L2 - Aetiology of Autoimmune Disease Flashcards
* Review classifications of autoimmune diseases * To understand the contribution of genetics to disease susceptibility * To understand that exposure to infection and environmental sensors influence autoimmune diseases
What is Aetioloy
The science of understanding how things develop
What means that autoreactive cells will be produced throughout life
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)
around how many genes are involved in the development of autoimmunity
anywhere between 30 to 300 genes
what does the immune system’s polymorpphic sensing abilities refer to
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
What are some environmental aetiology that affect the immune system
- infections ( both pathogenic and non pathogenic)
- Non infectious influences
- stochastic and timing effects in the development of disease
What kind of organisms have susceptibility to abnormalities in the immune system
every individual possibly every species down to bacteria ( in humans this is down to their genes and their environment)
Why does everyone have a different susceptibility to disease and autoimmunity
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)
What is the definition of an autoimmune disease
An immune process characterised by the activation of adaptive immune cells that respond to self antigens and cause immune pathology
what are the different types of autoimmune diseases
- Organ specific : T cell mediated and stimulating or blocking antibody mediated
- systemic
What is an example of an organ specific T cell mediated autoimmune disease
Multiple sclerosis
What will a scan of the brain from someone with MS look like
it will show patches of inflammation that come and go through time ( this demonstrates the relapsing nature of autoimmunity)
what is an example of an organ specific antibody stimulating autoimmune disease (antibody mediated)
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
what is an example of an organ specific antibody blocking autoimmune disease (antibody mediated)
Myasthenia Gravis which block the normal physiological functioning of acetylcholine receptors which prevents normal muscle signalling and leads to weakness
what is an example of a systemic autoimmune disease
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.
what is the ratio of systemic lupus erythematosus (SLE) in female: male
10:1 (females more susceptible)
what ethnicity is more likely to get systemic lupus erythematosus
more common in African-American and Hispanics
What is usually the cause of genetic autoimmune disease susceptibility
Heritability and usually multiple mutations in many genes ( rarely autoimmune diseases are caused by single mutations)
What is the advanatage of investigating autoimmune diseases that are caused by single mutations
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)
what does polygenic mean
many genes ( 10s / 100s genes can influence an immune phenotype)
what does polymorphic mean
a single gene with many forms e.g. PTPN22 ( exists in different forms in different individuals and remain functional)
PTPN22 gene role ***
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)
what does the diversity of the immune system allow for in a population
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
What is an example study demonstrating diverse immune responses to a similar pathogen
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 ….
example of single points of failure in tolerance checkpoints
- AIRE: APECED/ autoimmunity
- Fas/FasL : ALPS/MRL-Ipr&gid mouse
- Foxp3 : IPEX?scurfy mouse
- CTLA4: Immune dysregulation / fatal lymphoproliferation
AIRE function
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.
Fas/FasL function
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
FoxP3 function
plays a central role in the development and function of Tregs. Without these cells fail to develop properly and cannot suppress the immune response
CTLA4 function
acts as an off switch for T cells helping to prevent excessive immune responses by competing with CD28
what causes Autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy
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.
Why does APECED cause chronic mucocutaneous candidiasis?
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.
what does APECED stand for
Autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy
What is the best kind of immune response
one which is balanced in a way that is just good enough to clear the infection without causing any damage
Why was whole genome sequencing of sporadic primary immunodeficiencies useful in terms of autoimmunity
Primary immunodeficiencies (PID) go hand in hand and are characterized by recurrent infections, autoimmunity, and cancer
what percentage of patients with primary immunodeficiencies have autoimmune diseases and develop lymphoid malignancies
25% of patients have autoimmune disease and 10% develop lymphoid malignancies (allergies are also common)
What can be more useful than PIDs In terms of identification and clinical management of autoimmune diseases
- 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 )
which genetic association is the strongest / most consequential when it comes to the development of autoimmune diseases
MHC complex
In what year was the first association between MHC class II and Multiple sclerosis described
1972 (and then the second well validated genetic association with MS was established in 2007)
What is it about MHC genes that makes them so crucial in whether or not you develop auto immune diseases.
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.
how come not everyone develops autoimmune diseases despite the fact that all of us have autoreactive T cells in our peripheral circulation
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)
what is a genome-wide association study
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
pros and cons of genome wide association studies (GWAS)
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.
What are some examples of non MHC genes that have been associated with autoimmune diseases ( through GWAS)
- 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
what do GWAS catalogue loci clusters show
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
what is the catch 22 with autoimmunity and infection
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.
genes and autoimmunity summary
- 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.
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)
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)
What is the distribution of multiple sclerosis-like across the globe
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)
migration study findings that support environmental agent effects on autoimmune diseases
- 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)
infections and the microbiome effect on disease
pathogenic microbiota can cause or exacerbate human autoimmune disease
infectious agents and the autoimmune disease that they cause
- Group A streptococci = increased risk of Rheumatic Heart Disease from molecular mimicry
- C.Jejuni = increased risk of Guillain-Barre from molecular mimicry
- 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)
how many bacteria are there in the human gut
10^14 (one quadrillion) bacteria of more than 1000 different species
what does evidence suggest about life style and the gut flora correlate with
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)
is it possible that bacteria in the microbiome are driving auto immunity (and supporting studies)
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.
what are the origins for the hygiene hypothesis
- 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
What evidence from animal models supports the hygiene hypothesis for the following conditions: Type 1 diabetes, systemic lupus, and multiple sclerosis?
- NOD mice who were infected by e.g. mycobacteria, LCMV or LDHV had preventative effects for type 1 diabetes
- (NZBxNZW)F1 (mouse model for systemic lupus) who were infected with LDHV or Plasmodium berghei had preventative effects against systemic lupus
- Mouse and Rate EAE who were infected with Mycobacteria, Bordetella pertussis had multiple sclerosis disease suppressed
What evidence from clinical models supports the hygiene hypothesis for Multiple sclerosis
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.
What evidence from clinical models supports the hygiene hypothesis for Chron’s disease (IBD)
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.
what are the mechanisms of autoimmune disease protection following infection
- the presence of infection shifts the balance between Th1 and Th2 cells
- antigeic competition
- Infection alters systemic cytokine secretion.
- Induces regulatory cells (e.g. FoxP3+, IL-10-secreting cells).
- Stimulates non-antigen ligands like Toll-like receptors (TLRs).
Th1 vs Th2 cell function
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.
which response is responsible for autoimmune disseases vs allergies : Th1 and Th2
Th1 drives autoimmune diseases whilst Th2 drives allergies
what does antigenic competition suggest
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.
what is the question that arrises with using antigenic competition as a potential therapy
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.
How does infection influence systemic cytokine secretion in autoimmune protection?
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.
What role do regulatory cells play in autoimmune protection after infection?
Certain infections induce regulatory T cells (e.g., FoxP3+ cells) or IL-10-secreting cells, which suppress excessive immune responses and limit tissue damage.
How do non-antigen ligands like TLRs protect against autoimmunity?
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.
which vitamin has been shown to modulate the immune response and how
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.
why would those that live along the equator potentially be more protected against infectious diseases
because they get more direct sunlight and therefore produce more vitamin D
how do aryl hydrocarbon receptors (AHR) play a role in autoimmunity
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.
What is SGK1, and what is its role in autoimmunity?
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
