L2 - Aetiology of Autoimmune Disease

Question 2

What is Aetioloy

Answer 2

The science of understanding how things develop

Question 3

What means that autoreactive cells will be produced throughout life

Answer 3

The fact that there is a random rearrangement of antigen-specific receptors ( this is the immune system’s mechanism of dealing with an unpredictable world)

Question 4

around how many genes are involved in the development of autoimmunity

Answer 4

anywhere between 30 to 300 genes

Question 5

what does the immune system’s polymorpphic sensing abilities refer to

Answer 5

the ability of the immune system to recognise and respond to a wide variety of pathogens and foreign substances due to the diversity of its receptors which behave slightly differently within their physiological constraints

Question 6

What are some environmental aetiology that affect the immune system

Answer 6

• infections ( both pathogenic and non pathogenic)
• Non infectious influences
• stochastic and timing effects in the development of disease

Question 7

What kind of organisms have susceptibility to abnormalities in the immune system

Answer 7

every individual possibly every species down to bacteria ( in humans this is down to their genes and their environment)

Question 8

Why does everyone have a different susceptibility to disease and autoimmunity

Answer 8

because of the polymorphic nature of how the immune system is regulated and the exposure to triggering events that drive the immune system from being safe to being dangerous for the individual (random or from the environment)

Question 9

What is the definition of an autoimmune disease

Answer 9

An immune process characterised by the activation of adaptive immune cells that respond to self antigens and cause immune pathology

Question 10

what are the different types of autoimmune diseases

Answer 10

1. Organ specific : T cell mediated and stimulating or blocking antibody mediated
2. systemic

Question 11

What is an example of an organ specific T cell mediated autoimmune disease

Answer 11

Multiple sclerosis

Question 12

What will a scan of the brain from someone with MS look like

Answer 12

it will show patches of inflammation that come and go through time ( this demonstrates the relapsing nature of autoimmunity)

Question 13

what is an example of an organ specific antibody stimulating autoimmune disease (antibody mediated)

Answer 13

Graves disease where (thyroid stimulating hormone receptor ) antibody binds to a receptor and over stimulate downstream physiological effects e.g. increased basal metabolic rate and upregulated production of thyroid hormone

Question 14

what is an example of an organ specific antibody blocking autoimmune disease (antibody mediated)

Answer 14

Myasthenia Gravis which block the normal physiological functioning of acetylcholine receptors which prevents normal muscle signalling and leads to weakness

Question 15

what is an example of a systemic autoimmune disease

Answer 15

Systemic Lupus Erythematosus (SLE) which affects many different organs e.g. the skin and kidneys which relates to the deposition of immune complexes in tissues.

Question 16

what is the ratio of systemic lupus erythematosus (SLE) in female: male

Answer 16

10:1 (females more susceptible)

Question 17

what ethnicity is more likely to get systemic lupus erythematosus

Answer 17

more common in African-American and Hispanics

Question 18

What is usually the cause of genetic autoimmune disease susceptibility

Answer 18

Heritability and usually multiple mutations in many genes ( rarely autoimmune diseases are caused by single mutations)

Question 19

What is the advanatage of investigating autoimmune diseases that are caused by single mutations

Answer 19

It helps investigate mechanisms but they aren’t very common ( the fact that many genes usually influence autoimmune diseases demonstrates their polygenic and polymorphic nature)

Question 20

what does polygenic mean

Answer 20

many genes ( 10s / 100s genes can influence an immune phenotype)

Question 21

what does polymorphic mean

Answer 21

a single gene with many forms e.g. PTPN22 ( exists in different forms in different individuals and remain functional)

Question 22

PTPN22 gene role ***

Answer 22

important role in regulating the immune system by providing instructions for proteins e.g. lymphoid tyrosine phosphatase (LYP) which is a protein tyrosine phosphatase (PTPs)

Question 23

what does the diversity of the immune system allow for in a population

Answer 23

Enhances pathogen resistance and makes it less likely that an entire population will be wiped out by a single pathogen and a wider gene pool means there will be faster adaptation to a new threat

Question 24

What is an example study demonstrating diverse immune responses to a similar pathogen

Answer 24

A cohort of healthy young individuals had a version of COVID squirted a version of COVID in their noses and they found a broad range of responses e.g. some people didn’t get sick at all whilst others got really ill ….

