MED2042 WEEK 6 - Immunology
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- What is the function of the immune system?
- The function of the immune system is selective destruction.
- How does the immune system be selective?
- In order to be selective, the immune system must be able to discriminate between self and non-self.
- What is self?
- Self is what is present in the body all the time.
- What is nonself?
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Non self is structurally different from self (e.g. different amino acid sequence)
Comes in unexpectedly (ie not present all the time) - Why don't immune responses occur to itself?
- Because of self-tolerance.
- When was the first mention of the concept of self-tolerance?
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Paul Ehrlich, 1900
Dictum: "Horror autotoxicus"
(Did he intend to mean autoimmunity was impossible?) - Why was the concept of autoimmunity strongly resisted for most of the 20th century?
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Prehaps because of misinterpretation of Ehrlich's dictum.
We now know that autoimmunity arises as a result of failure of self-tolerance. - What was the misinterpretation of Ehrlich's dictum?
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"horror autotoxicus"
did not mean that autoimmunity was impossible (ie. incompatible with life)
All it meant was that autoimmunity was incompatible with health. - What is experimentally induced tolerance?
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MEDAWAR'S EXPERIMENT
Artificial induction of tolerance to nonself tissues
Fifty years ago, Medawar and his colleagues demonstrated transplantation tolerance elicited by infusion of foreign marrow into a newborn mouse (1). This was the first demonstration of acquired immunological tolerance, and as such, offered a challenge for achieving transplantation tolerance as a clinical goal in an immunologically mature adult; a goal yet to be realized as a routine procedure. Medawar's experiment was used as evidence to support the clonal selection theory and the notion that self-tolerance arises from purging of self-reactive lymphocytes from the immune repertoire. Later studies demonstrated that marrow infusions provided a source of stem cells able to establish a state of mixed (both recipient and donor) blood chimerism. This would guarantee a permanent source of donor antigen to ensure continuous purging of alloreactive lymphocytes, so setting the stage for current concepts of inducing tolerance therapeutically. - What are the mechanisms of self-tolerance?
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- Clonal deletion ("abortion") in primary lymphoid organs
- Clonal anergy (cells survive, but cannot respond to antigen.
- suppresion by "regulatory T cells" (CD4, CD25)
(but what regulates the regulators? - How could self-tolerance break down?
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- Somatic mutation in a T cell, making it autoreactive (mutation in T cell receptor or any gene controlling activation threshold)
- Environmental antigen that is similar to self, and induces an anti-self response?
- something going wrong with regulatory T cells? - What is the concept of autoimmune disease?
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Mackay and Burnet, 1963
Autoimmunity arises as a result of failure of self-tolerance. - What are some examples of autoimmune disease?
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Insulin-dependent diabetes mellitus
Rheumatoid arthritis
Multiple sclerosis
Thyrotoxicosis
Many others - How common is autoimmune disease?
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Third most common cause of disease after cardiovascular disease and cancer
Lifetime risk for all people is about 5-10% - What is known about the cuases of autoimmune disease?
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- Cuases of autoimmune disease is poorly understood.
- At present, it is generally best to think of risk factors rather than causes.
- Associateion with certian HLA types strongly implicates aberrant actiation of T cells as the primary problem. - What are the genetic risk factors of autoimmune disease?
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1. Being female
- Most (but not all) autoimmune diseases are more common in females. we don't know why
2. Particular HLA alleles
- Autoimmune disease are associated with particular HLA types (Most commonly class II, although the most dramatic associateions are with class I)
- This suggests involvement of helper T cells, but we do not understand the exact mechanism of pathogenesis.
3. Other genes
- several differnet loci
- most have not yet been identified
- subject of current research - How do T cells see antigen?
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ALways at cell surfaces.
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N.B.
- Antigen-presenting cells for primary T cell regions are dendritic cells.
- Antigen-presenting cells for secondary T cell regions can be alsmost any cell type. - What is HLA?
- The human leukocyte antigen system (sometimes human lymphocyte antigen) (HLA) is the general name of a group of genes in the human major histocompatibility complex (MHC) region on human chromosome 6 (mouse chromosome 17) that encodes the cell-surface antigen-presenting proteins. The proteins encoded by HLAs are the proteins on the outer part of body cells that are (effectively) unique to that person. These proteins are sometimes designated the Mhc, although this convention is rarely observed.
- How do cytoplasmic proteins get in the MHC class I groove?
- ?
- How is the genetic risk of autoimmune disease passed on?
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Risk is inherited in Mendelian fashion, but penetrance is incomplete
(in otherwords, not everyone who has high risk genes will get the diesease)
(In other words, not everyone who has high risk genes will get the disease. - Why is penetrance of "high risk" HLA alleles incomplete?
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- Many people with high risk HLA alleles do not get autoimmune disease.
- Other genes that modify HLA effects
- Environmental factors (infection, drugs?)
- Chance factors (somatic mutations affecting lymphocyte receptor specificity or threshold of activation) - Why is there a "clustering" of autoimmune disease?
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Individuals with one autoimmune diseas are more likely to develop other autoimmune diseases.
In other words, there appears to be a general genetic predisposition to autoimmunity. - What are the environmental causes of autoimmune diesease?
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These generally shoe themselves when the subject has a high risk genetic constitution.
Most causes of autoimmune disease do not have an identifiable environmental cause.
