Immunological tolerance

Question 1

Why is the immune system kept in a fine balance?

Answer 1

It must manage to fight infection whilst tolerating self to prevent autoimmunity

Question 2

What happens if the immune system is unable to tolerate self?

Answer 2

Autoimmune disorders develop

Question 3

Examples of autoimmune disorders

Answer 3

Psoriasis

Scleroderma

Multiple Sclerosis

Question 4

What is the disadvantage of having a wide range of antibodies?

Answer 4

There is increased risk of self-reactivity

Question 5

What is tolerance?

Answer 5

Prevents undesirable immune responses from taking place

Like those towards self antigens

Question 6

What are the two mechanisms of tolerance?

Answer 6

Peripheral tolerance

Central tolerance

Question 7

When does central tolerance take place?

Answer 7

During development

Question 8

Where does central tolerance take place?

Answer 8

B cells = bone marrow

T cells = thymus

Question 9

Describe the process behind central B cell tolerance

Answer 9

B cells undergo B cell selection

A functional antigen receptor is produced

If an immature B cell binds to a self-antigen in the bone marrow it can either:

• change specificity through receptor editing
• be deleted through negative selection

Question 10

Describe the structure of the thymus

Answer 10

Bi-lobed organ

Outer cortex

Inner medulla

Question 11

Describe the marker expression profile of a T cell

Answer 11

Initially, T cells express no receptors

Then they express both CD4 and CD8 receptors

During education, T cells downregulates one of the CD proteins

Question 12

Which two processes happen in the thymus during thymic education of T cells?

Answer 12

Positive selection

Negative selection

Question 13

Describe positive selection

Answer 13

All T cells need to recognise body cell MHC

The MHC class the T cell recognises determines the CD class they express

Involves checking that the TCR can recognise MHC on the APCs

Failure of positive selection causdes apoptosis since they cannot detect MHCs and are therefore not usegul

Question 14

Describe negative selection

Answer 14

This checks to see whether the T cell recognises self proteins

If they recognise the self proteins strongly, they are destroyed to prevent autoimmunity

Question 15

Where in the lymph node does positive selection take place?

Answer 15

Cortex

Question 16

Where in the lymph node does negative selection take place?

Answer 16

Medulla

Question 17

What is AIRE?

Answer 17

Autoimmune regulator

Transcription factor which turns on the expression of proteins belonging to different tissues in the thymus

So the thymus mimics all the proteins expressed throughout the body

This allows different tissue-specific proteins to be expressed in the thymus

Question 18

What happens if the thymus is AIRE-deficient?

Answer 18

Increase in T cells which recognise self-antigens

Leads to autoimmunity

Question 19

What is peripheral tolerance?

Answer 19

Deals with any self-reactive lymphocytes that escape central tolerance

Question 20

Where does peripheral tolerance take place?

Answer 20

Lymph nodes

Spleen

Mucosal and cutaneous lymphoid tissues

Question 21

What are the two mechanisms of peripheral tolerance?

Answer 21

Cell intrinsic mechanism - cell is controlling itself

Cell extrinsic mechanism - another cell is controlling the cell

Question 22

Which cell is involved in the cell extrinsic mechanism?

Answer 22

T regulatory cells

Question 23

What are the 4 types of cell intrinsic mechanisms?

Answer 23

Ignorance

Anergy

Phenotypic skewing

Apoptosis

Question 24

What is ignorance?

Answer 24

Self-reactive T cells might never encounter the self-protein they recognize and therefore exist in a state of ignorance.

Question 25

What is anergy?

Answer 25

Plays on the fact that activation of T cells relies on co-stimulation

The antigens that the self-reactive T cells react to come from the body, so there are no danger signals from the innate immune response accompanying them

Due to the lack of danger cytokines, the expression of costimulatory molecules on APCs is small or inexistent

Without the second signal, T cells are not activated and instead become anergic

Question 26

When is phenotypic skewing activated?

Answer 26

When the main ways of peripheral immune tolerance are not effective

Question 27

What is phenotypic skewing?

Answer 27

Since the body cannot prevent immune activation, it’s trying to downregulate the already ongoing response

For harm to be caused, they need to differentiate in a particular way

If they activate but differentiate into an unwanted cell, then functional tolerance will be preserved

Question 28

Where do Tregs develop?

Answer 28

In the periphery or in the thymus

Question 29

What do Tregs express?

Answer 29

CD25

Question 30

What transcription factor do Tregs express?

Answer 30

Foxp3

Question 31

Where do Tregs come from?

Answer 31

Develop from self-reactive T cells which are modified into becoming inhibitory

Question 32

Describe an experiment showing the importance of Tregs

Answer 32

Injection of all the T cells into a mouse lacking a thymus led to a healthy mouse

Injection of CD25-depleted T cells into a mouse lacking a thymus led to a mouse with autoimmune disease

This shows that our own T cells are dangerous unless kept in check by CD25+ T regs

Question 33

T cells recognising self peptide in the periphery are rare

TRUE or FALSE

Answer 33

FALSE

The mouse experiment showed this

T cells recognising self peptide are common

Question 34

Which inhibitory cytokines do T regs secrete?

Answer 34

IL-10

TGFb

Question 35

Mechanisms of action of Tregs

Answer 35

Secretion of inhibitory cytokines

Modifying CTLA-4 to alter the function of APCs through removing/blocking costimulatory ligands

Bind and consume IL-2 (growth factor for T cells)

Question 36

Why is it important to control T cells?

Answer 36

T cells control many other cell types