Question 25

example of single points of failure in tolerance checkpoints

Answer 25

1. AIRE: APECED/ autoimmunity 2. Fas/FasL : ALPS/MRL-Ipr&gid mouse 3. Foxp3 : IPEX?scurfy mouse 4. CTLA4: Immune dysregulation / fatal lymphoproliferation

Question 26

AIRE function

Answer 26

mostly expressed in thymic epithelial cells and promotes central tolerance ( process that ensures the immune system can distinguish between self and non self antigens) during negative selection.

Question 27

Fas/FasL function

Answer 27

pair of proteins that regulate cell death (apoptosis) -Fas : death receptor found on the surface of immune cells (e.g. T, B and macrophages) and can trigger programmed cell death when activated -FasL binds to the Fas receptor

Question 28

FoxP3 function

Answer 28

plays a central role in the development and function of Tregs. Without these cells fail to develop properly and cannot suppress the immune response

Question 29

CTLA4 function

Answer 29

acts as an off switch for T cells helping to prevent excessive immune responses by competing with CD28

Question 30

what causes Autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy

Answer 30

A mutation in the AIRE gene disrupts thymic selection. Normally, T cells that strongly recognize self-antigens or fail to recognize antigens in the MHC context are eliminated. AIRE mutations allow non-optimised T cells to escape the thymus allowing for a more diverse range of receptors in the periphery / circulation, leading to autoimmunity.

Question 31

Why does APECED cause chronic mucocutaneous candidiasis?

Answer 31

Escaped T cells support the production of antibodies that block or inhibit cytokines critical for Th17 responses. Th17 is essential for managing fungal infections, leading to susceptibility to chronic mucocutaneous candidiasis.

Question 32

what does APECED stand for

Answer 32

Autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy

Question 33

What is the best kind of immune response

Answer 33

one which is balanced in a way that is just good enough to clear the infection without causing any damage

Question 34

Why was whole genome sequencing of sporadic primary immunodeficiencies useful in terms of autoimmunity

Answer 34

Primary immunodeficiencies (PID) go hand in hand and are characterized by recurrent infections, autoimmunity, and cancer

Question 35

what percentage of patients with primary immunodeficiencies have autoimmune diseases and develop lymphoid malignancies

Answer 35

25% of patients have autoimmune disease and 10% develop lymphoid malignancies (allergies are also common)

Question 36

What can be more useful than PIDs In terms of identification and clinical management of autoimmune diseases

Answer 36

- family studies (can identify that the disease runs in families) - Earliest genetic association identified remains the strongest (It is the sum of many small changes which is what leads to the overall risk of disease )

Question 37

which genetic association is the strongest / most consequential when it comes to the development of autoimmune diseases

Answer 37

MHC complex

Question 38

In what year was the first association between MHC class II and Multiple sclerosis described

Answer 38

1972 (and then the second well validated genetic association with MS was established in 2007)

Question 39

What is it about MHC genes that makes them so crucial in whether or not you develop auto immune diseases.

Answer 39

MHC genes control which peptides T cell receptors recognise for activation and expansion. Dysregulated MHC genes can present autoantigens, allowing autoreactive T cells to escape immune regulation, increasing autoimmune risk.

Question 40

how come not everyone develops autoimmune diseases despite the fact that all of us have autoreactive T cells in our peripheral circulation

Answer 40

because not all MHC genes are equally risky. Some produce T cell repertoires that are more prone to autoimmunity, while others offer greater protection (each modify risk by a small amount - we can identify the genes relatively easily but understanding the mechanisms that explains the association is harder)

Question 41

what is a genome-wide association study

Answer 41

a methodology that allows us to map associations between disease and global gene expression patterns, often by using SNPs (single nucleotide polymorphisms) in many affected and unaffected individuals

Question 42

pros and cons of genome wide association studies (GWAS)

Answer 42

Pros: - Unbiased and hypothesis-free identification of risk factors. - Successful in discovering novel, plausible candidate genes. Cons: - Association ≠ causation. - Requires large sample sizes for discovery and replication. - Biological validation of association often lags behind genetic findings.

