Autoimmunity

Question 1

What is graves disease?

Answer 1

Grave’s disease- TSH receptor activating.

Question 2

What is Grave’s ophthalmopathy?

Answer 2

Grave’s ophthalmopathy, fibroblasts in the eye may express TSH leading to inflammation.

Question 3

Type 1 diabetes-

Answer 3

Type 1 diabetes- insulin producing cells of pancreas (inactivating beta cells).

Question 4

HLA B27-associated spondyloarthropathies:

Answer 4

Ankylosing spondylitis, undifferentiated spondyloarthropathy, reactive arthritis, psoriatic arthritis, urethritis, iritis.

Spectrum of severity and HLA B27 association.
Associated with bowel inflammation.

Question 5

What is a systematic autoimmune disease characterised by?

Answer 5

• Multi-system disease
• characterised by autoantibodies to nuclear antigens eg double stranded DNA
• Relapse and remission

Question 6

What is autoimmunity?

Answer 6

1. When you respond against your own proteins
2. The immune system has various regulatory controls to prevent it from attacking self-proteins and cells.
3. Failure of these controls will result in immune attack of host components – known as autoimmunity.

Question 7

What is Immune Tolerance?

Answer 7

• Immune system does not attack self-proteins or cells – it is tolerant to them
• We need to identify what is self and what is not

Question 8

What is central tolerance and peripheral tolerance

Answer 8

• 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 9

Describe B and T cell tolerance

Answer 9

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

• If binding to self MHC is too weak, 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, may allow signalling irrespective of whether self or foreign peptide is bound in groove
• Selection- remove useless and dangerous cells.
• Specialised transcription factor allows thymic expression of genes that are expressed in peripheral tissues.

Question 10

How can a T cell be 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

Question 11

What is the autoimmune regulator?

Answer 11

• Promotes self tolerance by allowing the thymic expression of genes from other tissues
• Mutations in AIRE result in multi-organ autoimmunity  fatal
• (Autoimmune Polyendocrinopathy Syndrome type 1)
• It promotes the expression of all the genome. It allows the thymus to express all peptides

Question 12

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

Answer 12

• B cells and autoimmune IgM, no T cell help and so no class switch..

Question 13

What are the 3 types of peripheral tolerance?

Answer 13

1. Ignorance
2. Anergy
3. Regulation

Question 14

Ignorance

Answer 14

Ignorance- antigen present in too low a concentration to reach TCR threshold. Immunologically privileged sites like eye and brain.

• Antigen may be present in too low a concentration to reach the threshold for T cell receptor triggering
• Immunologically privileged sites e.g. eye, brain
• You don’t see the antigen. You are not aware of the antigen. The T cells will never come across the antigen

Question 15

Anergy

Answer 15

Anergy- naïve T cells need costimulatory signals to be activated. Most cells lack these proteins and MHC class II. If naïve T cell sees MHC/peptide ligand without appropriate costimulatory protein, it becomes anergic and less likely to be stimulates in future, even with costimulatory signal present.

• 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 its MHC/peptide ligand without appropriate costimulatory protein it becomes anergic – i.e. Less likely to be stimulated in future even if co-stimulation is then present

Question 16

Regulation

Answer 16

Regulation- Treg cells inhibit self-reactive T cells by producing IL-10 and TGF-B. Defective Treg observed in MS.

• A subset of helper T cells known as Treg (T regulatory cells) inhibit other T cells
• IL-10 can dampen down the immune response. When Tregs bind an antigen, they can send a negative signal.
• Treg express transcription factor FOXP3, expressed in CD4 Treg cells
• Mutation in FOXP3 leads to severe and fatal autoimmune disorder - Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome.
• It is expressed in CD4 Treg cells
• If you knockout FOXP3, you get a smaller mouse

Question 17

How do endocrine factors influence AU disease?

Answer 17

• SLE (Systemic lupus erythematosus) is >10x more common in females than males.
• MS ~10x more common in females than males.
• Diabetes in men = women.
• Ankylosing spondylitis is ~3x more common in males than females.

Question 18

Can environmental factors cause AU disease and give some examples

Answer 18

• Hygiene hypothesis: NOD mice and SPF conditions. Migration and T1D, MS and SLE
• Smoking and rheumatoid arthritis
• 13 pairs of identical twins where 1 of each pair smoked and 1 of each pair had RA
• In 12/13 cases the twin with RA was the smoker
• If you don’t get exposed to bacteria when you are developing, the immune system is compromised.
• The mice who were kept in the pathogen free environment did not get diabetes.
• When you move to a rural environment from an urban environment, T1D, MS and SLE tend to become more prevalent.

