1. Introduction and Aetiology of autoimmune disease Flashcards
1
Q
What are the common themes of autoimmunity?
A
- Chronic inflammation
- T cell differentiation
- Innate lymphoid cells
- Therapy targeting cytokines
- Therapeutic manipulation of immunological balance
2
Q
What is chronic inflammation?
A
- A common cause of immunopathology
- Long term
- Treatable and manageable but no curable
- Differs from acute inflammation and infection responses
3
Q
What are some different cell types involved in chronic inflammation?
A
- Lymphocytes
- Neutrophils
- Monocytes
- Macrophages
- B cells
4
Q
What can single defect autoimmunity cause?
A
Immunodeficiency
5
Q
What is T cell differentiation?
A
The way that CD4 T cells change following an encounter with an antigen it can recognise.
6
Q
What are the different CD4 T cells effector phenotypes?
A
- Th1 and Th17 are often associated with organ specific autoimmunity
- Th2 is associated with asthma
- Tregs are important in controlling immune responses and disease
7
Q
What are innate lymphoid cells?
A
- Lymphoid cells that don’t have antigen specificity but are involved in mucosal surfaces by providing signals that heighten immune responses.
- Different types that correlate to different T cell subsets
8
Q
What are anti-cytokine therapies?
A
- Pro-inflammatory cytokines have a central role in autoimmunity.
- Often exist as part of a complex network of responses.
- Inhibiting specific cytokines can inhibit inflammation or T cell differentiation
9
Q
What is TNF?
A
- A pro-inflammatory cytokine
- Involved in inflammation and autoimmune disease
- Secreted by Th1 cells
10
Q
What is IFNy?
A
A pro-inflammatory cytokine that acts on inflammatory cells.
11
Q
What is IL-12?
A
- Stimulates Th1 differentiation
- Induced IFNy secretion in T cells and NK cells.
- Down regulates allergy.
12
Q
What is IL-1ß?
A
- Pro-inflammatory cytokine
- Generated by the inflammsome to recruit other immune cells.
13
Q
What is IL-6?
A
- Involved in the acute phase response
- Metabolic control and proliferation
- Inflammation
14
Q
What is IL-23?
A
- Promotes Th17 proliferation and survival which leads to IL-17 secretion and neutrophil production
- Important in maintaining intestinal homeostasis
15
Q
What are coinhibitory receptor blockades?
A
- Blocking these inverses autoimmunity to activate the immune system.
- This can be used to target tumours
- CLTA4 and PD1 were the 1st targets to be used in clinic and have been very successful.
16
Q
Why does autoimmunity occur?
A
Random rearrangement of antigen specific receptors cause autoreactive cells to be produced.
17
Q
Why are antigen specific cells randomly generated?
A
- This randomness deals with an unpredictable world.
- Novel antigen specific receptor shapes allow the immune system to produce an effective response to a novel pathogen.
18
Q
What 2 factors influence autoimmunity?
A
- Genetics
- The environment
19
Q
How do genetics cause autoimmunity?
A
- They play a big part in the development of autoimmunity.
- Between 30 and 300 genes
- Polymorphic sensing of the environment means lots of genes that modulate autoimmune responses come in many different forms.
- Generates a background susceptibility
20
Q
How can the environment cause autoimmunity?
A
- It can trigger the underlying risk.
- Infectious - both pathogenic and non pathogenic organisms
- Non- infectious
- Stochastic and timing in disease developments
21
Q
What are the 2 key steps needed to cause autoimmunity?
A
- Background susceptibility
- A trigger
22
Q
What defines background susceptibility to autoimmunity?
A
- Genes and the environment
- This means everyone has a different risk of developing autoimmunity.
23
Q
Why does everyone have a different risk of developing autoimmunity?
A
Due to the polymorphic nature of immune regulation
24
Q
What is the definition of autoimmune disease?
A
An immune process characterised by activation of adaptive immune cells that respond to self-antigens and cause immune pathology.
25
What are the types of autoimmune disease?
1. Organ-specific: T cell mediated
2. Organ-specific: Stimulating or blocking antibody mediated.
3. Systemic
26
What is an example of organ specific T cell mediated autoimmunity?