Question 43

What are some examples of non MHC genes that have been associated with autoimmune diseases ( through GWAS)

Answer 43

- PTPN22 (tyrosine phosphate) which is a minor allele associated with Type 1 diabetes (T1D) and Systemic Lupus Erythematosus (SLE) but confers protection in Celiac disease (CD) -IL23A (rCD25:IL-2 receptor alpha chain) which is a common allele associated with susceptibility to T1D but protects against MS

Question 44

what do GWAS catalogue loci clusters show

Answer 44

shared genetic features whereby ~69% of autoimmune disease loci for each disease were shared with other autoimmune diseases although no two diseases shared more than 38% of their loci

Question 45

what is the catch 22 with autoimmunity and infection

Answer 45

looking at gene expression (RNA seq), analysis of individuals who have less autoimmunity were more susceptibility to infection, contrasted to individuals with more autoimmunity were more resistance to infection.

Question 46

genes and autoimmunity summary

Answer 46

- genetic studies have shown that most autoimmune diseases are polygenic, arising from interactions between disease susceptibility and resistance genes. - Environmental factors, including pathogens and the commensal microbiome, also play a critical role.

Question 47

What was shown during the analysis of the incidence of diabetes in a strain of mouse - non obese diabetic (NOD) mouse colonies (who develop diabetes spontaneously)

Answer 47

three groups followed similar trends of increasing diabetes incidence with age (with a certain about of randomness) , whilst there was one group, which was exposed to a species of aerobic spore forming bacillus, had a significant difference (P<0.001) on the incidence of disease - much lower. This demonstrates the environmental impact. In this study mice were investigated over a period of 30 weeks (about middle aged)

Question 48

What is the distribution of multiple sclerosis-like across the globe

Answer 48

un-uniform with clusters in the northern and southern hemisphere. This ahs sparked many theories as to why this is e.g. genetic (viking genes) , environmental (infectious agents, sunlight and diet)

Question 49

migration study findings that support environmental agent effects on autoimmune diseases

Answer 49

- Diabetes is x6 fold higher in Finland than Karelian Russie despite genetic identity - T1D in Bulgaria and Romania is low compared to Western Europe - Children of immigrants to UK from Pakistan have UK rate of IDDM which is x10 higher than in Pakistan - SLE is significantly lower in W Africans than in black Americans of some ethnic origin - MS is relatively common in Israeli immigrants from Europe but rare in those from Africa and Asia (when you identify populations that you think are genetically homogenous, the environment that they have been brought up has had a big influence on the disease that they get)

Question 50

infections and the microbiome effect on disease

Answer 50

pathogenic microbiota can cause or exacerbate human autoimmune disease

Question 51

infectious agents and the autoimmune disease that they cause

Answer 51

1. Group A streptococci = increased risk of Rheumatic Heart Disease from molecular mimicry 2. C.Jejuni = increased risk of Guillain-Barre from molecular mimicry 3. Systemic infection = strong correlation with Multiple Sclerosis (pretty much necessary for you to have been infected with EBV to develop MS which suggests a very strong causative role even though this is yet to be explained mechanistically)

Question 52

how many bacteria are there in the human gut

Answer 52

10^14 (one quadrillion) bacteria of more than 1000 different species

Question 53

what does evidence suggest about life style and the gut flora correlate with

Answer 53

that life style associated changes in gut flora correlate with reduced immune regulation and increased susceptibility to allergy and autoimmune disease (evidence suggests that changes in the environment modify disease susceptibility in animals and humans)

Question 54

is it possible that bacteria in the microbiome are driving auto immunity (and supporting studies)

Answer 54

yes - and there are two studies that show this : 1. in TCR transgenic models, manipulating commensal organisms can precipitate autoimmune disease (this is a proof of principle and doesn't necessarily tell us about what is happening in more normal studies) 2. Th17 T cell responses implicated in both cases.

Question 55

what are the origins for the hygiene hypothesis

Answer 55

- in 1966 it was believed that poor hygiene might promote autoimmunity so investigated the correlation in multiple sclerosis and discovered the complete opposite - In 1989 Strachan finds a link between hay fever, allergies and hygeine - studies suggested that infection might prevent rather than cause diseases

Question 56

What evidence from animal models supports the hygiene hypothesis for the following conditions: Type 1 diabetes, systemic lupus, and multiple sclerosis?

