Lecture 14: Autoimmune diseases Flashcards
What is autoimmunity?
- Immune response to self antigens
- Failure of tolerance
What are known autoimmune diseases?
-Adaptive immune response to self antigen causes tissue damage
What is tolerance?
state of immunological non-reactivity to an antigen
Describe the selection of adaptive immune lymphocytes?
1) Gene segments…Either negative selection -Reduces auto-reactivity
OR positive selection:Ensure receptors are useful
Produces:
2) Naive B and T cell receptors; Small numbers of cells for each antigen but very large number of receptors overall
3) Infection causes expansion of best population
4) Resolution of infection and memory cells
What does the negative selection produce?
- Some potential auto-reactive T cells
- activates peripheral tolerance mechanism
Describe the rigorous process in the adaptive immunity?
Rigorous: low risk of autoimmunity but poor repertoir therefore increased susceptibility to infection
Describe the permissive process of adaptive immunity?
- Broad repertoire of antigens
- Therefore lower risk of infection but higher risk of auto-immunity
Describe the peripheral tolerance mechanism using immunological hierarchy and antigen segregation?
- CD4 T cells will not be activated unless antigen is presented in an inflammatory context with TLR ligation
- Antigen segregation- Physical barriers to the sequestered antigen (immunological priviledge)
Describe the peripheral tolerance mechanism using peripheral anergy and regulatory T cells?
Peripheral anergy: weak signalling between APC /CD4 T cell without co-stimulation causes T cells to become non-responsive
Regulatory T cells:
Cd25+FoxP3 positive T cells and other types of regulatory T cells actively suppress immune responses by cytokine and juxtacrine signalling
Describe the peripheral tolerance mechanism using cytokine deviation and clonal expansion?
Cytokine deviation:
Change in T cell phenotype eg Th1 to Th2 may reduce inflammation
Clonal Exhaustion: Apoptosis post activation by activation induced cell death
Name auto-immune diseases that are organ specific?
- T1Dm
- Pemphigus
- Graves
- Hashimotos -thryroditis
- Anaemia
- Thrmbocytopenia
Name the auto-immune diseases that affect the multi-system?
- Systemic lupus erythematosis
- RA
- Sjogrens syndrome
Describe the pathogenic mechanism in autoimmune disease?
Type hypersensitivity according to G cell and Coombes classification:
-Refers to disease where an antibody is clearly pathogenic that causes disease damage directly
Describe the criteria pathogenic mechanism in auto-immunity disease?
- disease cam transferred between experimental animal by infusion of serum, or during gestation to cause problems in feotus
- Removal of antibody by plasmapharesis is beneficial
- A pathogenic antibody is identified and characterised
Describe the mechanism of antibody mediated heamolytic anaemia?
- RBC and anti RBC antibody combine
- FcR cells in fixed mononuclear phagocytic system
- Phagocytosis and RBC destruction
AND…
- Complement activation and intravascular haemolysis
- Lysis and RBC destruction
Describe the symptoms of autoimmune hyperthyroidism (Graves)?
- Hyperthyroidism symptoms:
- Tachycardia, palpitations, tremor, anxiety, heat intolerance
- Goitre
- Grave’s ophthalmology
Describe how Graves has all the characteristics of antibody mediated disease?
- Neonatal hyperthyroidism if mother is affected
- Serum transfers disease between experimental animals
- Antibody detected and chartacerised
Describe the mechanism normal thyroid hormone production?
1) The pituitary gland secretes TSH, which acts on the thyroid to release the thyroid hormones
2) Thyroid hormones act on the pituitary to shut down the production of TSH supressing further hormone synthesis (negative feedback)
Describe the mechanism of antibody mediated immune response for Graves thyrodits?
1) Autoimmune B cells make antibodies against TSH receptor that also stimulate thyroid hormone production
2) Thyroid hormone shut down TSH production but have no effect on the auto-antibody production which continues to cause excessive thyroid production
Describe the symptoms of antibody mediated symptoms of myasthenia gravis?
- Muscle weakness and fatigability
- Eyelids, facisal muscles, chewing, talking and swallowing most affected
- Ptosis at rest- becomes worse after opening and closing of eyes repeatedly
Describe the mechanism of myasthenia gravis?
- Acetylcholine receptors internalised and degraded
- When neuronal impulse arrive, no Na+ influx therefore no muscle contraction
Describe how spontaneous urticaria occurs?
IgG FcR1 antibody cross links with mast cells receptor causing degranulation. manifests with hives and swelling
How does T cells cause damage in autoimmune disease?
- Via Type IV hypersensitivity
- Tissue damage is directly mediated by T cell dependent mechansim
- T cells activate macrophages and other elements of innate immunity
- CD8 T cells damage tissues directly
- Much more difficult to demonstrate autoreactive T cells in vitro than it is to demonstrate antibody
Describe how T cell mediated causes hashimotos thyroditis?
-Commonest cause of the hypothyroidism in the industrialised
countries
-Particularly women >30 years
-Autoimmune destruction of thyroid: organ infiltrated by CD4 and CD8 T cells