Multiple sclerosis
27
What is an example of stimulating antibody mediated autoimmunity?
1. Graves disease
2. The cause is stimulating antibodies causing TSH production.
3. The symptoms are caused by the downstream effects of the TSH hormone.
28
What is an example of blocking antibody mediated autoimmunity?
1. Myasthenia Gravis
2. Blocking antibodies to the acetylcholine receptor.
3. This causes muscle weakness
29
What is an example of systemic autoimmunity?
1. Systemic Lupus Erythematosus AKA lupus
2. Effects many organs particularly skin and kidneys
3. Antibodies to DNA, histones, RBC, platelets, leukocytes and clotting factors.
4. Deposition of immune complexes in tissues that then cause damage
30
What does finding the common features of autoimmune disease help us do?
Find some common rules that help find treatment that can cover many diseases.
31
What does autoimmune diseases running in families mean?
1. It implies some kind of heritability.
2. This was known before DNA was discovered.
3. Can show how some genes modulate the immune response and how this effects disease.
32
What type of autoimmune disease is rare?
An autoimmune disease caused by a single mutation.
33
What can single mutation autoimmune diseases help us understand?
The mechanisms of autoimmunity
34
What are most autoimmune diseases?
1. Caused or influenced by many genes.
2. Polymorphic
35
What does polygenic mean in terms of autoimmunity?
1. Lots of genes
2. Many of these genes can influence autoimmune phenotypes.
36
What is polymorphism?
Different forms of a single gene
37
What does polymorphism mean for autoimmunity?
1. Different polymorphisms are all functional but all slightly different at a molecular level.
2. This polymorphism creates diversity in the immune response across the population.
38
Why is a diverse range of immune responses important?
1. Everyone who experiences an infection will experience it differently.
2. There is a very broad range of immune responses.
3. This diversity protects the population against infections.
39
What causes diversity in immune responses?
polymorphism
40
What are the genes where a single mutation can cause autoimmunity?
1. AIRE
2. Fas/FasL
3. Foxp3
4. CTLA4
41
What is AIRE?
1. The Autoimmune regulator
2. shapes the T cell output from the thymus
3. Mutations cause APECED
42
What is Fas/FasL?
1. Cell death receptor which terminates the immune response
2. Mutations cause ALPS
43
What is Foxp3?
1. Treg transcription factor and phenotypic marker
2. mutations cause IPEX
44
What is CLTA4?
1. Coinhibitory receptor
2. Regulates the immune response
3. Mutations cause immune dysregulation
45
What types of genes cause autoimmunity with single mutations?
Genes at critical checkpoints that switch on or off the immune response.
46
What does APECED stand for?
Autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy
47
What causes APECED?
1. In a normal thymus T cells undergo negative selection.
2. AIRE partly controls this.
3. Mutations in AIRE disturb the selection processes and create a more diverse T-cell repertoire which can include potentially self reactive T cells.
4. In APECED, these T cells cause the production of autoantibodies to different immune cytokines.
48
What does everyone’s immune system need to be?
1. optimised and balance
2. A good immune response is one that does just enough to clear infection.
3. An over zealous immune response can cause unwanted side effects or damage.
49
What kinds of autoantibodies are produced in APECED?
1. Antibodies to cytokines needed for the Th17 response.
2. Anti-IL-17
3. Anti-IL-22
4. Anti-IL17-F
50
What is the result of APECED?
Changes in the T cell repertoire selection leads to an autoantibody response that leads to immunodeficiency especially in the fungal response.
51
What can Autoimmune defects also present as?
1. A primary immunodeficiency
2. about 25% of patients with immunodeficiency have evidence of autoimmune disease.
3. Also have higher than average allergy and develop lymphoid malignancies.
52
What can autoimmune susceptibility increase the risk of?
Autoimmune disease and immunodeficient disease.
53
What is the most common genetic contribution to autoimmunity?
1. Family studies indicate an inheritable risk of developing disease.
2. The strongest association is with the earliest identified genes but other genes do contribute.
54
What genes have the strongest association with autoimmune disease?
MHC complex (focus on MHC2 for this unit)
55
When was the association between MHC and autoimmunity first described?
