Autoimmunity Flashcards
What is a break in Tolerance?
The immune system mistakenly attacks itself, and fails to tolerate self-cells
Does autoimmune disease primarily affect males or females?
Females
Not sure why, possibly related to sex hormones or how the immune system functions in different sexes
What causes autoimmunity?
Genetics (several polymorphisms) in combination with infection and environmental exposures
How is nature of autoimmune disease determined?
Type of dominant immune response
Over time, how does the response to self change?
Changes from autoimmune response with a little inflammation, to low autoimmune response with lots of inflammation
What is central tolerance?
Development and education of the immune system (bone marrow, and thymus- B cells, T cells formation and education)
What is peripheral tolerance?
Where mature Immune cells can leave and go to Secondary lymphoid organs, and we have mechanisms here that can suppress autoimmune responses that can be lost (Treg).
What is molecular mimicry in relation to autoimmunity?
Bacterial epitope looks similar to something we have within ourselves.
So if we generate a response to a foreign bacteria that looks similar to our self cells, it may result in mounting an autoimmune response.
What is inappropriate activation of the immune system?
When a response is mounted by the immune system and said target is not appropriate, i.e. a response to self-cells
What type of regulation occurs within the central thymic centre in relation to limiting risk of autoimmunity?
Positive and negative selection of T cells
Killing of T cells that are self reactive, or not reactive enough
What type of regulation occurs within the peripheral
centre in relation to limiting risk of autoimmunity?
Regulatory T and B cells Dendritic cells and danger Co-stimulation Ignorance Privilege
What genes are related to autoimmune disease?
HLA genes (T cell communication) AIRE CTLA4 FOXP4 FAS C1q
Are most gene-related predispositions to autoimmunity monogenic or polygenic?
Polygenic
What is the hygiene hypothesis?
Too clean of an environment.
If we aren’t exposed to enough bacteria/viruses, our immune system wont be educated enough to effectively fight infection
What is the pathogenesis of autoimmunity?
Susceptibility gene -> Failure of self-tolerance -> persistence of functional self-reactive lymphocytes (they are there, but don’t drive pathology) -> Trigger event (can be environmental, stress, injury) -> activation of self-reactive lymphocytes -> immune response against self tissue
What cells are responsible for autoimmunity?
T cells and B cells forming autoantibodies
What is an autoantibody
Antibody that reacts to the epitope of a self-antigen.
May or may not be pathogenic
What are some autoimmune diseases involving autoantibodies? Name the target of the abs.
Graves Disease (TSH receptor)
Myasthenia Gravis (Acetyl choline receptor)
Idiopathic Thrombocytopenic purpura ITP (platelets)
Guillain-Barre Syndrome (Gangliosides within plasma membrane)
Multiple Sclerosis (related to demyelination)
How is Grave’s Disease caused?
Autoantibodies to TSH produced that can bind the TSH receptor stimulating thyroid synthesis.
Removes self-regulation of thyroid hormone to pituitary gland.
How is Myasthenia Gravis caused?
Autoantibody to acetylcholine receptor, binding to Ach receptor helping to induce internalisation and degradation of the receptor (therefore no response to Ach).
Can also bind to Ach receptor and block Ach interaction.
No/weakened muscle contraction
In autoimmune diseases involving autoantibodies, do T cells play a role?
Yes
T cell specific for auto–antigen may help generate anti-host response
What are some organ specific autoimmune diseases?
Hashimoto Thyroiditis Thyrotoxicosis Guillain-Barre Syndrome T1 Diabetes Multiple Sclerosis Atrophic Gastritis Addison's Disease Grave's Disease
What are some non-organ specific autoimmune diseases?
Systemic Lupus Rheumatoid Arthritis Scleroderma (attacks collagen) Dermatomyositis Mixed connective tissue disease Sjogren's Syndrome (attacks secretions- dry eyes/mouth)
What is organ specific autoimmunity?
Autoimmune attack against the self antigens of a specific organ
What is Guillain-Barre Syndrome?
A transient autoimmune disease
Auto-antibody mediated autoimmune disease to gangliosides of peripheral nerves
Infection with C. jejuni -> antibody formation for bacteria (similar to gangliosides in self- cell membranes). -> Can result in stripping of myelination from cells, inappropriate nerve firing, and lack of muscle innervation.
B cells response is tied to the infection, and B cells will stop producing the antibodies, but the other pre-existing antibodies will prolong and can cause the listed damage.
