26. Autoimmune Diseases

Question 1

What is the ideal state of immunity?

Answer 1

1. Balanced
2. Not enough immunity can be lethal.
3. Too much immunity can also be lethal.

Question 2

What determines a patient’s background susceptibility to autoimmunity?

Answer 2

Genetic and environmental factors

Question 3

What is needed for an autoimmune disease to develop?

Answer 3

1. A trigger
2. These are usually environmental
3. They can be stochastic (random) and unavoidable due to the immune system relying on randomness.

Question 4

What is an autoimmune disease?

Answer 4

An immune process characterised by activation of adaptive immune cells that respond to self-antigens and cause immunopathology.
This includes all type of hypersensitivity except type 1.

Question 5

What are the clinical groupings of autoimmunity?

Answer 5

1. Organ-specific: T cell mediated
2. Organ specific: Antibody mediated
3. Systemic

Question 6

How common is autoimmune disease?

Answer 6

1. At least 80 different human diseases.
2. 5-8% prevalence
3. Many different targets.

Question 7

Are autoimmune diseases increasing in incidence?

Answer 7

Yes…could be called an epidemic of autoimmunity.
They are also difficult to diagnose and new diseases continue to be found.

Question 8

How does the nature of immune genes lead to autoimmune disease?

Answer 8

1. They are highly polymorphic so there is lots of variability.
2. Individual proteins vary between people and are present above 2% of the population.
3. lots of proteins in the immune system are polymorphic.
4. This provides lots of potential targets

Question 9

How does the random rearrangement of antigen receptors lead to autoimmune disease?

Answer 9

1. The immune system relies on randomness to be effective.
2. It has evolved to produce an effective immune response to novel antigens.
3. All mechanisms to reduce self-reactive immune cells is done after gene rearrangement is done.
4. This means self-reactive receptors are generated all the time and some escape selection.

Question 10

How does the environment lead to autoimmune disease?

Answer 10

1. Via environmental triggers like infection.
2. You will produce an immune response to infection and this varies from person to person.
3. Some infections can trigger autoimmunity.

Question 11

Common autoimmune diseases: Graves’ disease

Answer 11

Stimulating antibodies against TSH receptor causing hyperthyroidism

Question 12

Common autoimmune diseases: Hashimoto’s thyroiditis

Answer 12

Blocking antibodies and destructive T cells against thyroid antigens causing hypothyroidism.

Question 13

Common autoimmune diseases: Rheumatoid Arthritis

Answer 13

Autoreactive T cells against joint synovium causing joint inflammation and destruction. Autoantibodies also present.

Question 14

Common autoimmune diseases: Type 1 diabetes

Answer 14

T cells against ß islet cells causing ß cells destruction and lack of insulin

Question 15

Common autoimmune diseases: Multiple Sclerosis

Answer 15

T cells against brain antigens causing destruction of myeline sheath and loss of nerve axons.

Question 16

Common autoimmune diseases: SLE (lupus)

Answer 16

Autoantibodies to DNA, chromatin proteins and ribonucleoprotein antigens causing many systemic symptoms like glomerulonephritis and vasculitis.

Question 17

What are the typical clinical features of autoimmune diseases?

Answer 17

1. Family history showing a common hyperactive immune system.
2. female predisposition.
3. T-helper cell dependant or autoantibodies.
4. Common association with HLA class 1
5. Chronic course, relapses and remits
6. Responds to immunosuppressive therapy.

Question 18

What are some genetic causes of autoimmunity?

Answer 18

Lots of points where a single gene mutation can lead to autoimmune disease but they are not common:
1. Fas/FasL affecting the deletion of autoreactive T cells.
2. Foxp3 affecting the generation of Treg cells.
3. CTLA4 affecting the inhibition of immune cells

Question 19

What is sporadic autoimmunity?

Answer 19

Autoimmunity that arises in someone with autoimmune disease in the family but with a non-obvious genetic cause.
This is modulated by polymorphisms in many genes.

Question 20

What is the link between autoimmunity and resistance to infection?

Answer 20

1. The immune system is designed to produce the best response but it is not perfect.
2. If you develop a more aggressive response to infection it leads to resistance to infection
3. BUT it can also lead to autoimmunity if it is triggered in the wrong way.

Question 21

What shows the link between genetics, the environment and autoimmune disease?

Answer 21

1. As genetic sharing increases the risk of autoimmune disease also increases.
2. But even if you are identical twins the other twin will only have a ~1/3 chance of also developing autoimmunity.
3. This shows there are strong environmental factors at play.

Question 22

What do a lot of autoimmune diseases have a strong link to?

Answer 22

With different MHC alleles

Question 23

What genes are commonly associated with autoimmune disease?

Answer 23

1. MHC genes that regulate autoantigen presentation and T cell repertoire selection.
2. Genes that influence immune system activation and regulation.
3. Most of these associations have unknown mechanisms.

Question 24

Why are MHC genes heavily linked to autoimmunity?

