T1 L9 Mechanisms of tolerance

Question 1

What is immunological tolerance?

Answer 1

Refers to mechanisms by which a lack of immunological reactivity is induced and maintained.

Question 2

What is the immune system tolerant to?

Answer 2

Self
Harmless antigens e.g. food or environmental
Commensal microbiota

Question 3

What is self-tolerance?

Answer 3

Differentiating between self and non-self

Question 4

What happens if T-cell receptors are harmful?

Answer 4

They are negatively selected

Question 5

What happens if T-cell receptors are useful?

Answer 5

They are positively selected

Question 6

How many T-cells mature per day in the mouse thymus?

Answer 6

5x10^7

Question 7

Where does T-cell development occur?

Answer 7

In defined thymus microenvironment

Question 8

What is positive selection?

Answer 8

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

Question 9

What is negative selection?

Answer 9

Selection of the harmful

Removal of thymocytes expressing T-cell receptors that recognise self-antigens presented by self MHC

Question 10

What is the selection of cells in the thymus dependent on?

Answer 10

Strength of binding

Strong binding to self antigens causes apoptosis (negative selection)

Question 11

What is AIRE (autoimmune regulator)?

Answer 11

Transcription factor expressed at high levels by thymus medullary epithelial cells

Question 12

What is the consequence of mutations of AIRE?

Answer 12

Autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia

Question 13

What is peripheral tolerance?

Answer 13

Tolerance to foreign antigens is induced and maintained in mature lymphocytes

Question 14

Why is peripheral tolerance important?

Answer 14

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

Question 15

What does a breakdown of peripheral tolerance lead to?

Answer 15

Auto-immunity

Allergy

Question 16

What are the 4 mechanisms of peripheral tolerance?

Answer 16

Ignorance - lymphocytes fail to recognise or respond
Clonal anergy
Clonal exhaustion
Suppression

Question 17

What is clonal anergy?

Answer 17

Binding of antigen makes lymphocytes unresponsive

Question 18

What is clonal exhaustion?

Answer 18

Continued stimulation by persistent antigen may ‘wear out’ responsive cells

Question 19

What is suppression?

Answer 19

Interaction with other cells or cytokines may inhibit responsiveness

Question 20

Why does clonal ignorance occur?

Answer 20

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

Question 21

Describe immunologically privileged sites

Answer 21

Eyes, testis, uterus and placenta

Self-antigens in these sites aren’t exposed to immune system

Question 22

What happens if there is trauma to the eye?

Answer 22

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

Question 23

What happens if a sequestered antigen is released?

Answer 23

Autoimmunity

Question 24

What does CTLA-4 do and how can it be used therapeutically?

Answer 24

Limits immune response to tumours

Anti-CTLA-4 antibody approved for tumour immunotherapy as it enhances immune response against tumour

Question 25

Describe the involvement of Treg cells in suppression

Answer 25

Treg suppress activation of effector responses to regulate homeostasis and tolerance to self-antigens.

Question 26

What is a deficiency of Treg cells associated with?

Answer 26

Aggressive autoimmunity IPEX which is a fatal autoimmune disorder

Question 27

What is the therapeutic role of Tregs in promoting tolerance?

Answer 27

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 28

How an antigen is presented to lymphocytes depends on what?

Answer 28

``` Concentration Tiiming Persistence Tissue distribution Nature of cell presenting the antigen ```

Question 29

Describe the link between molecular weight of antigens and tolerance

Answer 29

Smaller, soluble, not-aggregated molecules favour tolerance | Large, aggregated, complex molecules favour immunogenicity

Question 30

Describe the link between dosage of antigens and tolerance

Answer 30

Very small or large doses favours tolerance | Intermediate doses favours immunogenicity

Question 31

How can oral tolerance be used therapeutically?

Answer 31

Multiple sclerosis using myelin basic or protein antigen Rheumatoid arthritis using type II collagen antigen Type I diabetes using insulin antigen

Question 32

Describe hyposensitisation oral immunotherapy?

Answer 32

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