T1 L7: Mechanisms of tolerance

Question 1

What is meant by immunological tolerance?

Answer 1

When lack of immunological reactivity is induced and maintained

Question 2

Where is tolerance to self-antigens induced?

Answer 2

In the lymphoid organs and then maintained in the periphery

Question 3

What are the mechanisms of B-cell self-tolerance in the bone marrow?

Answer 3

• Deletion of the cell by apoptosis
• Anergy (paralysis of function)
• Receptor editing to alter the specificity

Question 4

What is Di-George syndrome?

Answer 4

When there is a lack of mature T-cells

Question 5

By what age is degradation of the thymus complete?

Answer 5

30 years

Question 6

What is immunosenescence?

Answer 6

Progressive deterioration of the immune responses mainly associated with age

Question 7

What is the microenvironment for T-cell development?

Answer 7

In the thymic stroma (epithelial cells and connective tissue) create the microenvironment

Question 8

What is positive selection?

Answer 8

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

(Selection of the useful)

Question 9

What is negative selection?

Answer 9

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

(Selection of the harmful because they bind too much)

Question 10

What is the function of AIRE?

Answer 10

It’s an autoimmune regulator that regulates gene transcription and stimulates the expression of self antigens normally restricted in peripheral tissues

Question 11

What conditions do mutations of AIRE lead to?

Answer 11

Autoimmune polyendicrinopathy with candidiasis and ectodermal dysplasia (APECED) also known as autoimmune polyendocrine syndrome (APS-1)

AIRE mutations lead to failure to express self antigens in the thymus

Question 12

What impact does tolerance have on allergies?

Answer 12

It’s caused by a breakdown in peripheral tolerance

Question 13

What are unresponsive (helpless) B-cells?

Answer 13

An auto-reactive B-cell that can be present without being able to be activated if there is no help available

Question 14

What is split tolerance?

Answer 14

Tolerance in certain compartments of the body but not others

Question 15

What are the 4 mechanisms of peripheral tolerance?

Answer 15

• Ignorance: Lymphocytes fail to recognise or respond
• Clonal anergy: Binding to an antigen makes the lymphocyte unresponsive
• Suppression: Interaction with a suppressor cell or cytokine to inhibit lymphocyte responsiveness
• Clonal exhaustion: Continued stimulation by persistent antigen wears out responsive cells

Question 16

What are immunologically privileged sites?

Answer 16

Sites where even foreign antigens accessing these tissues do not trigger immune responses

Eg. Eye, Testes, uterus/placenta

If these sequestered antibodies are released, it can result in autoimmunity Eg. anti-sperm antibodies after a vasectomy

Question 17

What is sympathetic ophthalmia?

Answer 17

When there is physical trauma to the eye that initiates an autoimmune response because T-cells are now released. It causes blindness is the damaged and undamaged eye

Question 18

What is the function of CTLA-4?

Answer 18

It stops cells from killing each other including cancer cells. It stops the action of CD28

Blocking CTLA-4 promotes tumour rejection

Question 19

What us the function of CD28?

Answer 19

It’s the major co-stimulation pathway for naive T-cell activation. CTLA-4 blocks the pathway

Question 20

What is the function of Treg (T regulatory cells)?

Answer 20

They supress activation of of effector responses and are critical for regulating homeostasis and tolerance of self-antigens

Question 21

What happens if there is an absence of Treg?

Answer 21

Associated with aggressive autoimmunity

Question 22

What is the function of FOXP3?

Answer 22

It’s the Forkhead/winged helix transcription factor critical for Treg activity and development

Question 23

What do mutations in FOXP3 gene cause?

Answer 23

It causes IPEX: Immunodysregulation, Polyendocrinopathy, and Enteropathy Xlinked syndrome

It’s a fatal autoimmune disorder characterised by systemic autoimmunity in the first year of life

Question 24

What is activated-induced cell death (AICD)?

Answer 24

When repeated stimulation of T-cells by persistent antigens results in apoptosis of the activated cell