Autoimmunity

Question 1

Types of autoimmune diseases

Answer 1

Organ specific

Systemic

Question 2

Grave’s Disease

Answer 2

Organ-specific autoimmune disease characterised by an antibody response (autoantibodies) against TSH receptors in the thyroid (excess stimulation)
-excess thyroxine produced causing hyperthyroidism

*disease can be transferred into animals with IgG antibodies

Question 3

Type I Diabetes

Answer 3

Type 1 Diabetes –organ specific autoimmune=immune system attacks the pancreatic β cells, reducing the amount of insulin produced by the pancreas

Question 4

Myasthenia gravis

Answer 4

Autoimmune disease caused by autoantibodies which bind to nicotinic Ach receptors at neuromuscular junction and block them

• leads to receptor internalisation and degradation
• results in muscle weakness

Question 5

Describe an example of MHC-specific autoimmunity.

Answer 5

HLA B27-associated spondyloarthropathies are an example of MHC-specific autoimmunity.

The spondyloarthropathies include:

• ankylosing spondylitis
• undifferentiated spondyloarthropathy
• reactive arthritis
• psoriatic arthritis
• urethritis
• iritis

There is a spectrum of severity and HLA B27 association.
It is associated with bowel inflammation.

Question 6

Describe lupus as a systemic autoimmune pathology.

Answer 6

SLE (systemic lupus erythematosus). It is a multi-system disease.

It’s characterised by autoantibodies to nuclear antigens e.g. double stranded DNA. forming immune complexes deposited in tissues (e.g. blood vessels, joints, renal glomerulus)

You get devascularization of the fingers, membrane ulcerations, and alopecia are all manifestations of SLE.

Can lead to activation of complement and phagocytic cells

Immune complexes depositing in kidney can lead to renal failure
It is a disease of relapse and remission.

Question 7

What is autoimmunity?

Answer 7

The immune system has various regulatory controls to prevent it from attacking self proteins and cells.

Failure of these controls will result in immune attack of host components – known as autoimmunity.

Question 8

What is immune tolerance?

Answer 8

Immune system does not attack self proteins or cells – it is tolerant to them.

To do this, we need to be able to identify what is self and what is not self.

Question 9

Define the two mechanisms of tolerance.

Answer 9

Central tolerance: destroy self-reactive T or B cells before they enter the circulation.

Peripheral tolerance: destroy or control any self reactive T or B cells which do enter the circulation.

Question 10

Central tolerance of B cells

Answer 10

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

If immature T-cells recognise the self-antigen presented by AIRE (AutoImmunty REgulator), it is destroyed.

Question 11

Central tolerance of T cells

Answer 11

T Cell selection in the thymus:

Is it useless?

• doesn’t bind to any self-MHC at all → useless
• death by neglect (apoptosis)

Is it dangerous?

• binds self-MHC too strongly
• apoptosis triggered → negative selection

Is it useful?

• binds self MHC weakly→ apoptosis
• binds self MHC with a high enough affinity, receiving survival signal → positive selection

Question 12

How do we control TCR and MHC binding?

Answer 12

We need to be able to select for T cell receptors which are capable of binding self MHC.

If binding to self MHC is too weak, it may not be enough to allow signalling when binding to MHC with foreign peptides bound in groove.

If binding to self MHC is too strong, it may allow signalling irrespective of whether self or foreign peptide is bound in groove

We need to find that intermediate level of affinity.

Question 13

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

Answer 13

A specialised transcription factor (AIRE) allows thymic expression of genes that are expressed in peripheral tissues → promotes self-tolerance

*AIRE= autoimmune regulator

Question 14

What is the consequence of AIRE mutations?

Answer 14

Mutations in AIRE result in multi-organ autoimmunity

-Autoimmune Polyendocrinopathy Syndrome type 1

Question 15

What happens to autoreactive T cells that survive central tolerance control?

Answer 15

Some autoreactive T cells and B cells do escape central tolerance and get out of the thymus/bone marrow. We need to have a second way of dealing with these cells.

-if they escape central tolerance, they come under the control of peripheral tolerance

Question 16

What are the three parts of peripheral tolerance?

Answer 16

• ignorance
• anergy
• regulation

Question 17

Describe ignorance in peripheral tolerance.

Answer 17

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

It could also be because the antigen is present in an immunologically privileged site e.g. eye, brain, where the immune system simply doesn’t go.

Question 18

Describe anergy in peripheral tolerance.

Answer 18

T cells can be made non-responsive to antigens presented on APCs if the T cell engages an MHC molecule on an antigen presenting cell (signal 1) without engagement of co-stimulatory molecules (signal 2).
- Naïve T cell becomes anergic

*less likely to be stimulated in future even if co-stimulation is then present

Question 19

Describe regulation in peripheral tolerance.

Answer 19

Suppression of self-reactive T cells by CD4 Tregs. Tregs use several different mechanisms to suppress autoimmune reactions:

• Bind antigen on an APC and produce cytokines (IL-10 and TGF-β) which send a negative signal to other self-reactive T cells
• Inhibit other self-reactive T cells by contact inhibition

Question 20

Treg levels in some cases of cancer and autoimmune disease

Answer 20

In some cases of cancer, there are increased Treg cells.

In autoimmune diseases, there are too few Treg cells
- defective Treg cells have been observed in multiple sclerosis

Question 21

What gives Tregs their function?

Answer 21

Tregs express transcription factor FOXP3. This molecule is expressed in CD4 T-regs and it gives them their effector function (regulatory T cell)

Question 22

How can we identify Treg cells?

