9. Mechanisms of Tolerance

Question 1

What is immunological tolerance?

Answer 1

Immunological tolerance refers to the mechanisms by which lack of immunological reactivity is induced and maintained

Question 2

Which syndrome is characterised by a lack of thymus?

Answer 2

Di-George syndrome

Question 3

Repertoire selection of T cells

Answer 3

Due to random process of producing TCRs (for diversification), its specificity is also randomn

TCRs of different affinities to self-antigens are produced
-Harmful TcRs–high affinity to self-receptors= negatively selected

Useless TCRs- no affinity

-Useful TCRs- strong affinity to foreign antigens- positively selected

Question 4

Thymus microenvironment

Answer 4

Immature T cells start off as double negative T cells

In the cortex: positive selection
Medulla: negative selection

Thymocytes able to recognise self MHC expressed on the surface of cortical epithelial cells SURVIVE

Question 5

Autoimmune polyendocrine syndrome

Answer 5

Mutations of AIRE

autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia

Question 6

Peripheral tolerance

Answer 6

Tolerance to foreign antigens is induced and maintained outside the thymus

Question 7

Mechanisms of Peripheral Tolerance [4]

Answer 7

IGNORANCE:
lymphocytes fail to recognise or respond

CLONAL ANERGY:
binding of ag makes lymphocyte unresponsive

CLONAL EXAUSTION:
continued stimulation by persistent antigen may ‘wear out’ responsive cells

SUPPRESSION:
interaction with other cells (or cytokines) may inhibit responsiveness

Question 8

Clonal anergy

Answer 8

T cells encounter antigens but do not undergo co-stimulation (C40L/CD28) or its signalling is inhibited by CTLA-4.

Question 9

CTLA-4

Answer 9

Receptor on T cells that bind to CD80/86/B7 on B cells to block downstream signalling

• Induces anergy of T cells
• Limits immune response to tumours

Anti-CTLA-4 antibody is approved for tumor immunotherapy