Autoimmunity

Question 1

What are some examples of autoimmune diseases?

Answer 1

There is a huge range in autoimmune diseases from organ specific (graves diseases+ T1DM) to systematic (Systematic lupus erythematosis (SLE))

Question 2

Give examples of organ specific autoimmune disease

Answer 2

• Graves disease
  
  • Autoantibodies will bind to and stimulate the TSH receptor on thyroid gland
    
    • Presents with inflammation of the eyes (exophthalmos)
      
      • We have a low level of TSH receptors expressed on the fibroblasts on the eye, autoimmune antibodies attack these leading to inflammation
• Type 1 diabetes
  
  • Immune system attacks insulin-producing cells of the pancreas

Question 3

Describe an example of MHC-specific autoimmunity

Answer 3

HLA B27- associated spondyloarthropathies

The spondyloathropathies include:

• Ankylosing spondylitis
• Undifferentiated spondyloarthropathy
• Reactive arthiritis
• Psoriatic arthiritis
• Urethritis
• Iritis
  
  • There is a spectrum of severity and HLA B27 association
  • It is associated with bowel inflammation

Question 4

What is an example of a systematic autoimmune pathology?

Answer 4

• Lupus is also known as SLE (systemic lupus erythromatosus).
  
  • It is a multi-system disease
• It is characterised by autoantibodies to nuclear antigens
  
  • e.g dsDNA
• Mutliple symptoms = devascularization of fingers, membrane ulcerations, proteinuria, discoid lesions, raynaud’s phenomenon, photosensitivity
  
  • It is a disease of relapse and remission

Question 5

What is autoimmunity?

Answer 5

The break down of the controls preventing the immune system from attacking host components

Question 6

What is immune tolerance?

What are the two forms?

Answer 6

Immune tolerance = unresponsiveness to self antigens (immune system does not attack self-proteins or cells)

Two forms are

1. Central = Destroy self-reactive T or B cells before they enter the circulation
2. Peripheral = Destroy or control any self-reactive T or B cells which do enter the circulation

Question 7

Expand on central tolerance

Answer 7

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

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

Question 8

How do we control TCR and MHC binding? How are specific T-cells are selected for?

Answer 8

We need to select for T-cell receptors which are capable of binding self MHC

• If binding 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 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 is the selection process of T-cells?

Answer 9

1. Is it useless?
   
   1. If the cell doesn’t bind any self-MHC at all it is useless and there will be death by neglect
2. Is it dangerous?
   
   1. If the cell binds self MHC too strongly then it may bind without the presence of a foreign peptide therefore apoptosis is triggered and the cell dies = negative selection
3. Is it useful?
   
   1. Binds to self MHC weakly
   2. 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

• Most antigens are expressed on localisation
  
  • We have different antigens expressed in fingernails, eyes etc.
• Therefore, the T cells in the thymus has to be exposed to all the likely cell peptides it may come cross
  
  • The specialised transcription factor (AIRE)
    
    • AutoImmune REgulator promotes self tolerance by allowing thymic expression of genes which are expressed in peripheral tissues and selects T-cells that are going to be useful

Question 11

What can mutations in AIRE (AutoImmune REgulator) result in?

Answer 11

Mutations in AIRE can result in multi-organ immunity called autoimmune polyendocrinopathy syndrome type 1

Question 12

What happens to autoreactive T cells that survive central tolerance?

Answer 12

Some T/ B-cells will escape central tolerance and become auto-immune; this is dealt by peripheral tolerance.

Question 13

What are the three components of peripheral tolerance? (IAR)

Answer 13

1. Ignorance
2. Anergy
3. Regulation

Question 14

Describe ignorance in peripheral tolerance

Answer 14

• This occurs when you don’t see the antigen (may be at a low concentration) therefore you may have not reached the threshold previously for T-cell receptor triggering and marked as an autoreactive T-cell
• This can occur at immunologically privileged sites for example e.g. brain and eye

Question 15

Describe anergy in peripheral tolerance

Answer 15

• Naive T-cells need costimulatory signals in order to become activated
  
  • B7 (CD80/86)/CD28
  • APC T-cell
• Most cells will lack co-stimulatory proteins and MHC Class II
• If a naive T cells sees its MHC/peptide ligand without costimulatory proteins it will become anergic
  
  • And is less likely to be stimulated in the future even if co-stimulation is then present

Question 16

Describe regulation in peripheral tolerance

Answer 16

• T-regulatory cells will inhibit other self-reacting T-cells
• They do this by producting cytokines
  
  • IL-10 and TGF-beta

Question 17

What cytokine do T-regulatory cells release which can dampen down immune responses?

Answer 17

IL-10, these can go and calm down overactive immune responses. They do this either by the release of cytokine or direct contact inhibition.

Question 18

How can we identify Treg cells?

Answer 18

• CD4 are CD25 are both markers of T-regulatory cells
• FOXP3+ is a transcription factor which enables the function of T-regulatory cells

Question 19

What can a mutation in FOXP3 lead to?

