Mechanisms of tolerance

Question 1

Immunological tolerance

Answer 1

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

Question 2

Thymic involution

Answer 2

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

Question 3

Why is a mechanism for repertoire selection and self tolerance needed?

Answer 3

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)

Question 4

Which cells complete their maturation and form the peripheral T cell pool?

Answer 4

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

Question 5

T cells in thymus

Answer 5

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

Question 6

T cell development in microenvironment

Answer 6

Thymic stroma (epithelial cells and connective tissue) provides the microenvironment for T cell development and selection

Question 7

Thymocytes

Answer 7

Intimately associated with epithelial cells as they develop in the thymus

Question 8

Positive selection

Answer 8

Retention of thymocytes expressing TcR that are restricted in their recognition of antigen by self MHC

e.g. selection of the useful

Question 9

Negative selection

Answer 9

Removal of thymocytes expressing TcR that either recognise self antigens presented by self MHC

e.g. selection of the harmful

Question 10

Autoimmune regulator

Answer 10

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

Question 11

How is self tolerance established to antigens that cannot be expressed in the thymus?

Answer 11

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

Question 12

Peripheral tolerance

Answer 12

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

Question 13

Ignorance

Answer 13

Lymphocytes fail to recognise or respond

Cells neither die nor become anergic

Question 14

Clonal anergy

Answer 14

Binding of ag makes lymphocyte unresponsive

Question 15

Clonal exhaustion

Answer 15

Continued stimulation by persistent antigen may wear out responsive cells

Question 16

Suppression

Answer 16

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

Question 17

Eye anterior chamber

Answer 17

Immune privileged site

Self antigens in this site are not exposed to the immune system

Question 18

Induction of anergy

Answer 18

Presentation without costimulation

CTLA-4 signalling

Question 19

Therapeutic application of anergy

Answer 19

Blocking CTLA-4 promotes tumour rejection

CTLA-4 limits immune responses to tumours

Question 20

Activation induced cell death

Answer 20

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

Question 21

Deficiency of T regulatory cells

Answer 21

Associated with aggressive autoimmunity IPEX

Fatal autoimmune disorder characterised by systemic autoimmunity in the first year of life

Question 22

Therapeutic potential Treg

Answer 22

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

Question 23

Molecular weight

Answer 23

Smaller, soluble not-aggregated molecules favours tolerance

Large, aggregated, complex molecules favours immunogenicity

Question 24

Dosage

Answer 24

Very small or large favours tolerance

Intermediate favours immunogenicity

Question 25

Routes of administration

Answer 25

Oral, intratracheal, orbital exposure can activate T cells to secrete TGFbeta

Question 26

Clinical application: oral tolerance

Answer 26

Multiple sclerosis: myelin basic protein

Rheumatoid arthritis: type II collagen

Type I diabetes: insulin

Question 27

Hyposensitisation immunotherapy

Oral immunotherapy

Answer 27

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