Immune Tolerance

Question 1

Why is immune regulation necessary?

Answer 1

Avoid excessive lymphocyte activation and tissue damage during normal protective responses against infections
Prevent inappropriate reactions against self antigens

Question 2

Give the definition of autoimmunity

Answer 2

Immune response against self antigen

Question 3

Is autoimmunity physiological or pathological?

Answer 3

Pathological

Question 4

What are the features of autoimmune disease?

Answer 4

• Imbalance between immune activation and control
• Underlying cause: failure of control mechanisms
• Underlying causative factors: susceptibility genes + environmental influences (more prevalent in women)

Question 5

What is Crohn’s Disease caused by?

Answer 5

Immune responses against microbial agents

Question 6

What is the definition of an allergy?

Answer 6

Harmful immune responses to non-infectious agents that cause tissue damage and disease.

Question 7

What are allergic reactions mediated by?

Answer 7

• IgE antibody and mast cells (acute anaphylactic shock)

- T cells - delayed hypersensitivity

Question 8

In Hypercytokinemia and Sepsis, what is wrong with the immune response?

Answer 8

Too much immune response
Often a positive feedback loop
Triggered by pathogens entering wrong compartment (sepsis) of failure to correctly regulate immune response

Question 9

Give the steps of cell-mediated immunity

Answer 9

Induction - Cell infected DC collects material
MHC:peptide TCR interaction
Effector - Naive T cell becomes effector
Effector cell sees MHC:peptide on infected cell; performs function (e.g, apoptosis - CD8)
Memory - Effector pool contracts to memory

Question 10

What is the cardinal feature of all immune responses?

Answer 10

Self-limitation
Immune response eliminates antigen that initiated the response and then immune response declines as activation signals decrease

Question 11

What are the 3 signals that are required to activate the T or B cells?

Answer 11

Antigen Recognition
Co-Stimulation - protein interactions on cell surface of APC, T cells and B cells
Cytokine Release

Question 12

Describe the 3 possible end outcomes of infection

Answer 12

Resolution - No tissue damage, returns to normal. Phagocytosis of debris by macrophages.
Repair - Healing with scar tissue and regeneration. Fibroblasts and collagen synthesis.
Chronic Inflammation - Active inflammation and attempts to repair damage ongoing.

Question 13

What is meant by immunological tolerance?

Answer 13

Tolerance is specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen.

Question 14

What condition occurs when there is a lack of immunological tolerance?

Answer 14

Autoimmunity

Question 15

What is the therapeutic potential of immunological tolerance?

Answer 15

• Can be exploited to prevent graft rejection, treat autoimmune and allergic diseases

Question 16

What are the 2 types of tolerance?

Answer 16

Central - destroy self-reactive T or B cells before they enter circulation
Peripheral - destroy self-reactive T or B cells once they are in circulation

Question 17

How does B cell selection occur in the bone marrow?

Answer 17

If immature B cells encounter antigen in a form which can crosslink their IgM, apoptosis is triggered.

Question 18

Which 3 ways does T cell selection occur in the thymus?

Answer 18

Useless - Doesn’t bind to any self-MHC at all; death by neglect (apoptosis)
Dangerous - Binds to self-MHC too strongly; apoptosis triggered (negative selection)
Useful - Binds self-MHC weakly; signal to survive (positive selection)

Question 19

How can a T-cell developing in the thymus encounter MHC bearing peptides expressed in other parts of the body?

Answer 19

Specialised transcription factor - Autoimmune Regulator (AIRE) - allows thymic expression of genes that are expressed in peripheral tissue

Question 20

What happens if there is a mutation in AIRE?

Answer 20

Multi-organ immunity (APECED)

Question 21

What are the fates of self-reactive lymphocytes in central tolerance?

Answer 21

Apoptosis
Change in receptors (receptor editing - B cells)
Development of regulatory T cells (CD4 + T cells only)

Question 22

What are the fates of self-reactive lymphocytes in peripheral tolerance?

Answer 22

Anergy
Apoptosis
Suppression

Question 23

What are the 3 pathways that a B cell can go into after maturation?

