Immune tolerence

Question 1

What is immune regulation required for?

Answer 1

• To avoid lymphocyte activation and tissue damage during normal protective responses against infection
• To prevent inappropriate reactions against self antigents (“tolerance”)

Question 2

What is immune regulation?

Answer 2

Control of immune response to prevent inappropriate reactions

Question 3

What is autoimmunity?

Answer 3

Immune response against self antigen (pathologic)
Disorders are often classed as immune-mediated inflammatory disease
My be caused by T cells or antibodies

Question 4

What are examples of autoimmune diseases?

Answer 4

Rheumatoid arthritis
Grave's disuse
Addison's disease
Myasthenia gravis
SLE
Multiple sclerosis

Question 5

What are causes of autoimmune disease?

Answer 5

Imbalance between immune activation and control

Underlying causative factors: susceptibility genes and environmental influences

Question 6

What are allergies?

Answer 6

Harmful immune response to non-infectious antigens that causes damage and disease

Can be mediated by:

• antibodies (IgE) and mast cells- acute anaphylactic shock or
• T cells- delayed type hypersensitivity

Question 7

What is hypercytokinemia and sepsis?

Answer 7

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

Question 8

What are the 3 stages of cell mediated immunity?

Answer 8

Induction -> Effector -> Memory

1. Cell infection causes dendritic cell to present antigens on surface
2. MHC/peptide interaction and TCR interaction
3. Naive T cell becomes effector
4. Effector sees MHC/peptide in infected cell and performs function
5. Effector pool contracts memory

Question 9

What are the 3 signals used to regulate immune response?

Answer 9

1. Antigen recognition
2. Co-stimulation
3. Cytokine release

This licences the cell to respond

Question 10

What is another way to regulate immune response?

Answer 10

make them self-limiting- naturally decline over time unless there’s continued presence of antigen to stimulate cells:

• immune response eliminated antigen that initiated response
• first signal for lymphocyte activation is eliminated
• overall decline in immune response as amount of antigen decreases

Question 11

What are the 3 outcomes of an immune response?

Answer 11

Resolution- no tissue damage, returns to normal. Phagocytosis by macrophages
Repair- healing with scar tissue and regeneration. Fibroblasts and collagen synthesis
Chronic inflammation Active inflammation and attempts to repair damage ongoing

Question 12

What is immune tolerence?

Answer 12

A specific response to an antigen that is caused by exposure of lymphocyte to antigen
All individuals are tolerant of their own antigens- a breakdown of self tolerance leads to autoimmunity

Question 13

What is the therapeutic potential of immune tolerence?

Answer 13

Inducing self tolerance may be used to prevent graft rejection, treat autoimmune diseases and allergic diseases

Question 14

At what points does tolerance occur?

Answer 14

Destruction of self T or B cells before they enter circulation (Central)
Destruction of self-reactive lymphocytes once they enter circulation (Peripheral)

Question 15

What is central tolerance?

Answer 15

From thymus and bone marrow
Destruction of B and T cells before they enter circulation
Because there are 10^15 possible TCR and antibodies some of these will be self reactive so they need to be removed

Question 16

How does central tolerance affect B cells?

Answer 16

If a B cell encounters an antigen in a form which can cross link their IgM, apoptosis is triggered

Question 17

How does central tolerance affect T cells?

Answer 17

T cell selection occurs in the thymus
It’s more complex than B cell selection because of MHC-TCR interactions
Its therefor important TCRs which can recognise MHC but are not self-reactive are selected

Question 18

How can T cells developing in the thymus encounter an MHC bearing peptides expressed in other parts of the body?

Answer 18

Specialised transcription factor allows thymus expression of genes that are expressed in other parts of the body
AIRE (Autoimmune regulator) promotes self tolerance by allowing thymus expression of genes from other tissues
Mutations in AIRE results in multi-organ autoimmunity

Question 19

What is peripheral tolerance?

Answer 19

Destruction of any self reactive T or B cell which do enter circulation

Question 20

How is tolerance broken by B cells?

Answer 20

Unlike T cells, B cells can change specify after they leave the bone marrow (somatic hypermutation)
This is normally good because it improves antigen quality
However exposure to self antigens or environmental antigens can create autoantibodies

Question 21

What are the mechanisms of peripheral tolerance?

Answer 21

Regulation

Anergy- Naive T cell need co-stimulatory signals to be activated- most cells lack this and MHC II. Without the co-stimulation T cell becomes anergic

Ignorance- antigen may be too low in concentration to reach TCR trigger threshold

Deletion/ Antigen Induced Cell Death (AICD)- activation through TCR can cause apoptosis- often caused by induction of death ligand in peripheral T cells

Question 22

What cells regulate immune response?

Answer 22

A subset of helper T cells called Treg (T regulatory cells)
They express CD4 co-receptor and CD25, a component of the high IL-2 receptor and low IL-7 receptor- they’re CD4+CD25+

They also express the nuclear transcription factor Forkhead box P3 (FoxP3)- this determines natural Treg development and function

Question 23

What is the role of FoxP3?

Answer 23

FoxP3 is important for suppression of the immune system- mutations in it can lead to severe and fatal autoimmune disorders (Immune dysregulation, polyendocrinopathy, enteropathy, x-linked in humans and scurfy in mice)

Question 24

What is the role of Treg?

Answer 24

Suppresses activation, proliferation and cytokine production of CD4+ and CD8+ T cells and can suppress B cells and DCs

They secrete TGF- beta and IL-10 and adenosine which are immune suppressors

They inactive DCs or responding lymphocytes

Question 25

What is natural Treg?

Answer 25

Additional markers of natural Treg are CD152 and GITR

They develop in the thymus and require recognition of self antigen during T cell maturation

They reside in peripheral tissue to prevent harmful reactions against self antigens

Question 26

What are inducible Tregs?

Answer 26

iTreg

Develop from mature CD4 T cells that are exposed to antigen in the periphery- no role for thymus

They may be generated in all immune responses to limit collateral damage

Question 27

Whats the role of IL-10?

Answer 27

Key anti-inflammatory cytokine
Multi-functional (pleiotropic)
Acts in range of cells
Blocks pro-inflammatory cytokine synthesis including TNF, IL-6, IFN gamma, IL-8

Question 28

What are cytokines?

Answer 28

Cytokines programme the immune response- they focus it for the right kind of response
They can be inflammatory or anti-inflammatory

Question 29

What are chemokines?

Answer 29

Chemokines drive movement around the body

Act like dress labels sending things to the right place

Question 30

How do T cell cytokines drive Ig class switch?

Answer 30

T cells produce cytokines
Cytokines programme B cells to make different classes of antibody
B cells activates a family of gene transcription meaning different variable regions are added or removed