Question 19

What might trigger a breakdown of self tolerance?

Answer 19

• Loss of/dysfunction of regulatory cells.
• Release of sequestered antigen.
• Modification of self- Citrulline is an AA not coded for by DNA. Arginine converted to citrulline as post-translational modification by peptidylarginine deiminase (PAD) enzymes. Citrullination may be increased by inflammation. Autoantibodies to citrullinated proteins seen in rheumatoid arthritis- now used in clinical diagnosis.
• Molecular mimicry- rheumatic fever triggered by streptococcus pyogenes infection. Antibodies to strep cell wall antigens may cross-react with cardiac muscle.
• Grave’s disease can be transferred by IgG antibodies across the placenta. Plasmapheresis can remove maternal anti-TSHR antibodies to cure baby.

Question 20

Describe Molecular mimicry – rheumatic fever

Answer 20

• Disease is triggered by infection with Streptococcus pyogenes
• Antibodies to strep cell wall antigens may cross-react with cardiac muscle

• These antibodies can react with the heart muscle

• Response to infection, cross reacts with some heart tissue
• Image shows plasma cell producing antibodies for bacteria, antibody binds to bacteria and clears the disease
• But same antibodies also cross react with some of the proteins in the heart, causing inflammation within the heart – this is molecular mimicry

Question 21

Describe graves disease

Can it be transferred from mother to fetous?

Answer 21

• Auto-antibodies bind Thyroid stimulating hormone (TSH) receptor and stimulate it, resulting in hyperthyroidism
• Disease can be transferred with IgG antibodies
• Disease can transfer from mother to foetus as IgG is small and can get through placenta

• In Hashimoto’s, the antibody binds to the same receptor but just causes inflammation

Question 22

Describe Antibodies in autoimmune pathology (2) – Myasthenia Gravis

Answer 22

• Autoantibodies bind to acetylcholine receptor and block the ability of acetyl choline to bind
• Also lead to receptor internalisation and degradation
• Results in muscle weakness
• Myasthenia Gravis is response against acetylcholine receptors
• Normally, at a neuromuscular junction get a neural impulse producing NTs which bind to ACh receptors, causes Na influx, and causes muscle contraction
• In myasthenia you get an antibody response against these receptors, essentially blocking these receptors
• In myasthenia gravis, same production of ACh but not activating the nerve cell receptors as they are blocked resulting in muscle weakness

Question 23

Describe Antibodies in autoimmune pathology (3) – Immune complexes in SLE and vasculitis

Answer 23

• SLE disease characterised by anti-DNA antibodies, anti-dDNA
• Autoantibodies to soluble antigens form immune complexes
• Immune complexes can be deposited in tissue e.g. blood vessels, joints, renal glomerulus and cause many problems
• Can lead to activation of complement and phagocytic cells
• Immune complexes depositing in kidney can lead to renal failure

Question 24

Describe T Cells in autoimmune pathology

Answer 24

• Direct killing by CD8+ CTL
• Self-destruction induced by cytokines such as TNFa
• Recruitment and activation of macrophages leading to bystander tissue destruction
• CD4 cells providing help for Ab and cytotoxicity
• CD4 cells direct the immune response.
• Multiple sclerosis  CD4 cells are important
• Insulin dependent diabetes mellitus  CD4 cells are important
• CD4 cells direct the immune response

Question 25

Describe Th17 cells in AU disease

Answer 25

• Th17 cells are helper T cells that produce the cytokine IL-17  a very powerful inflammatory cytokine
• 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 26

What therapeutic strategies can be used to treat AU diseases?

Answer 26

• Anti-inflammatories: NSAID  good way to get the immune system to dampen down, corticosteroids
• T & B cell depletion (Rhematoid Arthritis: anti-CD4 (used to deplete T cell population), anti-CD20 (used to deplete B cell population))  not used often though as it can remove the whole immune system.
• Therapeutic antibodies (anti-TNF; anti-VLA-4 (blocks adhesion))
• Antigen specific therapies, in development. Glatiramer acetate  increases T-regs so you will dampen down the immune system.