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
SLE: what is it and what form of antibody-mediated disease mechanism is it involved with?
Systemic lupus erythematosus - Immune complexes deposit in small blood vessel walls (kidney, joints, skin) and initiate inflammatory reaction, potentially resulting in arthritis, “butterfly” rash, vasculitis, glomerulonephritis, etc
Deposition of immune complexes
Concordance: does it support autoimmunity having an environmental or genetic basis?
Concordance in identical twins is higher than in non-identical twins - supports the idea of a genetic aspect
Concordance is ~<50% suggesting there is also some kind of environmental factor
Polymorphisms: what are they, what forms can they have, and what degree of impact do they have to autoimmunity?
Many genes are polymorphic i.e. present in population in more than one form e.g. MHC
Can be structural or non structural:
- Structural polymorphism: Different forms of protein are made (if in protein coding gene region) e.g. MHC
- Non-structural Polymorphism: Altered protein activity or protein levels-(if in non-protein coding region/promoter/ enhancer region)
Susceptibility to autoimmunity is generally due to expression of different gene alleles - not mutations, yhe degree to which an allele of a gene increases susceptibility is called the RELATIVE RISK (RR)
Relative risk of genes: how much do genes impact autoimmunity, what happens when multiple present together, and what effects do they have on the body?
Genes identified as risk factors account for only a small proportion of the genetic risk (often only 10-20%) - each gene alone confers only a small increased risk
It is the combination of these genes that enhances risk of developing autoimmune disease - they are MULTIGENIC i.e. Many genes contribute to susceptibility
- Affect autoantigen availability and clearance
- Apoptosis
- Signalling thresholds
- Cytokine expression/signalling
- Costimulatory molecules/receptors
- Regulatory T cells
Sex-related basis of autoimmune responses
75% of autoimmune diseases are found in females
Usually arises during child-bearing years
Can vary during pregnancy
Ankylosing spondylitis is one of the few autoimmune diseases that is more common in males
Environmental basis of autoimmunity: what supports this?
Rapid increase in incidence over the last 40-50 years - too quick to be explained by genetics alone
Geographical movement
Populations moving from low to high autoimmune areas develop a higher incidence
- Vitamin D - Active form of Vitamin D may suppress Th17 development
- Drugs - drugs or metabolites may bind to self-Ag and then Ag appears foreign
- Toxins – pollutants, UV, pesticides, smoking, may cause damage and expose areas for autoantibody mediated damage
- Microbiota/Hygiene - Associated with certain commensal bacteria/lack of bacteria, less pathogen exposure
- Microbial agents (pathogens) - May resemble self-antigens or interact with risk genes
EBNA2: what is it and how may it affect autoimmunity?
Epstein-Barr virus nuclear antigen 2 (EBNA2)
Interacts with several genetic risk loci associated with lupus
Also increased risk of 6 other autoimmune diseases including T1DM, rheumatoid arthritis, MS
NK cells and EBV-specific CD8+ T cell associated with a significantly raised risk of multiple sclerosis.
Can b-cells get activated without T-cells?
Mitogens, substances that promote mitosis, may activate b cells and cause them to differentiate - ie bacterial products like LPS, etc
Usually transient, though
Rheumatic Fever
Streptocococcal cell wall antigens stimulate antibodies
Antibodies against Streptococcal M-antigen also react against heart myosin, joints and kidney
Why can pseudo-antigens cause autoimmunity?
Drugs or infections that trigger Th, are finite i.e. should stop once infection cleared/drug course completed but in genetically susceptible people this can triggers Th cells for self-antigen and/or results in other self antigens being exposed and autoimmunity.
Pseudo-antigens: what are they and what can they be caused by?
Self-antigens that have been modified
Toxins, drugs, etc