Body defences: Tolerance and Autoimmunity

Question 1

Why must the immune system be regulated?

Answer 1

To avoid a permanent immune response and chronic inflammation.

Question 2

What do Treg cells do?

Answer 2

Regulatory T cells have suppressor activity and have an important role in maintenance of self-tolerance

Question 3

What causes immunological tolerance?

Answer 3

Lack of response to self antigens which is induced by exposure of lymphocytes to these antigens.

Question 4

What decides whether a lymphocyte is activated or not?

Answer 4

The nature of the antigen Location of antigen (Antigens present in generative organs can be negatively selected to induce central tolerance) Additional signals present when antigen is exposed to the immune system (costimulation) Duration of antigen exposure (Short term exposure to microbial antigens reflects effective immune response, long term persistence induces apoptosis (prolonged TCR engagement)

Question 5

What do CD4+ regulatory T-cells do?

Answer 5

Some immature CD4+ T cells that recognize self antigens in the thymus with high affinity do not die and instead develop into Treg cells and migrate to peripheral tissues.

Question 6

How are regulatory T cells produced?

Answer 6

When naive T cells are selected they undergo a test of affinity. Positive and negative selection take place for too little and too much affinity respectively leading to apoptosis of the cells. However, sometimes some high affinity cells do not undergo negative selection and instead become regulatory T cells.

These Treg cells migrate to peripheral tissues.

Question 7

How is central tolerance produced?

Answer 7

There are many self proteins normally only present in peripheral tissues that are also expressed in the epithelial cells of the thymus. These proteins are expressed as a result of AIRE proteins (autoimmune regulator). A mutation in this gene can result in autoimmune disorders (due to lack of antigen to use for selection)

Question 8

Why is there need for peripheral tolerance?

Answer 8

Negative selection is imperfect and so many self-reactive lymphocytes are present in the periphery of healthy individuals.

Question 9

What are the mechanisms of peripheral T cell tolerance?

Answer 9

For proliferation and differentiation of naive T cells to occur there is need for co-stimulation between B7 on APCs and CD28 on T cells. (Costimulation)

Anergy

Suppression by regulatory T-cells (via regulatory T cells)

Deletion (apoptosis)

Question 10

What are the mechanisms of anergy?

Answer 10

Low levels of co-stimulation which leads to an antigen not being able to send activation signals and induce energy. This is caused by intracellular enzymes that modify signalling proteins and targets them for intracellular destruction thus resulting in cells that survive but are incapable of responding to the antigen.

Delivery of inhibitory signals from receptors other than the TCR complex. (Inhibitory co-stimulation) This occurs via 2 receptors Cytotoxic T lymphocyte associated antigen 4 (CTLA-4/CD152) and Programmed death protein 1 (PD-1).

Question 11

What does CTLA-4 do?

Answer 11

Involved in shutting off T-cell responses by reducing co-stimulation.

Question 12

What receptor does CTLA-4 bind and what does it do?

Answer 12

It binds to B7 (which normally binds CD28) and has a higher affinity for B7 than CD28 resulting in inhibition of co-stimulation and it blocks and removes B7 from surface of APCs and it may send inhibitory signals to T-cells if there is a low level of B7 on APC surface. If there is a high level of B7 it results in activation of T cell.

Question 13

How does PD-1 inhibit activation of T cells?

Answer 13

It is expressed on CD4 and CD8 T-cells after antigen stimulation.

It has an immunoreceptor tyrosin-based inhibitory motif (ITIM) typical of receptors that deliver inhibitory signals.

It terminates responses of T-cells to self antigens.

It terminates T-cell responses to chronic infections (mostly viral infections)

Question 14

How can PD-1 be used therapeutically?

Answer 14

Treatment with antibodies that block PD-1 can be used to increase immunity and can be used in treatment of cancer.

Question 15

What are regulatory T cells?

Answer 15

T cells that develop in the thymus and are relocated to peripheral tissues on recognition of self antigens. Most are CD4+ and express high levels of CD25 which is the alpha chain of IL-2 receptor.

These cells express FoxP3 which is a transcription factor required for their development and function.

Question 16

What do Treg cells do?

Answer 16

They suppress the activation and differentiation of lymphocytes specific for self antigens.

Question 17

What other cells can Treg cells inhibit?

Answer 17

B cells and NK cells

Question 18

How do Treg cells suppress the immune system?

Answer 18

They produce cytokines (such as IL-10 and TGF-β) that inhibit activation of lymphocytes, DCs, and macrophages.

Expression of CTLA-4 which blocks or removes B7.

Due to high level of IL-2 receptor expression they may bind and consume IL-2 preventing it from being used by other T-cells to grow.

Question 19

Under normal circumstances how do T cells respond to antigens and how is that different in peripheral T cell deletion?

Answer 19

T-cells respond to antigen by producing IL-2 and expressing anti-apoptotic proteins resulting in proliferation and differentiation.

Self antigen recognition by T-cells without co-stimulation leads to deficiency of intracellular anti-apoptotic proteins and excess of pro-apoptotic proteins thus resulting in apoptosis.