1. 1972
2. from an association with MS
(another associated gene was not found until 2007)
56
What is the most consequential gene for developing autoimmunity?
MHC
57
Why are MHC genes so strongly associated with autoimmune disease?
1. MHC genes restrict the action of T cells and select T cells in the thymus.
2. Autoantigen presentation in the thymus by MHC can create autoreactive T cells in the periphery.
3. Different MHC genes can present different antigens and produce different T cell repertoires with different likelihoods for autoimmunity.
58
What do you need for active autoimmunity?
1. Autoantigen presentation on an MHC
2. A T cell that can recognise that autoantigen on MHC.
59
How do different genes influence autoimmunity?
1. Each gene modifies the risk of autoimmunity a small amount.
2. Then there is a cumulative polygenic effect.
3. The effect can be positive or negative
4. The mechanism of this influence is not well understood
60
What are genome-wide association studies (GWAS)?
1. GWAS's map gene expression patterns by using SNPs.
2. When comparing the GWAS of affected and unaffected individuals, you can associate the disease with locations on the genome and its SNPs.
61
What are SNPs?
Single nucleotide polymorphisms
62
What are the pros of GWAS?
1. unbiased
2. identifies risk factors
3. Successful identification of novel candidate genes
63
What are the cons of GWAS?
1. Association doesn’t equal causation.
2. Large sample sizes mean expensive and lots of validation is needed.
3. Given more genes than we do or can understand.
64
What are most autoimmune associated genes linked with?
1. More than one autoimmune disease
2. They can be protective for 1 disease but harmful for another.
65
What is TNFAIP3 associated with?
1. Rheumatoid arthritis
2. Lupus
66
What is IL2RA associated with?
1. Type 1 diabetes
2. Multiple sclerosis
67
What is a GWAS catalogue loci?
1. Show shared genetic features in different diseases
2. Show the same genes can influence susceptibility in many autoimmune diseases.
68
What do GWAS show?
A large number of genes regulate immune responses and impact susceptibility of autoimmune disease.
69
What can a lower risk of autoimmunity cause?
A higher susceptibility to infection.
70
What can a higher risk of autoimmunity cause?
A stronger and more protective response to infection
71
What are the main properties of autoimmune-associated genes?
1. Non-MHC gene candidates are genes associated with both adaptive and innate immune function.
2. They are usually non-coding.
3. around 60% are enriched in enhancers associated with stimulated CD4 cells and B cells.
4. 10-20% alter transcription binding sites.
5. Genes that confer susceptibility in 1 disease could be protective in others.
6. There is an overlap with genes that influence susceptibility to infection.
72
What does a non-optimal immune response cause?
a risk of autoimmunity
73
What interacts with genetics to influence the risk of autoimmunity?
The environment and microorganisms in it.
74
What are the environmental connections with autoimmunity?
1. Non-deterministic (stochastic)
2. Geography
3. Infections and microbiome
4. Environmental sensors
75
How does the environment effect autoimmunity?
We don’t really know the mechanisms of interaction
76
What effects does stochasticity have on the development of autoimmunity?
1. NOD mice are genetically identical mice that are kept in uniform conditions.
2. You still cannot predict which mice will develop disease and when.
3. This shows the stochastic (random) nature of autoimmune disease.
4. It also shows there is an external factor that is needed to trigger disease.
77
What is the global distribution of autoimmune disease using MS as an example?
1. It mainly clustered in the northern hemisphere and Australia.
2. This distribution could be due to genetic or environmental factors.
78
What environmental factors could influence auto immune disease risk?
1. Infection (Pathogenic and non-pathogenic)
2. Sunlight levels
3. Diet
(these are all important in regulating the immune response)
79
What are migration studies?
1. Observing people living on either side of a border with very different rates of a disease.
2. This is done to control the amount of genetic variability in the population so the impact of environmental influences can be seen.
3. They show that the environment you grow up in is important for rate of disease.
80
How can pathogenic microbiota cause or exacerbate autoimmune disease?
Molecular mimicry
81
What is molecular mimicry?
A pathogen's antigen looks like a self antigen.
82
What autoimmune disease is group A streptococci linked to?