Answer 56

1. NOD mice who were infected by e.g. mycobacteria, LCMV or LDHV had preventative effects for type 1 diabetes 2. (NZBxNZW)F1 (mouse model for systemic lupus) who were infected with LDHV or Plasmodium berghei had preventative effects against systemic lupus 3. Mouse and Rate EAE who were infected with Mycobacteria, Bordetella pertussis had multiple sclerosis disease suppressed

Question 57

What evidence from clinical models supports the hygiene hypothesis for Multiple sclerosis

Answer 57

a. Individuals with parasitic infections experienced reduced MS exacerbations. This was linked to high eosinophilia caused by the infection and elevated levels of IL-10 and TGF-β produced by peripheral blood leukocytes. b. this led to the hookworm trial which concluded that there was a measurable beneficial effect but the beneficial effects didn't justify giving people hookworm infections as a therapy.

Question 58

What evidence from clinical models supports the hygiene hypothesis for Chron's disease (IBD)

Answer 58

In a clinical study, 21 out of 29 Crohn's patients infected with Trichuris suis (pig whipworm) every three weeks for six months showed significant symptom improvement.

Question 59

what are the mechanisms of autoimmune disease protection following infection

Answer 59

1. the presence of infection shifts the balance between Th1 and Th2 cells 2. antigeic competition 3. Infection alters systemic cytokine secretion. 4. Induces regulatory cells (e.g. FoxP3+, IL-10-secreting cells). 5. Stimulates non-antigen ligands like Toll-like receptors (TLRs).

Question 60

Th1 vs Th2 cell function

Answer 60

Th1 cells: These are primarily involved in cell-mediated immunity, driving inflammatory responses by activating macrophages and cytotoxic T cells. They play a key role in combating intracellular pathogens. Th2 cells: These cells are responsible for humoral immunity by promoting antibody production. They achieve this by releasing cytokines that stimulate B cells to proliferate and differentiate into antibody-secreting plasma cells, particularly in response to extracellular pathogens.

Question 61

which response is responsible for autoimmune disseases vs allergies : Th1 and Th2

Answer 61

Th1 drives autoimmune diseases whilst Th2 drives allergies

Question 62

what does antigenic competition suggest

Answer 62

that immune responses have a limited capacity to deal with antigens which means that if you have many infections antigens this could override weak responses to allergens or self antigens.

Question 63

what is the question that arrises with using antigenic competition as a potential therapy

Answer 63

does this then require persistent infection? is it then ethical to infect a large number of people with a disease e.g. hookworm to stop a small amount of disease.

Question 64

How does infection influence systemic cytokine secretion in autoimmune protection?

Answer 64

Infections can modulate the cytokine environment, shifting immune responses to reduce autoimmunity by promoting anti-inflammatory cytokines (e.g., IL-10, TGF-β) or altering pro-inflammatory cytokines.

Question 65

What role do regulatory cells play in autoimmune protection after infection?

Answer 65

Certain infections induce regulatory T cells (e.g., FoxP3+ cells) or IL-10-secreting cells, which suppress excessive immune responses and limit tissue damage.

Question 66

How do non-antigen ligands like TLRs protect against autoimmunity?

Answer 66

Non-antigen ligands, such as TLRs (e.g., TLR 2, 3, 4, 7, or 9), are stimulated during infections. This activation can modulate immune signalling pathways, reducing the prevalence or severity of autoimmunity.

Question 67

which vitamin has been shown to modulate the immune response and how

Answer 67

Vitamin D which is made in the skin on exposure to the sun. It stimulates the production of antimicrobial peptides which directly kill the bacteria and virus. It can also influence the differentiation of T cells and development of T reg cells which suppress immune responses and prevent autoimmunity.

Question 68

why would those that live along the equator potentially be more protected against infectious diseases

Answer 68

because they get more direct sunlight and therefore produce more vitamin D

Question 69

how do aryl hydrocarbon receptors (AHR) play a role in autoimmunity

Answer 69

AhR can influence the differentiation of various immune cells and form part of the metabolic response to the microbiome which makes understanding how they work in these different diseases complex. It has been found that when the ligand for this receptor is present, the level of experimental auto immunity was reduced.

Question 70

What is SGK1, and what is its role in autoimmunity?

Answer 70

Serum and glucocorticoid-inducible kinase 1 s a protein kinase and sodium chloride sensor involved in regulating key signalling pathways and many different aspects of physiological functions in the body. Genetic studies have highlighted its role in autoimmunity, showing that activation of SGK1 by a high-salt diet can increase susceptibility to autoimmune diseases compared to a low-salt diet. Whether it can be used as a therapeutic target remains to be determined