Autoimmunity

Question 1

Give some examples of organ-specific autoimmune disease.

Answer 1

Graves disease – overstimulation of TSH receptors in thyroid

Type 1 Diabetes –immune system attacks insulin-producing cells of the pancreas

Question 2

Describe an example of MHC-specific autoimmunity.

Answer 2

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 3

Describe lupus as a systemic autoimmune pathology.

Answer 3

Lupus is also known as SLE (systemic lupus erythematosus). It is a multi-system disease.

It’s characterised by autoantibodies to nuclear antigens e.g. double stranded DNA.

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

It is a disease of relapse and remission.

Question 4

What is autoimmunity?

Answer 4

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 5

What is immune tolerance?

Answer 5

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 6

Define the two mechanisms of tolerance.

Answer 6

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 7

Describe central tolerance.

Answer 7

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 8

How do we control TCR and MHC binding?

Answer 8

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 9

What are the ‘filters’ the T cells go through to be selected in the thymus?

Answer 9

Is it useless?:

• this is if it doesn’t bind to any self-MHC at all
• results in death by neglect (apoptosis)

Is it dangerous?

• this is if it binds self MHC too strongly
• results in apoptosis triggered – negative selection

Is it useful?

• this is if it binds self MHC too weakly
• loses the signal to survive – positive selection

Question 10

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

Answer 10

A specialised transcription factor allows thymic expression of genes that are expressed in peripheral tissues.

AutoImmune REgulator (AIRE) promotes self tolerance by allowing the thymic expression of genes from other tissues.

Mutations in AIRE result in multi-organ autoimmunity (Autoimmune Polyendocrinopathy Syndrome Type 1).

Question 11

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

Answer 11

We need to have a second way in dealing with these cells. This is where peripheral tolerance comes in.

Question 12

What are the three parts of peripheral tolerance?

Answer 12

• ignorance
• anergy
• regulation

Question 13

Describe ignorance in peripheral tolerance.

Answer 13

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 14

Describe anergy in peripheral tolerance.

Answer 14

Naive T cells need costimulatory signals in order to become activated.

Most cells lack costimulatory proteins and MHC class II.

If a naive T cell sees it’s MHC/peptide ligand without appropriate costimulatory protein it becomes anergic – i.e. it becomes less likely to be stimulated in the future even if co-stimulation is then present.

Question 15

Describe regulation in peripheral tolerance.

Answer 15

IL-10 is a cytokine that can dampen down the immune response. It, amongst others, is released by cells called Treg, which go around calming down overactive immune responses. They do this either by the release of cytokine, or by direct contact inhibition.

Question 16

How can we identify Treg cells?

Answer 16

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 17

What are the implications of the high variability of MHC?

Answer 17

Each copy of chromosome 6 carries 3 different MHC class I and 3 different MHC class II genes.
Thus, it contains high levels of genetic variation (polymorphism).

MHC is associated with more disease than any other region of the genome.

Question 18

What are the implications of endocrine factors in autoimmunity?

Answer 18

SLE is >10 times more common in females than males.

MS is approximately 10 times more common in females than males.

Diabetes is equally common in females and males.

Ankylosing spondylitis is approximately 3 times more common in males than females.

It seems that females, who experience more hormonal changes during their lifetime, are more susceptible to certain autoimmune disease.

Question 19

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

Answer 19

The hygiene hypothesis states that if you do not get exposed to bacteria when you are developing, your immune system will be compromised.

Smoking has been found too be linked to RA.

Question 20

What might trigger a breakdown of self tolerance?

Answer 20

• 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 21

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

Answer 21

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 22

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

Answer 22

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 23

How can antibodies be implicated in autoimmune disease?

Answer 23

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 24

How can antibody diseases be transferred between mother and child?

Answer 24

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 25

How are T cells implicated in autoimmune disease?

Answer 25

They can kill by:

• direct killing by CD8+ CTL
• self-destruction induced by cytokines such as TNFa

There is also recruitment and activation of macrophages leading to bystander tissue destruction.

CD4 cells provide help for Ab, and stimulate cytotoxicity against it.

Question 26

How are Th17 cells implicated in autoimmune disease?

Answer 26

Th17 cells are helper T cells that produce the cytokine IL-17.
They are implicated in autoimmune diseases including spondyloarthropathy, MS and diabetes.

They are highly inflammatory and produce cytokines which are involved in the recruitment, migration and activation of immune cells.

Question 27

What are the therapeutic strategies undertaken to treat autoimmune disease?

Answer 27

We can use many different strategies:
- anti-inflammatories: NSAID, corticosteroids

• T & B cell depletion (RA: anti-CD4, anti-CD20)
• therapeutic antibodies (anti-TNF; anti-VLA-4 (blocks adhesion of certain cells to endothelium, which would stop inflammation))
• antigen specific therapies (in development), e.g. Glatiramer acetate, increases T-regs