Immune Tolerance

Question 1

What is immune regulation?

Answer 1

Control of the immune response to prevent inappropriate reactions

Needed to abound excessive lymphocyte and tissue damage
And to prevent inappropriate reactions against self antigens “tolerance”

Question 2

What is an autoimmune disease?

Answer 2

An immune response against a self antigen

Pathological

Can be systemic or organ specific

Question 3

What are some features of autoimmune diseases?

Answer 3

Chronic with prominent inflammation

Involve and imbalance between immune activation and control

Can be driven by susceptibility genes and environmental influences

Can be in response to self antigens or microbial antigens from the microbiome

Caused by T cells and antibodies

Self perpetuating (there will always be more self antigen to attack)

Question 4

What is an allergy?

Answer 4

Harmful immune responses to non infectious antigens that cause tissue damage and disease

Can be mediated by antibody (IgE) and mast cells - possibly leading to anaphylactic shock. Or can be mediated by T cells (delayed type hypersensitivity

Question 5

What are the three phases of cell mediated immunity?

Answer 5

1. Induction - a dendritic cell picks up and presents an antigen on its MHCII complex. It then moves to a lymph node. Specific T cells bind to this and undergo clonal expansion
2. Effector - the activated T cells return to the site of infection and carry out the specific T cells role

3 memory - once pathogen has been cleared effector pool contracts to memory

Question 6

What is a cardinal feature of all immune responses?

Answer 6

Self limitation

Removes the source of the infection and closes down afterwards

It does this by eliminating the antigen that triggered the response

(First trigger for lymphocyte activation is eliminated)

Question 7

What are the three signals in the thre signal model?

Answer 7

1. Antigen recognition
2. Co-stimulation (eg T cells activate B cells )
3. Cytokine release

Without any one of these you don’t get activation

Question 8

What are the three possible outcomes at the end of a response?

Answer 8

Resolution: no long term tissue damage

Repair: healing woth scar tissue and regeneration

Chronic inflammation: active i flammatinn and attempts to repair damage ongoing

Question 9

What is the definition of tolerance?

Answer 9

Specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen

All individuals are tolerant of their own antigens

Question 10

What are the two points at which tolerance occurs?

Answer 10

Central: before T or B cells enter circulation

Peripheral: once they are in the circulation

Question 11

How does central tolerance work?

Answer 11

Lymphocytes that recognise self antigens are eliminated or made harmless in the generative organs as part of the maturation process

This contributes to the immune repertoire but getting rid of Cells that respond to self antigens

Question 12

How does central tolerance work with B cells?

Answer 12

If Immature B cells in the bone marrow encounter antigen in a form which can cross link their IgM, apoptosis is triggered

These antigens will be self

Question 13

How does central tolerance work with T cells?

Answer 13

More complex because of TCR MHC interactions

Is the T cell useless? If it doesn’t bind to any Self MHC at all it undergoes apoptosis

Is the T cell dangerous? If it binds to self MHC too strongly apoptosis is triggered (negative selection)

Is the T cell useful? If it binds to self MHC weakly it is signaled to survive (positive selection )

The thymus needs to express proteins from all around a the body so the T cells won’t react agains these when mature. It does this using a transcription factor (AIRE - auto immune regulator) which allows the thymus to express all genes in peripheral tissues

Question 14

Why are B cells able to break central tolerance?

Answer 14

They have three paths once activated by T cells
1. Plasma antibody secreting cell

2. Memory cell
3. Affinity maturation

In affinity maturation the antibody can slightly change its shape so it can bind to a pathogen better (or self antigen?) in the process of somatic hypermutation

Question 15

The first method of peripheral tolerance is called anergy, what is this?

Answer 15

Naive T cells need co stimulatory signals to become activated

Most cells one of either the co stimulators or MHC II

If a naive T cell sees it’s MHC/peptide ligand without the costimatory protein it becomes anergic

This means it is less likely to be stimulated in the future when the co stimulation is present (it is essentially unreactive)

Question 16

The second method of peripheral tolerance is called ignorance, what is this?

Answer 16

The antigen May be present in too low a concentration to reach the threshold for T cell receptor triggering

This often occurs in privileged sites such as the brain or the eye

Question 17

The third method of peripheral tolerance is called antigen induced cell death, what is this?

Answer 17

Activation through T cell receptor can result in cell death

Influenced by the nature of the initial T cell activation events

In peripheral T cells it is often caused by the induction of expression of the death ligand (FasL)

Question 18

What is T cell mediated regulation?

Answer 18

A subset of T helper cells know as Treg (T regulatory cells) inhibit other T cells and other cells

They do this through the production of cytokines to either:

1. Inhibit the activation of T cells
2. Inhibit the effector functions of T cells

Question 19

What transcription factors to Treg cells express?

Answer 19

Factor FoxP3

People with a mutation in this leads to a severe and fatal immune disorder called IPEX syndrome

Question 20

What is the main cytokine used by Treg cells?

Answer 20

IL-10 (master regulator)

Key inflammatory cytokine

Multi functional and acts on a range of cells

Blocks pro inflammatory cytokine synthesis (TNF, IL-6, IL-8)

Downregulates macrophage functions

Question 21

What are the types of Treg cells?

Answer 21

Natural:
Develop in thymus and require recognition of self antigen during maturation. They reside in the peripheral tissues

Inducible:
Develop from mature CD4 T cells that are exposed to antigen in the periphery

Question 22

What are cytokines?

Answer 22

Program the immune response

Focus it to the right kind of response

Whether inflammatory of antibiotic inflammatory

Eg. Interferon gamma, IL-2, IL-10

They perpetuate themselves (eg cytokines released by Th1 cells will activate more of these cells) they can also down regulate different types of T cells

Question 23

What is a chemokine?

Answer 23

Drive movements around the body

Act as a dress labels

Their receptor profiles change woth activation states if the cells

They work along a gradient. The T cell moves up the gradient