Self antigens may lead to expression of death receptors and their ligands (Eg. Fas and FasL)

Question 20

How is B-cell tolerance different for Polysaccharides, lipids, and nucleic acids compared to tolerance in protein antigens?

Answer 20

In proteins T-cell tolerance may be enough due to the need for “help” for the B cell response (this is not always the case though as seen in systemic lupus erythematosus in which the tolerance is defective in both T and B cells). Polysaccharides, lipids and nucleic acids require tolerance from the B cells themselves to prevent autoantibody production.

Question 21

What happens if B lymphocytes are able to interact with self antigens in the bone marrow? (mechanisms of B cell central tolerance)

Answer 21

Change in B cell receptor specificity (receptor editing)

B-cell apoptosis (negative selection or deletion)

Anergy - reduced antigen receptor expression making cell unresponsive

Question 22

How is the B cell receptor edited in response to reacting to self antigen?

Answer 22

Some immature B cells recognizing self antigens may re-express recombinase-activating gene (RAG), resume Ig light-chain gene recombination, and express a new Ig light chain that associates with the heavy chain that was previously expressed.

(25 - 50% of mature B cells may have been edited during maturation)

Question 23

What induces apoptosis during B cell central tolerance?

Answer 23

If editing fails immature B cells recieve death signals and die.

Question 24

What causes B cells to undergo anergy as the mechanism for B cell central tolerance?

Answer 24

Some self antigens in the bone marrow are recognized with low affinity (avidity) and these cells survive but antigen expression is reduced resulting in anergy.

Question 25

What are the mechanisms of B-cell tolerance in peripheral lymphoid tissues? (Mechanisms of peripheral B cell tolerance)

Answer 25

Anergy (Lack of T cell help = lack of B cell activity)

Apoptosis (Self recognizing B cells die)

Inhibition (Inhibitory receptors on B cells prevents their action)

2 other possible mechanisms:

Regulatory T cells may contribute to B cell tolerance.

Somatic hypermutation of Ig genes in germinal centers resulting in self reactive B cells are killed off via high levels of Fas.

Question 26

How does peripheral anergy take place in self-recognizing B cells?

Answer 26

T-cells are eliminated for self or are anergic which results in B cells also being anergic for self protein antigens.

Question 27

How do B-cells undergo apoptosis as a mechanism of B cell perihperal tolerance?

Question 28

What happens to anergic B cells?

Answer 28

They may be excluded from the follicles resulting in them losing signals that allow them to survive and so they die.

Question 29

What causes autoimmunity?

Answer 29

A failure of self-tolerance resulting in immune response against self antigens.

Tissue injury in autoimmune diseases may be caused by antibodies or by T-cells reacting to self antigens - particularly self-reactive CD4+ T-cells. Response can be due to presence of foreign antigen or even a normal self-antigen.

Question 30

Are autoimmune diseases organ specific?

Answer 30

They can be organ specific but they can also be systemic causing widespread tissue injury and clinical manifestations.

Question 31

How do autoimmune diseases cause disease?

Answer 31

Susceptibility genes may interfere wtih pathways of self-tolerance and lead to the persistence of self-reactive T and B lymphocytes.

Question 32

What genetic disorders result in autoimmunity?

Answer 32

Inherited risk for most autoimmune diseases is located on multiple gene loci.

Largest contribution is by MHC genes. Some MHC molecules may be especially effective at presenting self peptides to autoreactive T cells and some may be inefficient at displaying certain self-antigens in the thymus leading to non-selection of cells that should have been negatively selected.

Question 33

What gene is associated with a higher risk of ankylosing spondylitis and how common is it?

Answer 33

HLA-B27 which is associated with 90x higher risk

Question 34

Genes where mutation causes autoimmune disease due to weakness in self tolerance pathways:

Answer 34

AIRE (gene in the thymus leading to elimination of self-reactive T cells)

CTLA4 (breaks down or inhibits B7 co stimulator)

FOXP3 (Important for Treg cell function)

FAS (important for apoptosis)

FCγRIIB (important for feedback inhibition of B cells)

Question 35

What kind of autoimmune responses result from environmental stimuli?

Answer 35

Molecular mimicry

By-stander activation

Antigens that don’t see the immune system very often (sequestered antigens) suddenly becoming present in blood or other places where immune cells are located.

Question 36

How is autoimmunity caused by molecular mimicry?

Answer 36

A T-cell specific for a foreign antigen that is similar to self-tissue ends up reacting to self tissue and thus results in an immune response to both the pathogen and the self proteins.

Question 37

What is bystander activation?

Answer 37

A dendritic cell that is presentinc self-proteins instead of microbial peptides might become activated indirectly by cytokines produced in response to microbial products as a bystander effect. (i.e self antigen presented on 1 cell but non-self antigens on another and due to presence of cytokines nearby that stimulate proliferation and differentiation there is activation of the self antigen presenting APC.)

Question 38

What risk factors increase chance of autoimmunity?

Answer 38

Release of sequestered self antigens and exposure of these antigens to the immune system.

Abundance and composition of the microbiome.

Gender (Hormonal effects?)

UV radiation

Question 39

Potential aetiological factors of autoimmunity:

Answer 39