Answer 24

1. They regulate antigen presentation so if you have a self antigen that cannot be presented on MHC then you cannot get autoimmunity against it.
2. You need to have a MHC that can present autoantigens for autoimmunity to be triggered.
3. Different MHC alleles have different abilities to present antigens.
4. MHC also present antigens in the thymus for T cell selection and elimination of self reactive T cells.

Question 25

Why are T cell responses so important in auto immune disease?

Answer 25

They also effect T cell dependant B cell responses.

Question 26

What do other genes associated with autoimmune disease control?

Answer 26

1. How fast the immune response is 2. How strong the immune response is 3. How long the immune response lasts

Question 27

How are infections linked to autoimmune disease?

Answer 27

1. Some autoimmune diseases are always preceded by a certain infection. 2. It doesn’t mean you will develop the disease if you get infected. 3. BUT it does mean the infection is necessary to develop the autoimmune disease.

Question 28

What are 2 examples of autoimmune disease associated with infections?

Answer 28

1. Group A streptococci and Rheumatic Heart disease due to molecular mimicry. 2. Epstein-Barr virus and Multiple Sclerosis

Question 29

What are infections also associated with?

Answer 29

Relapsing in autoimmune diseases

Question 30

What is the hygiene hypothesis?

Answer 30

1. The hypothesis that infection might sometimes prevent autoimmune disease and allergy. 2. People who had more infection as a child has less autoimmune response as adults

Question 31

What trends were seen as infectious diseases decreased?

Answer 31

As infectious diseases decreased in incidence autoimmune diseases increased.

Question 32

What can make autoimmune diseases hard to study?

Answer 32

Their inherent randomness.

Question 33

How has migration shown the impact of environment on autoimmunity?

Answer 33

1. Migrants moving from Pakistan to the UK show the UK trends in autoimmunity if they move as children. (under 15) 2. This shows that childhood exposure is important for developing resistance to autoimmunity.

Question 34

Why do infections help with immunity?

Answer 34

1. Individual immune systems are unique and a product of their education. 2. These help educate central and peripheral tolerance mechanisms. 3. This education lasts for life.

Question 35

What are the triggering mechanisms that lead to autoimmunity?

Answer 35

1. Molecular Mimicry 2. Bystander activation 3. Abnormal immune regulation

Question 36

How does molecular mimicry lead to autoimmune disease?

Answer 36

An epitope from an infection looks the same as a self protein

Question 37

How does bystander activation lead to autoimmune disease?

Answer 37

1. An ongoing infection can trigger a lot of damage and damage signals. 2. This triggers a more aggressive adaptive immune response in the organ. 3. This causes upregulation of cells including some self-reactive cells. 4. This can be triggered by trauma.

Question 38

How does abnormal immune regulation lead to autoimmune disease?

Answer 38

The immune system doesn’t shut down after infection leading to failures in regulation of self-reactive T cells.

Question 39

T cell-mediated autoimmunity in a specific organ/tissue

Answer 39

1. A type 4 hypersensitivity reaction 2. Autoantigen specific CD4 T cells. 3. Usually Th1 and Th17 induced by IFNy and Th17. 4. Tissue destruction and disruption/loss of function. 5. Autoimmunity is limited to the organ expressing the antigen.

Question 40

Antibody-mediated autoimmunity in target organs

Answer 40

1. Autoantibodies occur in the absence of disease or precede disease. 2. Type 2 hypersensitivity 3. T helper cell dependant antibody isotypes. 4. Some of these disease associated with tumours.

Question 41

What is different about autoantibody mediated diseases?

Answer 41

The presence of autoantibodies does not always mean clinical disease will be present.

Question 42

How does Graves' disease work?

Answer 42

1. Normally thyroid hormones are stimulated by TSH binding the TSH receptor and is controlled by negative feedback limiting the amount of TSH. 2. In Graves' disease an Autoantibody binds the TSH receptor and stimulates hormone synthesis independent from any regulation. 3. This causes overproduction of thyroid hormones.

Question 43

Where do immune complex mediated system autoantibodies develop?

Answer 43

In the blood and then are distributed to the organs

Question 44

What do immune complex mediated system autoantibodies develop against?

Answer 44

DNA nucleoproteins

Question 45

What is systemic lupus erythematosus?

Answer 45

1. High female bias 2. Fever, weakness, arthritis, rashes, kidney dysfunction 3. more common in african-american and hispanics 4. antibodies to DNA, histones, RBCC platelets, leukocytes and clotting factors 5. immune complexes form

Question 46

Diagnosis of autoimmune disease

Answer 46

1. Clinical diagnosis 2. Confirm with diagnostic tests 3. exclude infections

Question 47

Treatment of autoimmune disease

Answer 47

1. Replacement like in diabetes 2. Immunosuppression

Question 48

What is the goal of treating autoimmune disease?

Answer 48

To be able to shut down antigen specific response and treat without systemic side effects.