1. Drugs (rarely)
2. Microbial infection (sometimes) - How do drugs provoke an autoimmune disease?
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- Myasthenia gravis can be provoked by penicillamine (arthritis drug) in genetically susceptible people
- Haemolytic anaemias can be provoked by many different drugs
- Hydrallazine and procaine amide can provoke a lupus-like syndrome which disappears when the drug is stopped. - How do microbial infections provoke an autoimmune disease?
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- Rheumatic fever and acute glomerulonephritis often follow infection with group A beta-haemolytic streptococci
- Inflammatory joint disease is often a sequel of enteric bacterial infections
- Viral infections (Coxsackie virus and other viruses have been suggested but not proven) - What are the mechanisms of tissue damage in autoimmune disease?
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Evidence for immunological causation:
1. Lymphoid infiltration of tissues is commonly seen, and in some cases have been shown to cause tissue damage
2. Autoantibodies to affected tissues are commonly seen, and in some cases have been shown to cause tissue damage
- In some instances, such as myasthenia gravis and thyrotoxicosis, a direct role for autoantibodies has been proven
- but in most others, autoantibodies are persent but it is not clear whether they do any damage
- In many instances, damage is thought to be due to autoreactive T cells (either direct cytotoxicity by CD8 killer T cells or through the effects of cytokines secreted by CD4 helper T cells. - What is the classicication of autoimmune disease types?
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1. Organ specific
2. Systemic - What are some examples of organ-specific autoimmune disease?
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Insulin-dependent diabetes mellitus
Thyrotoxicosis (Grave's disease)
Hashimoto's disease
Myasthenia gravis
Some haemolytic anaemias
Rheumatoid arthritis
Multiple sclerosis
Pernicious anaemia
Many others... - What happens in Rheumatic fever?
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- commonly preceded by infection with group A beta-haemolytic streptococci
- "barks at the joints, but bites the heart"
- transient arthritis, long-term damage to heart valves
- mechanism of tissue damage not known - not due to autoantibodies
- long term risk of valve stenosis (narrowing) or incompetence (leaking) and bacterial endocarditis
- Incidence has declined in recent years, but still common in aboriginal populations (associated with poverty) - What happens in Coeliac disease? (organ specific)
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- symptoms often vague, but may include diarrhoea, malabsorption, weight loss, tiredness
- Atrophy of mucosa of small bowel, with lymphoid infiltration in submucosa
- Clearly identifiable environmental cause: gluten, a componenet of wheat flour. Elimination of wheat from diet results in normal bowel
- Most cases have HLA-DQ2 or DQ8
- Autoantibodies to tissue transglutaminase enzyme are present in most cases. - What are the causes of myasthenia gravis? (organ specific)
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- HLA types (risk increased with HLA DR3)
- Drugs (penicillamine)
- so far, no other environmental trigger has been found. - What happens in diabetes mellitus (insulin dependent)? (organ specific)
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- onset is typically in teens, but can occur at any age
- primary problem is lack of insulin due to destruction of beta-cells of pancreatic islets
- asymptomatic until most of the pancreatic islets are destroyed
- treatment is by insulin injections
evidence for immunological causation. - What happens in thyrotoxicosis (Graves disease)?(organ specific)
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- Very common (up to 2% of all women; especially young women) but can occur at any age ad in males.
- Thyroid is over-active
- Bulging eyes (exophthalmos)
- Sweating, intolerance to heat
- Anxeity
- Tremor
- Loss of weight - What happens in Hashimoto's disease?(organ specific)
- Destruction of thyroid by infiltrating lymphocytes, leading to hypothyroidism.
- What happens in Multiple sclerosis?(organ specific)
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- Chronic relapsing neurological disease with highly variable course
- Focal areas of demyelination in the CNS
- Resulting in scattered neurological defects
- Diagnosis difficult: lesions scattered in time and location, with no other identifiable cause
- Most likely auto-immune - What happens in gastric immunity? (organ specific)
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- Quite common, but many cases undiagnosed
- Atrophy of gastric mucosa
- Due to attack on acid-secreting parietal cells by T cells
- Autoantibodies to parietal cells are usually present, but probably do not cause damage
- The autoantigen is the proton pump (ATPase) that secretes gastric acid
- parietal cells also secrete "intrinsic factor" into the somach
- intrinsic factor binds vitamin B12, and is essential for B12 uptake in the terminal ileum
- Autoantibodies to intrinsic factor are often present
- Failure to absorb vitamin B12 results in pernicious anemia - What happens in autoimmune haemolytic anaemias? (organ specific)
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- Autoantibodies to membrane proteins of red blood cells
- Resulting in destruction of red cells by phagocytosis and possibly complement-mediated damage
- Sometimes caused by drug reaction - What happens in Systemic lupus erythematosus (SLE)?
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- Disease is due to circulating complexes of DNA-anti-DNA antibodies
- The circulating immune complexes activate complement
- Leading to widespread nonspecific inflammation
- Kidney damage due to deposition of complexes in glomeruli often leads to renal failure
- Many other complications, often due to vaculitis - How is autoimmune disease diagnosed?
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History and examination
Investigations;
- Test for presence of auto-antibodies (but correlation with presence of antibodies is highly variable
- Disease can be present without autoantibodies, and autoantibodies can be present in large amounts without disease
- Histology: lymphoid infiltration of affected tissues - What is the treatment of autoimmune disease?
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- Cure is not possible but control can often be achieved through the use of drugs
- Mainstay is use of immunosuppressive drugs, including glucocorticoids, methotrexate, cyclosporin, others
- Antigen-specific intervention is not yet possible, but is the subject of current research
- The "holy grail" would be to find a way of inducing antigen-specific tolerance, which would also revolutionise transplantation