Answer 22

Tregs express transcription factor FOXP3.

A mutation in FOXP3 leads to a severe and fatal autoimmune disorder - Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome.

Question 23

Factors which contribute to autoimmunity

Answer 23

Genetic Factors
Environmental Factors
Endocrine Factors

Question 24

Genetic Factors in autoimmunity

Answer 24

Major histocompatibility complex (MHC)

• Each copy of chromosome 6 carries 3 different MHC Class I and 3 different MHC Class II genes
• High levels of genetic variation (polymorphism) because it needs to be able to recognise a wide variety of peptides and non-peptide antigens

MHC genes (HLA) are the prevailing contributors of genetic susceptibility to autoimmune diseases.

-binding the wrong antigens on the peptide binding groove within MHC molecules increases risk of developing autoimmune disease.

Question 25

What are the implications of endocrine factors in autoimmunity?

Answer 25

· Systemic Lupus Erythematosus (SLE) is >10x more common in females than males
· MS is approximately 10x more common in females than males
· Diabetes is equally common in females and males
· Ankylosing spondylitis is approximately 3x more common in males than females

Question 26

List some environmental factors that could contribute to the risk of autoimmune disease.

Answer 26

Hygeine hypothesis
-if you don’t get exposed to pathogens when developing, then your immune system is compromised

Smoking

• experiment with 13 pairs of identical twins where 1 of each pair smoked and 1 of each pair had rheumatoid arthritis
• in 12/13 cases the twin with rheumatoid arthritis was the smoker

Question 27

What might trigger a breakdown of self tolerance?

Answer 27

• loss of/problem with regulatory cells
• release of sequestered antigen (where they are not seen by the immune system)
• modification of self
• molecular mimicry

Question 28

Describe an example of modification of self that lead to an autoimmune disease.

Answer 28

Citrullin is an amino acid that is not coded for by DNA.
Arginine can be converted to citrulline as a post-translational modification by peptidylarginine deiminase (PAD) enzymes.
Citrullination may be increased by inflammation.

Auto-antibodies to citrullinated proteins are seen in rheumatoid arthritis; this is now used for clinical diagnosis.

Question 29

What is molecular mimicry?

Answer 29

close resemblance between foreign and self-antigen which causes an autoimmune response

Question 30

Describe an example of molecular mimicry that lead to an autoimmune disease.

Answer 30

Rheumatic fever is a disease triggered by infection with Streptococcus pyogenes.

Antibodies to strep cell wall antigens may cross-react with cardiac muscle, causing a rheumatic fever.

Question 31

Antibodies in Autoimmune Pathology

Answer 31

• Graves’ Disease
• Myasthenia Gravis
• SLE and Vasculitis

Question 32

How can antibodies be implicated in autoimmune disease?

Answer 32

GRAVES DISEASE:
Auto-antibodies bind the thyroid stimulating hormone (TSH) receptor and stimulate it, resulting in hyperthyroidism.
The disease can be transferred via IgG antibodies.

MYASTHENIA GRAVIS:
Autoantibodies bind to the acetylcholine receptor and block the ability of acetyl choline to bind.
It also leads to receptor internalisation and degradation.
This results in muscle weakness.

SLE:
Autoantibodies to soluble antigens (such as double-stranded DNA and RNA) form immune complexes.
These complexes are deposited in tissues e.g. blood vessels, joints, renal glomerulus.

This can lead to activation of complement and phagocytic cells. The immune complexes depositing in the kidney can lead to renal failure.

Question 33

How can antibody diseases be transferred between mother and child?

Answer 33

Using the example of Grave’s disease, a patient with the disease makes anti-TSHR antibodies. These antibodies are transferred across the placenta into the foetus.

The newborn infant also suffers from Grave’s disease.
However, plasmapheresis can remove maternal anti-TSHR antibodies, and cure the child.

Question 34

How are T cells implicated in autoimmune disease?

Answer 34

Autoimmune pathology is also caused by T cells (not just B cells)
· Direct killing by CD8+ CTL
· Self-destruction induced by cytokines such as TGF⍺
· T cells can recruit other immune cells and activate them (e.g. macrophages) leading to bystander tissue destruction
· Autoimmune CD4+ T cell can activate CD8+ cytotoxic T cells and antibodies to become killers against an autoantigen
>Multiple sclerosis
>Insulin dependent diabetes mellitus

Question 35

What kind of cells are Th17 cells?

Answer 35

· Th17 cells are helper T cells that produce the cytokine IL-17

Question 36

How are Th17 cells implicated in autoimmune disease?

Answer 36

· Implicated in autoimmune diseases including spondyloarthropathy, MS and diabetes
· Highly inflammatory
· Produce cytokines which are involved in the recruitment, migration and activation of immune cells

Question 37

What are the therapeutic strategies undertaken to treat autoimmune disease?

Answer 37

Anti-inflammatories

• NSAIDs
• Corticosteroids

T & B Cell Depletion

• Depleting immune cells to dampen down the immune response
• E.g. rheumatoid arthritis anti-CD4 (depleting T cell population), anti-CD20 (depleting B cell population)
• Not used very often because it dampens down the rest of the adaptive immune response

Therapeutic Antibodies

• Anti-TNF → stop inflammation (treat disease such as rheumatoid arthritis)
• anti-VLA-4 → block adhesion of certain cells, stopping inflammation

Antigen Specific Therapies (in development)
- Glatiramer acetate → increases Tregs to dampen down immune response