Answer 23

Antibody Production
Memory
Affinity maturation (self-reactive B cells can develop at this point)

Question 24

Describe what affinity maturation is

Answer 24

B cells can change specificity after leaving bone marrow
This improves antibody quality
Exposure to environmental antigens self-antigens in the context of infections can make them less tolerogenic

E.g Anti-Streptococcus pyrogens antibodies can cross react with heart muscle

Question 25

What is Anergy?

Answer 25

Anergy is one of three processes that induce tolerance, modifying the immune system to prevent self-destruction.

Question 26

How does Ignorance lead to peripheral tolerance of T cells?

Answer 26

T cells contract as a population, become anergic or no longer reactive

Question 27

At which sites specifically, would ignorance occur in this context?

Answer 27

Immunologically privileged sites (or compartmentalisation of cells) where T cells don't come into contact with antigen Immune reactions may cause more harm than good and so antigens in these sites do not elicit an immune response, e.g. eyes or brain

Question 28

Describe Antigen Induced Cell Death in context of peripheral tolerance of T cells

Answer 28

Activation of T cell receptors influenced by nature of initial T cell activation events can result in apoptosis instead of development into memory cell In peripheral T cells it is often caused by induction of expression of death ligand, Fas ligand CD95

Question 29

What do T regulatory cells do?

Answer 29

Block T cell activation Inhibit effect of matured T cells Inactive DCs and other lymphocytes Through production of immune-suppressive cytokines (TGF-beta, IL-10, IL-35)

Question 30

What transcription factor do Treg cells express and what condition is caused by a mutation in this TF?

Answer 30

FoxP3 Severe and fatal autoimmune disorder - IPEX syndrome Scurfy in mice

Question 31

Describe the function of IL-10

Answer 31

``` Key anti-inflammatory cytokine Pleiotropic - multi-functional Blocks pro-inflammatory cytokine synthesis including TNF, IL-6, IL-8, IFN-gamma Acts on a range of cells Down-regulates macrophage function Has viral mimics (EBV virus) ```

Question 32

What might be the reason for T-regulatory cells being present in only mammals?

Answer 32

Critical in pregnancies Foetus gets half MHC from mum and other half from dad These may be seen as foreign antigens Immunological tolerance is necessary

Question 33

Describe the 2 different types of T-regulatory cells

Answer 33

Natural T-regulatory cells (nTreg) - Development in thymus and requires recognition of self antigen during T cell maturation - Reside in peripheral tissues to prevent harmful reactions against self Inducible regulatory T cells (iTreg) - Develop from mature CD4 T cells that are exposed to antigen in periphery - May be generated during immune responses to prevent collateral damage Tregs reflect the Th subsets seen in T effectors

Question 34

What is the function of chemokines?

Answer 34

Chemokines drive movement around the body Act like address labels sending stuff to the right place Chemokine receptor profiles change with activation state of cells Cells move up chemokine gradient

Question 35

What are the functions of cytokines?

Answer 35

Program the immune response Focus it for the right kind of response Can be inflammatory or anti-inflammatory Examples: IFN-gamma, IL-2, IL-10

Question 36

What defines T helper cell type?

Answer 36

Transcription factors | Cytokines shake transcription factor pathways

Question 37

What is it called when CD4 cells neutralise one another?

Answer 37

Cross regulation

Question 38

Explain how T cells boost antibody responses (in terms of licensing model)

Answer 38

1. Antigen T cell - MHC:peptide on DC or B cell B cell - soluble antigen 2. Co-stimulation T cell - expresses CD40L to activate B; expresses CD28 to be activated B cell - expresses CD40 to be activated by T cell; expresses B7 to activated T cell 3. Cytokine: IL-21

Question 39

Explain the process in which T cells shape the antibody response

Answer 39

``` CD4 T cells release a certain type of cytokine Cytokine detected by B cell The antibody that the B cell will produce will now have it constant region altered (gene cassettes can be swapped in and out), determining its class (A, D, E, G or M) This way, the class of antibody produced is dependent on the cytokine triggered The cytokine released depends on T helper cell type ```