Autoimmunity

Question 1

What is the action of Graves’ disease?

Answer 1

It is an antibody response against the TSH receptor in the thyroid. It leads to inflammation in the eyes due to low levels of TSH receptors expressed by the fibroblast in the eye. Therefore, thought to be mediated by B cells due to the antibodies.

Question 2

What is the action in Type 1 disease?

Answer 2

T cells attack the beta cells in the pancreas leading to no production of insulin. Therefore, thought of to be mediated by T cells due to the direct killing of the cell.

Question 3

What are spondyloarthropathies?

Answer 3

A family of long-term (chronic) diseases of joints. It is MHC specific autoimmunity.

Question 4

What is the major gene associated with spondyloarthropathies?

Answer 4

HLA-B27

HLA B27-associated spondylarthropathies

Question 5

Give examples of HLA B27-associated spondylarthropathies diseases

Answer 5

Ankylosing spondylitis, undifferentiated spondyloarthropathy, reactive arthritis, psoriatic arthritis, urethritis, iritis.
All of these are associated with bowel inflammation as well.

Question 6

What is spondyloarthropathy in the knee?

Answer 6

Arthritis in the knee joints and spine

Question 7

What is psoriasis?

Answer 7

Disease of the skin cut can get arthritis inflammation of the joint associated with B27.

Question 8

What is systemic lupus erythematosus (SLE)?

Answer 8

A multi-system disease characteristed by autoantibodies to nuclear antigens such as dsDNA. It is a disease of relapse and remission.

Question 9

What is autoimmunity?

Answer 9

When the immune system has various regulatory controls to prevent it from attacking self-proteins and cells. The failure of these controls will result in immune attack of host components which is autoimmunity.

Question 10

What are the 2 pathways that allow the immune system to know what to attack?

Answer 10

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 cell which now enter the circulation.

Question 11

Describe the central tolerane of B cells

Answer 11

B cells mature in the bone marrow and go through a series of maturation and differentiation pathways. They gain specific surface bound immunoglobulins which will be complementary to antigen.
When they mature in the bone marrow, if they recognise a self-antigen (for example from a stromal cell) and they bind to it via their IgM, an apoptotic signal will be triggered, and they will get destroyed.

Question 12

Describe the action of T cells

Answer 12

• T cells recognise antigens that are presented to them by MHC proteins.
• Therefore, the T cells need to be able to recognise foreign peptides that are bound to self-MHC on either APCs.
• This happens so a certain threshold is reached for the T cell to get activated.

Question 13

What is important about the binding between TCR and MHC binding?

Answer 13

TCR need to bind to self MHC not too weakly or else there will not be enough signalling when binding to the foreign antigen peptide and not too strongly binding otherwise lead to signalling and activation of the T cell irrespective of whether there is a foreign antigen on the groove or not.

Question 14

How is the central tolerance in T cells checked?

Answer 14

• Is it useless: if it doesn’t bind to any self-MHC than it is killed by apoptosis.
• Is it dangerous: if it binds to MHC too strongly, it is killed by apoptosis via negative selection.
• Is it useful: If it binds to MHC weakly (but too weakly), it will survive via positive selection.

Question 15

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

Answer 15

A specialised transcription factor allows thymic expression of genes that are expressed in peripheral tissues. This gene is called AIRE.

Question 16

What is AIRE (autoimmune regulator)?

Answer 16

This is a gene which promotes self-tolerance by allowing in the thymic expression of genes from other tissues.

Question 17

What happens if there is mutations in the AIRE gene?

Answer 17

Mutations in this gene leads to multi-organ autoimmunity. It causes other diseases such as hypoparathyroidism, candidasis etc.

Question 18

What is the function of peripheral tolerance for auto-active B cells and T cells?

Answer 18

They are able to escape central tolerance, and enter the circulation, therefore there needs to be a second way of controlling them. This is peripheral tolerance which is broken down into 3 main areas.

Question 19

What are the 3 main areas of peripheral tolerance?

Answer 19

• Ignorance
• Anergy
• Regulation

Question 20

What is the ignorance of peripheral tolerance?

Answer 20

• This is when the T or B cells is not aware of the antigen presence, due to it being present in low concentrations.
• Therefore, the threshold to activate the cell is not reached.
• This may be in immunological privileged sites such as the eye or the brain.

Question 21

What is anergy of T cells (peripheral tolerance)?

Answer 21

• This is when co-stimulatory signals needed to activate the cell such as naive T cells are not present. Most cells lack costimulatory proteins and MHC II.
• This means that even if a naive T cell sees a self MHC antigen peptide molecule, without the appropriate costimulatory signals it becomes anergic.
• This means it is less likely to be stimulated in the future even if the presence of co-stimulation.
• Also, for a T cell to work, they need to see the MHC antigen complex on a professional APC (dendritic cell) and therefore, if it presented by a different type of cell for example it won’t get activated.
• Therefore, anergy is a state where the immune cell will not response even though it recognises the MHC molecule because the correct signals are not present.

Question 22

What is the regulation of T cells in peripheral tolerance?

Answer 22

A subset of T cells are known as Treg cells (T regulator). These are inhibitor other T cells and prevent the overactivation of the immune system. When Treg cells bind to antigens on the surface of APCs, they can send negative signals to other cells via IL20 and TGFbeta. Treg cells express transcription factor FOXP3 which allows them to do their function.

Question 23

What happens to Treg when there are mutations?