What is the evolving pathogenesis of rheumatoid arthritis (name the phases)?
Genetic predisposition + environmental factors
Pre-articular or lymphoid phase (RF, CCP-specific ab, collagen specific response, GF 39-specific response)
Transition phase (some sort of insult)
Articular phase (articular localization, CVD, osteoporosis, functional decline)
How long to pre-clinical trials typically take?
3-5 years
What is phase 1 clinical trials?
Study of effects on health human (20-50)
What is phase 2 clinical trials?
Limited study of patients (50-100)
What is phase 3 clinical trials?
Comparative studies on large number of patients (500-5000)
Cost millions by this point
What is NDA phase of clinical trials?
Authorization process
What is phase 4 clinical trials?
Continued comparative studies
Evaluate long term impacts
How much do clinical trials cost, and how long do they typically last?
5-8 years
Costs over 150million
What 3 symptoms do NSAIDs try to target?
Analgesic- pain
Antipyretic- reduce body temp
Anti-inflammatory- at higher disease- reduce inflammation
What is the process of enzyme activation in creating inflammatory responses in the body?
Phospholipases create arachidonic acid
AA is converted by Cox2 to prostaglandin G2, and then into prostacyclin (PGI2), PGD2 and PGE2 (primary role in pyrogenics), which all contribute to vasodilation and inflammation.
What does prostacyclin I and E do?
I- Causes vasodilation, inhibits platelet aggregation
E- Important mediator of inflammatory responses and causes fever and pain
What does thromboxane do?
Causes vasoconstriction, promotes platelet aggregation
How does Aspirin impact inflammation? Describe its mechanism of action.
Prevents prostacyclin/ thromboxane a2/prostaglandin production by inhibiting Cox1 and Cox2 non-selectively.
This inhibition prevents conversion of arachidonic acid into prostaglandin G2 (PGG2) and the listed products.
What does Cox1 produce?
Thromboxane A2
What does Cox2 produce?
PGE2, PGD2, and PGI2
Has a side pocket
Do NSAIDs impact cox1 or 2?
Both
What impact does paracetamol have within the body?
Analgesia
Anti-pyretic (via inhibiting pyrogens, like IL1 released from leukocytes, acts directly on thermoregulatory centre in hypothalamus)
Can be hepatotoxic
What impact does aspirin have within the body?
Analgesia
Anti-platelet
Anti-inflammation (although not primary use)
How do NSAIDs impact the gastric mucosa?
Prostaglandin (produced using Cox1) pushes mucosa out to protect the stomach lining
Aspirin will block prostaglandin preventing bicarbonate and mucosa production.
This means gastric lining can be damaged by acid, causing peptic ulcers, perforation and septicaemia
What do exogenous corticoid drugs mimic within the body?
Drugs mimic endogenous hormones (glucocorticoids (immunosuppressants) and mineralocorticoids (salt and water metabolism)) that are normally produced by adrenals
What is a side effect of exogenous corticoids?
They impact our metabolism as they are very close to the mineralocorticoids (which can impact electrolyte/fluid balance- aldosterone is a mineralocorticoid)
How do exogenous corticoids work?
Increase transcription of anti-inflammatories (annexin-1) and decrease transcription of inflammatory mediators (cytokines, chemokines, adhesion molecules)
What is annexin 1?
A protein that blocks the production of arachidonic acid by binding/inhibiting phospholipases
VERY strong, and more effective than NSAIDs
Used in many auto-immune diseases
What are the side effects of annexin-1?
Mess up metabolism (fat stomach, thin arms) Cataracts Mood (euphoria then depression) Poor wound healing Osteoporosis Tendency for hyperglycaemia
What pathology commonly and safely utilizes corticosteroids for treatment?
Asthma via inhalers
Not a systemic use, it is direct in the lungs
There is some exchange into systemic circulation
There is a modified version that is inactivated via first-pass metabolism in the liver
What are biological agents?
Monoclonal antibodies
They are biological drugs that are every specific
Problems: Increased risk of infection, expensive, intolerance/inadequate response in some patients
What are immune-checkpoint inhibitor drugs?
Check point proteins block T cell activity, so inhibiting them will result in an immune boosting.
“They work by blocking checkpoint proteins from binding with their partner proteins. This prevents the “off” signal from being sent, allowing the T cells to kill cancer cells.”
Used in treating cancer- but have side effects with people with chronic inflammatory disorders