Rheumatic heart disease
83
What autoimmune disease is C.jejuni linked to?
Guillain-Barre
84
What autoimmune disease is Epstein-Barr Virus linked to?
Multiple sclerosis
85
Can the commensal microbiome cause or exacerbate autoimmune disease?
1. Yes
2. Evidence shows that lifestyle-associated changes in the gut flora correlate with reduced regulation and increased susceptibility to allergy and autoimmune disease.
86
How have commensal microbiota been shown to promote autoimmunity?
1. TCR transgenic mice models have been used to prove this.
2. Changing the microbiome can cause autoimmune disease.
3. This is mainly effecting Th17 responses.
4. As these are transgenic models, they are only proof of principle and don't tell us about the normal situation.
87
How was the hygiene hypothesis proposed?
1. In 1966 people thought that poor hygiene could promote MS.
2. When investigated they found the opposite.
3. People from places with lower levels of sanitation had lower levels of autoimmunity and allergy.
88
What is the hygiene hypothsis?
1. The historic fall in infections correlates to a rise in autoimmune disease and allergy.
2. Autoimmune disease is increasing at a more rapid rate then can be explained by genetic so things in the environment are driving autoimmunity.
(there are other theories)
89
What can viral infection do in NOD mice?
Prevent the development of diabetes.
90
What can some infections do to the risk of autoimmunity?
Some infectious agents can alter the susceptibility of animals to developing autoimmune disease in a way that is beneficial so they don't develop disease.
91
What clinical evidence is there for infections being protective for autoimmunity?
1. MS is less common in people with high parasitic burdens.
2. Hookworm provides a measurable benefit for MS but not enough to justify giving hookworm as a therapy.
92
What are the mechanisms of autoimmune protection following disease?
1. Th1 to Th2 shift
2. Antigenic competition
3. Immune regulation
4. non-antigen ligands
93
How is a Th1 to Th2 shift protective for autoimmunity?
1. Infection can cause a shift in T cell response from Th1 to Th2.
2. This could be beneficial in organ specific autoimmunity.
3. But it is hard to reconcile this with allergy and autoimmunity increasing in the environment.
94
How is antigenic competition protective for autoimmunity?
1. Some theories suggest the immune response has a limited capacity to deal with antigens
2. If you have lots of infectious antigens there could be too many for the body to deal with.
3. This could override or prevent weak responses to self antigens and allergy.
4. But this method could require constant infection to be protective.
95
How is immune regulation protective for autoimmunity?
1. Infection can alter levels of secreted cytokines.
2. They can also induce regulatory cells (Foxp3+) that dampen tissue damage.
96
How are non-antigen ligands protective for autoimmunity?
1. Infections produce PAMPs that bind PRR.
2. These non-antigen ligands can bind PRR can be protective for autoimmunity.
97
What does the immune response need?
It needs to be calibrated and measured against the environment.
98
What are some environmental sensors associated with autoimmune disease?
1. Vitamin D
2. Aryl hydrocarbon receptor
3. SGK1
99
How is vitamin D associated with autoimmune disease?
1. Produced by sunlight in the skin.
2. Shown to be protective in model autoimmune disease EAE.
100
What is EAE?
Experimental autoimmune encephalomyelitis
101
What other evidence shows vitamin D is protective against autoimmune disease?
People living by the equator with more sun exposure have less autoimmunity
102
How is Aryl hydrocarbon receptor associated with autoimmune disease?
in the presence of the ligand EAE is reduced.
103
What is the function of these environmental sensors?
1. To alter metabolism and responses due to the environment.
2. They are not there to modify autoimmunity.
3. This makes understanding them complex.
104
How is SGK1 associated with autoimmune disease?
1. It is the sodium chloride sensor
2. It is activated with a high salt diet and causes an increase in susceptibility to autoimmunity.
3. Shown in genetic studies to be important in autoimmunity.
4. Widely involved in normal body function so would be a tricky therapeutic target.
105
What are the environmental sensors?
1. Probably polymorphic so they can have different responses to the same things.
2. This alters the immune response
3. This makes them tricky therapeutic targets.
106
What causes autoimmunity?
It is unclear, and there is no single cause.
