L16 - Autoimmunity Flashcards
Are auto-reactive B/T-cells inherently bad?
Not really, auto-reactive T and B cell clones are present in all normal healthy immune systems but are controlled by mechanisms of self-tolerance
Autoimmune response: what causes it, what cells are they caused by, why is it specifically these cells, what specific requirements must be met for autoimmunity to occur, and when does it become chronic?
Immune response against one or more self-antigens - due to a loss of tolerance to “Self”
Autoimmune disease caused by high-affinity auto-antibodies or autoreactive T cells
Everyone has autoreactive B cells but normally don’t make autoantibodies due to lack of antigen-specific T cell help
Must either lose T cell tolerance/get T cell help or bypass the need for T cell help
Chronic:
* Develop via positive feedback from inflammation
* Inability to clear self-antigen
* Broadening of autoimmune response - epitope spreading as hidden or cryptic epitopes revealed
Autoimmune disease: what mechanisms are triggered, what statistics are there regarding autoimmune diseases, and what immunological features are there?
Normal effector mechanisms triggered
Often not possible to clear self-antigen so results in a chronic response:
* 5-8% of population
* >80 different autoimmune diseases
* Symptoms and severity vary
* Patients frequently suffer from >1
* Once they occur, most persist for life (chronic)
Immunological features:
* Auto-antibodies in the serum - can use for detection
* deposited in tissues
* Formation of immune complexes
* Cellular infiltrate
-T cells (CD4 & CD8)
- B cells
Autoimmune disease: classification, how each type works, and their examples
Based on whether one tissue (organ-specific) or multiple tissues are affected (systemic):
- Organ-specific – Effector functions target Ag confined to the affected organ:
- Multiple sclerosis - myelin sheath on axons in CNS
- Type I diabetes - Beta cells of the pancreas targeted
- Systemic– Ag widespread, found in most cells:
- Systemic Lupus Erythematosis – anti-nuclear antigens (ANA)
- Rheumatoid arthritis
Failures in the development of self-tolerance: what examples are there and what does it lead to?
- Mutations in AIRE - involved in “promiscuous gene expression” to help screen out i.e. delete strongly self-reactive T cells during T cell development
- Mutations in FoxP3 - involved in Treg development, linked with IPEX (immunological polyendocrinopathy X-linked disease)
IPEX: what is it, what is it caused by, when is it presented, how doe sit present, and what is the treatment?
Immunodysregulation, Polyendocrinopathy, Enteropathy,
defects in the FoxP3 gene (Tregs)
Systemic autoimmunity, typically beginning in the first year of life.
Presentation is most commonly a clinical triad of watery diarrhoea, endocrinopathy (usually diabetes mellitus), and eczematous dermatitis.
Treatment incl. bone marrow transplant and immunosuppressive agents
Pathology of autoimmune diseases: what types are there?
Primary pathology - a direct consequence of the autoimmune disease
Secondary pathology - arise as a consequence of the primary pathology
What leukocytes are present autoimmune diseases?
CD4+ Th cells - they drive other autoimmune effector functions - in nearly all autoimmune diseases
Increasingly Th17 cells implicated in autoimmune disease
Also have autoreactive Tc
Recruit and amplify innate effector mechanisms (e.g. macrophages)
Even if the pathology is B cell mediated you require T cells to provide help to the B cells for antibody production. Could also amplify responses such as macrophage responses
What autoimmune disease mechanisms do T-cells mediate?
- Production of pro-inflammatory cytokines
- Damage to epithelial barrier integrity (can involve Tc)
- Promote CD8 cytotoxic T cell function
- Promote macrophage mediated destruction
- Drive the inflammatory response
- Promoting antibody responses
Disease mechanisms induced by autoantibodies
In some cases, auto-antibody is the main or only feature and mediates pathology:
* Damage or destruction
* Complement-mediated lysis (cMAC)
* Opsonisation and phagocytic removal
* Alteration of function (destroy receptors - TSH)
* Stimulation of receptors (Agonist)
* Inhibition of function (blocking receptor)
* Blockage of Function
* Deposition of immune complexes
Autoimmune haemolytic anaemia: what is it and what form of antibody-mediated disease mechanism is it involved with?
A condition where antibodies bind to RBCs and trigger the complement membrane attack complex (cMAC), resulting in anaemia
Complement-mediated lysis
Autoimmune thrombocytopenia: what is it and what form of antibody-mediated disease mechanism is it involved with?
A condition where antibodies tag platelets for opsonisation, resulting in platelet destruction and causing excessive bleeding
Opsonisation
Graves disease: what is it and what form of antibody-mediated disease mechanism is it involved with?
A condition where antibodies prevent thyroid hormones from shutting down the thyroid-stimulating hormone in the pituitary gland and result in excessive TH production, resulting in hyperthyroidism (excessive stimulation)
Alteration of function
Myasthenia gravis: what is it and what form of antibody-mediated disease mechanism is it involved with?
A condition where antibodies block Ach receptor binding and also destroy the receptor, leading to weakened signals to muscles and muscle weakness
Inhibition of function
Pernicious anaemia: what is it and what form of antibody-mediated disease mechanism is it involved with?
A condition where parietal cells in the kidney produce intrinsic factor to absorb vitamin B12 but antibodies block IF and cause vitamin B12 deficiency, reduced RBC production, tiredness, and neurological changes (tingling)
Blockage of function