Answer 19

• FOXP3 is a transcription factor which enables the function of T-regualtory cells
• Mutations in FOXP3 can lead to a severe and fatal autoimmune disorder = IPEX Syndrome
  
  • Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked syndrome

Question 20

What are the implications of high variabillity of MHC?

Answer 20

• Each copy of chromosome 6 carries 3 different MHC Class I and 3 different MHC Class II genes
  
  • MHC Class I isotypes are HLA-A, B and C
  • MHC Class II isotypes are HLA-DR, DP and DQ
• Thus it contains high levels of genetic variation (polymorphism)
• MHC is associated with more disease than any other region of the genome

Question 21

What is the HLA B27 allotype linked to?

Answer 21

• MHC Class I molecule
• More likely to get ankylosing spondylitis

Question 22

What are endocrine factors of autoimmunity?

Answer 22

• SLE is 10 times more common in females compared to 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 are more susceptible to certain autoimmune diseases

Question 23

List some environmental factors which can contribute to the risk of autoimmune disease

Answer 23

• Hygiene hypothesis
  
  • If you are not exposed to bacteria when you are developing, then your immune system can become compromised
    
    • Scientific supporters of the hygiene hypothesis
      
      • Migration and T1D, MS and SLE = in the human population the number of diseases become more apparent when moving from a rural environment to an urban environment these diseases become more apparent
  • Smoking has also been found to link to rheumatoid arthiritis

Question 24

What might trigger a breakdown of self-tolerance?

Answer 24

• Loss of/problem with regulatory cells e.g mutation in FOXP3 (IPEX syndrome)
• Release of sequestered antigen (immunologically privileged sites may release sequestered antigens during trauma)
• Modification of self
• Molecular mimicry

Question 25

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

CITRULLINATION

Answer 25

• Citrullin is an amino acid (NOT CODED FOR BY DNA)
• Arginine can be converted to citrulline via post-translational modification by peptidylarginine deaminase (PAD) enzymes
  
  • This makes them more suceptible to proteolytic degradation and presented by HLA Class II to CD4+ T cells
• Citrullination may be increased by inflammation
  
  • Auto-antibodies to cirtrullinated proteins are seen in rheumatoid arthritis

Question 26

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

Answer 26

• Rheumatic fever is an example of an autoimmune disease which occurs due to molecular mimicry
• This disease is triggered by infection with Streptococcus pyogenes
  
  • In some individuals the antibodies produced to strep wall antigens may cross-react with cardiac muscle

Question 27

List some examples of antibodies which are implicated in autoimmune diseases

Answer 27

1. Myasthenia Gravis
   
   1. Autoantibodies bind to nAchR and block the abillity of Ach to bind
   2. It also leads to receptor internalisation and degradation
   3. This results in muscle weakness
2. Graves Disease
   
   1. Autoantibodies bind to thyroid stimulating hormone (TSH) receptor and stimulate it resulting in hyperthyroidism
   2. The disease can be transferred via IgG antibodies
   3. In hashimoto’s is not stimulatory this is where autoantibodies present against thyroid peroxidase, thyroglobulin and TSH receptors gradually destroying the thyroid gland

Question 28

What is the example of antibodies involved in an autoimmune pathology that is systemic

Answer 28

• Autoantibodies to soluble antigens e.g dsDNA/RNA from immune complexes
• These immune complexes can form large aggregates of antigens and antibodies which are deposited in tissues causing inflammation of vessels, joints and renal glomerulus
• Can lead to activation of complement and phagocytic cells
• Immune complexes depositing in kidney can lead to renal failure

Question 29

How can a mother with an autoimmune disease implicate the devloping foetus?

Answer 29

• IgM is a pentamer and cannot easily cross the placenta, however IgG can easily cross the placenta
  
  • Graves’ disease
    
    • Patient will make anti-TSHR antibodies which can cross the placenta and enter the foetus
    • The newborn infant can therefore also suffer from Graves disease

Question 30

How can we treat a newborn infant that is suffering from Graves disease due maternal transfer of IgG from their autoimmune mother?

Answer 30

• Plasmapheresis can remove the maternal anti-TSHR antibodies and cure the disease

Question 31

What are examples of other diseases where autoantibodies can cross the placenta and cause disease in foetal newborns?

Answer 31

Question 32

How are T-cells implicated in autoimmune disease?

Answer 32

They can kill by:

1. Direct killing by CD8+ CTL
2. Self-destruction induced by cytokines such as TNF-alpha

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

• Autoimmune CD4+ T cells can cause activation of CD8+ and cause them to be killers against autoantigens (Check this!)
  
  • In MS and Insulin dependant diabetes mellitus are both diseases that CD4+ T cells play a role in

Question 33

How are Th17 cells implicated in autoimmune disease?

Answer 33

• Th17 cells are helper T cells that produce 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 recruitment, migration and activation of immune cells

Question 34

What are therapeutic strategies undertaken to treat autoimmune diseases?

Answer 34

• Anti-inflammatories = NSAID, corticosteroids
• T and B cell depletion (RA; anti-CD4, anti-CD20)
• Therapeutic antibodies (Anti-TNF; Anti-VLA4(blocks adhesion))
• Antigen specific therapies in development
  
  • Glatiramer acetate, increases T-regs