Answer 23

• Defective Treg cells are associated with multiple sclerosis.
• Certain cytokines such as IL10 dampen down the immune response.
• In cancer, there are increased levels of Treg.
• In autoimmune diseases, there are decreased levels of Treg.
• Mutation in FOXP£ leads to severe and fatal autoimmune disorder called IPEX.

Question 24

What is IPEX?

Answer 24

A severe and fatal autoimmune disorder which stands for immune dysregulation, polyendocrinopathy, enteropathy X linked syndrome.

Question 25

Summarise anergy, ignorance and immune regulation in Peripheral T cell tolerance

Answer 25

Anergy: Exposure to antigen but without appropriate costimulatory signals so no activation. Ignorance: Immune privilege and sequestered antigen Immune regulation: regulatory cells, Treg

Question 26

What is the genetics of MHC?

Answer 26

Each copy of chromosome 6 carries 3 different MHC class I genes and 3 different MHC class II genes. There are high levels of genetic variation polymorphisms, this is so the MHC molecule is able to recognise wide variety of antigens and peptides. MHC is associated with more diseases than any other region of the genome.

Question 27

In which gender is systemic lupus erythematosus (SLE) more common in?

Answer 27

It is 10 times more common in females than males.

Question 28

In which gender is multiple sclerosis more common in?

Answer 28

10 times more common in females than males.

Question 29

In which gender is diabetes more common in?

Answer 29

Equally common in females and males

Question 30

In which gender is ankylosing spondylitis more common in?

Answer 30

Approximately 3 times more common in males than females.

Question 31

What are the environmental factors that can influence the development of autoimmune diseases?

Answer 31

Hygiene hypothesis: NOD mice and SPF conditions | Smoking and rheumatoid arthritis

Question 32

What might trigger a breakdown of self-tolerance?

Answer 32

- Loss of function or problem with regulatory cells - Release of sequestrated (hidden) antigen - Modification of self - Molecular mimicry

Question 33

What is citrullin?

Answer 33

An amino acid, not coded for by DNA.

Question 34

How is arginine converted to citrulline?

Answer 34

It is converted to citrulline as a post-translational modification by peptidylarginine deiminase (PAD) enzyme which means the structure is not different.

Question 35

What can lead to an immune response in the change in Citrullin and Arginine?

Answer 35

The change in shape of peptides might lead to immune response. Citrullination may be increased by inflammation.

Question 36

What is a modification of self-citrullination that can lead to an autoimmune disease?

Answer 36

- The change in shape of peptides might lead to immune response. - Citrullination may be increased by inflammation. - There are auto-antibodies against citrullinated proteins seen in rheumatoid arthritis. - These are now used in clinical diagnosis.

Question 37

What is rheumatic fever?

Answer 37

- It is a disease triggered by infection with Streptococcus pyogenes. - Antibodies which attack the bacteria cell wall, can sometimes cross-react with cardiac muscles leading to rheumatic fever.

Question 38

Describe the pathology behind Graves' disease

Answer 38

1. Auto-antibodies bind to TSH receptors and stimulate them, resulting in hyperthyroidism. 2. The disease can be transferred with IgG antibodies. 3. In Hashimotos, the anitbody binds to the same receptor but causes inflammation instead of overactivity.

Question 39

Describe the pathology behind Myasthenia Gravis

Answer 39

1. Autoantibodies bind to acetylcholine receptor and block the ability of acetylcholine to bind. 2. It also leads to receptor internalisation and degradation. 3. This results in muscle weakness.

Question 40

Describe the pathology behind SLE and Vasculitis

Answer 40

1. Autoantibodies and soluble antigens form immune complexes. 2. These get deposited in tissues such as blood vessels, joints and renal glomerulus. 3. This leads to activation of complement and phagocytic cells 4. The immune complexes depositing in the kidney can lead to renal failure.

Question 41

What is the difference between autoimmune diseases mediated by IgG and normal autoimmune disease?

Answer 41

1. Autoimmune diseases mediated by IgG can be transferred across the placenta. 2. The patient makes anti-TSHR antibodies. 3. This means if a mother has Graves' disease, her antibodies can cross the placenta to the baby and bind to the baby's TSH receptors leading to the baby suffering with Graves as well.

Question 42

What can cure Graves' disease in baby's?

Answer 42

Plasmapheresis removed maternal antibodies and cures the disease

Question 43

How can T cells activate autoimmune pathology?

Answer 43

1. T cells can lead to the direct killing by CD8+ cells. 2. They can release cytokines such as TNFalpha which leads to self-destruction of the cells. 3. This recruits and activates macrophages which lead to bystander tissue destruction. 4. T helper CD4 cells provide help for antibodies and cytotoxicity. 5. This can all lead to multiple sclerosis and insulin dependent diabetes mellitus.

Question 44

What are Th17 cells?

Answer 44

Th17 cells are helper T cells that produce the cytokine IL17.

Question 45

What is the cytokine IL17?

Answer 45

It is a highly inflammatory cytokine which leads to recruitment, migration and activation of immune cells to the site of inflammation.

Question 46

Where do Th17 cells reside?

Answer 46

These cells live in the mucosal surfaces and the skin.

Question 47

What are Th17 cells associated with?

Answer 47

They are associated with autoimmune diseases such as spondyloarthropathy, MS and diabetes.

Question 48

What are therapeutic strategies of autoimmune diseases?

Answer 48

- Anti-inflammatories such as NSAIDs and corticosteroids. - T and B cell depletion via anti-CD4 and anti-CD8. - Anti-TNF only works for a short amount of time as there will be a production of antibodies against those antibodies. - Anti-VLA-4 interferes with adhesion to stop inflammation. - Glatiramer acetate increases Treg cells.