Mouse knockout: failure to express many self antigens in the thymus and expression of autoantibodies
How is self tolerance established to antigens that cannot be expressed in the thymus?
T cells bearing TcR reactive with proteins expressed in the thymus are deleted
Some self proteins are not expressed in the thymus e/g/ antigens first expressed at puberty
Self tolerance needs to be induced and maintained outside the thymus
Peripheral tolerance
Tolerance to foreign antigens is induced and maintained in mature lymphocytes
Not all potential self molecules are present in the thymus during TRC development
Don’t want to make an immune response against harmless things/ food
Don’t want excessive lymphocyte activation and tissue damage during normal protective responses against infections
Auto-immunity/ allergy- breakdown of peripheral tolerance: the immune system responds to self or environmental agents
Ignorance
Lymphocytes fail to recognise or respond
Cells neither die nor become anergic
Clonal anergy
Binding of ag makes lymphocyte unresponsive
Clonal exhaustion
Continued stimulation by persistent antigen may wear out responsive cells
Suppression
Interaction with other cells (or cytokines) may inhibit responsiveness
Treg cells are critical components in the maintenance of peripheral tolerance through ‘suppressive’ mechanisms
Tregs suppress the activation of effector responses and are critical for regulating homeostasis and tolerance to to self antigens
Eye anterior chamber
Immune privileged site
Self antigens in this site are not exposed to the immune system
Induction of anergy
Presentation without costimulation
CTLA-4 signalling
Therapeutic application of anergy
Blocking CTLA-4 promotes tumour rejection
CTLA-4 limits immune responses to tumours
Activation induced cell death
Repeated stimulation of T lymphocytes by persistent antigens results in death by apoptosis of the activated cell
Elimination of T cells specific for abundant peripheral antigens: clonal exhaustion
Deficiency of T regulatory cells
Associated with aggressive autoimmunity IPEX
Fatal autoimmune disorder characterised by systemic autoimmunity in the first year of life
Therapeutic potential Treg
Critical role of Treg in promoting tolerance may be exploited to
- 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
Molecular weight
Smaller, soluble not-aggregated molecules favours tolerance
Large, aggregated, complex molecules favours immunogenicity
Dosage
Very small or large favours tolerance
Intermediate favours immunogenicity
Routes of administration
Oral, intratracheal, orbital exposure can activate T cells to secrete TGFbeta
Clinical application: oral tolerance
Multiple sclerosis: myelin basic protein
Rheumatoid arthritis: type II collagen
Type I diabetes: insulin
Hyposensitisation immunotherapy
Oral immunotherapy
Using small amount of allergens to induce antigen specific tolerance
Continuous administration of the allergen, rather than its elimination, to promote the development and maintenance of tolerance
Oral/ sublingual desensitisation immunotherapy for peanut allergy holds promise for control
