Immunology 8 - Regulation of lymphocyte responses

Question 1

Why is immune regulation important?

Answer 1

• To avoid excessive lymphocyte activation and tissue damage during normal protective responses against infections
• To prevent inappropriate reactions against self antigens (‘tolerance’)

Question 2

Define autoimmunity

Answer 2

Immune response against self (auto-) antigen = pathologic

Question 3

What are the general principles of the autoimmune response?

Answer 3

• Pathogenesis: Susceptibility genes + environmental triggers
• Systemic (relating to a system) or organ-specific

Question 4

What can cause an immune-mediated inflammatory disease?

Answer 4

• Immune responses against self antigens (autoimmunity) or microbial antigens (Crohn’s disease?)
• T cells and antibodies

Question 5

What is allergy?

Answer 5

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

Question 6

What is allergy mediated by?

Answer 6

• Antibody (IgE)
• Mast cells (acute anaphylactic shock)
• T cells (delayed type hypersensitivity)

Question 7

What cases hypercytokinemia and sepsis?

Answer 7

• Too much immune response
• Often in a positive feedback loop
• Triggered by pathogens entering the wrong compartment (sepsis) or failure to regulate response to correct level

Question 8

How does self limitation occur in regard to immune responses?

Answer 8

There is a decline of the immune response as the antigen is eliminated, meaning the signal for lymphocyte action is eliminated.

Question 9

What occurs to lymphocytes when the infection is eliminated?

Answer 9

• There is apoptosis of lymphocytes that lose their survival signals
• Memory cells are the survivors

Question 10

Define immunological tolerance.

Answer 10

Specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen (tolerogen vs immunogen)

Question 11

What is the significance of immunological tolerance?

Answer 11

• All individuals are tolerant of their own antigens (self-tolerance); breakdown of self-tolerance results in autoimmunity
• Therapeutic potential: Inducing tolerance may be exploited to prevent graft rejection, treat autoimmune and allergic diseases

Question 12

What are the two types of tolerance

Answer 12

• Central tolerance

- Peripheral tolerance

Question 13

What is central tolerance?

Answer 13

Destroying self-reactive T or B cells before they enter the circulation

Question 14

What is peripheral tolerance?

Answer 14

Destroy or control any self reactive T or B cells which do enter the circulation

Question 15

What happens in central tolerance to suppress the immune response?

Answer 15

• Apoptosis
• Editing of B cell receptors
• Development of regulatory lymphocytes (only in CD4+ T cells)

Question 16

What happens in peripheral tolerance to suppress the immune response?

Answer 16

• Anergy (lymphocyte doesnt react to their antigen)
• Apoptosis
• Suppression

Question 17

How is apoptosis of B cells triggered in the bone marrow?

Answer 17

When immature B cells in bone marrow encounter antigen in a form which can crosslink their IgM.

Question 18

How are T cells selected in the thymus?

Answer 18

• If the t cell cant bind to any self-MHC there is death by neglect (apoptosis)
• If the T cell binds to self MHC too strongly, there is negative selection (apotosis)
• If the T cells binds to MHC weaky there is a signal to survive (positive selection)

Question 19

How do T cells in the thymus encounter MHCs with petides expressed in other parts of the body?

Answer 19

• A specialised transcription factor (AIRE) allows thymic expression of genes that are expressed in peripheral tissues
• Promotes self tolerance by allowing the thymic expression of genes from other tissues

Question 20

What do mutations in AIRE cause?

Answer 20

Multi-organ autoimmunity

Question 21

What are the 4 possible outcomes in peripheral tolerance when there is an abnormal T cell response?

Answer 21

• Anergy
• Ignorance
• Deletion
• Regulation

Question 22

Describe the process of anergy

Answer 22

• When naive T cells are activated there are costimulatory signals
• If a naive T cells sees an MHC without the right costimulatory protein it will be less likely to be stimulated in the future
• This is true even when costimulation is present

Question 23

Describe the process of ignorance in T cells

Answer 23

• The antigen is present in such a low concentration the threshold is not reached for T cell activation
• Occurs in the brain and eyes, where infection is unlikely
• Can occur by compartmentalisation of cells

Question 24

Describe the process of antigen induced cell death in T cells

Answer 24

• Activation through the T cell receptor results in apoptosis
• In peripheral cells this is caused by Fas ligand (FasL)

Question 25

Describe the process of regulation in T cells

Answer 25

- T regulatory cells (Treg) inhibit other cells - Secrete immune-supressive cytokines - Inactivate dendric cells/responding lymphocytes

Question 26

What are the types of Treg cells?

Answer 26

- Natural regulatory T cells (nTreg) | - Inducible regilatory T cells (iTreg)

Question 27

How do nTreg cells develop and where do they reside?

Answer 27

- Development requires recognition of self antigens during T cell maturation - Reside in peripheral tissues to prevent harmful reactions against self.

Question 28

How do iTreg cells develop and when are they generated?

Answer 28

- Develop from mature CD4 T cells that are exposed to antigen in the periphery; no role for thymus - May be generated in all immune responses, to limit collateral damage

Question 29

Why is regulation important in pregnancy?

Answer 29

- Pregnancy is like a parasitic infection - Half of the antigens present are from the husband, so are non-self - Therefore, there is foreign MHC I

Question 30

What is resolution after the immune response?

Answer 30

Where there is no tissue damage, everything returns to normal

Question 31

What is repair after the immune response?

Answer 31

Healing with scar tissue and regeneration - involving fibroblasts and collagen synthesis.

Question 32

What is chronic inflammation after the immune response?

Answer 32

Active inflammation and attempts to repair damage ongoing.

Question 33

What can cause tolerance to end?

Answer 33

- Exposure to environmental antigens or self antigens in the context of infections can alter the outcome - Antibodies can cross react with heart muscle - Exposure in the wrong place - e.g. peanut oil onto broken skin can induce inflammation - Exposure + inflammation may trigger lack of tolerance

Question 34

How does cross regulation of T cells occur?

Answer 34

- The T helper cell that is dominating the immune response produces cytokines to inhibit the other T helper cell types. - This focuses the immune response so that unnecessary responses don't occur (eg. you don't want a fungal response to a virus)

Question 35

Why is IL-10 reffered to as the master regulator?

Answer 35

- Key anti-inflammatory cytokine - Multi-functional (pleiotropic) - Acts on a range of cells - Blocks pro-inflammatory cytokine synthesis - Downregulates Macrophages - Mimicked by some viruses

Question 36

Summarise T and B cell collaboration and the mechanisms governing the generation of antibody classes

Answer 36

- B cells are selected for by T cells which bind to processed antibodies on their cell surface - T cells then produce cytokines to activate the B cells - B cells can bind to soluble antigens¬ T cells cant. - T cells cause the Ig class switch by different classes producing different types of cytokines.