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4 common targets for organ-specific autoimmunity (with examples)
- thyroid: Grave's disease, Hashimoto's thryroiditis
- stomach: pernicious anaemia
- pancrease: T1D
what makes the common targets for organ-specific autoimmunity common? (2)
- well vascularised
- make organ specific proteins
3 non-organ specific targets for autoimmunity (with examples)
- skin: scleroderma
- kidney: SLE (systemic lupus erythematosis)
- joints: RA
3 general mechanisms of autoimmune pathology
- immune complex
- t cell
Autoantibodies: 5 examples
- Her Royal Majesty GG
- Grave's disease: to TSH receptor: hyperthryoidism (bulging eyes, nervousness, heat intolerance
- Myasthenia Gravis: to ACh receptor: downregulation of AchR: muscle weakness
- Rheumatic fever:
- Haemolytic anaemia: to Rh blood group antigens: RBC destruction
- Goodpasture's syndrome: to collagen type IV: glomerulonephritis
Explain the problem with 'immune complex mediated' autoimmunity
- Deposition in tissues
- Depletion of complement
How are immune complexes normally removed?
Complement binds antigen. IgM binds to C3bR on RBCs. Transport to liver and spleen for destruction by macrophages.
2 examples of immune complex mediated autoimmunity
- SLE: Systemic lupus erythematosus: anti-cytoplasmic and anti-nuclear antibodies: complement depletion. Butterfly rash on face, glomerulonephritis, vasculitis, arthritis. Complement deficiencies that impair immune clearance (Eg C1, C2, C4) are predisposing.
- SBE: Subacute bacterial endocarditis: to bacterial antigens: endocarditis, glomerulonephritis
4 mechanisms of damage with T cell mediated autoimmunity
- CTL mediated destruction
- Macrophage activation
- TNF-alpha mediated destruction
- Induction of apoptosis by Fas ligand
3 examples of T cell mediated autoimmunity
- Mr T
- RA: to synovial joint antigens: joint inflammation and destruction
- MS: to myelin basic protein proteolipoprotein: brain degeneration, paralysis
- T1D: to pancreatic beta cells
Exp for T cell mediated autoimmunity
- Infect mouse with MBP and CFA. It gets EAE (experimental autoimmune encephalomyelitis). Isolate T cells with receptors specific for MBP. Inject these into a healthy mouse. They all get EAE, most die.
- Because the T cells attack self MBP.
Most important genetic risk factor for autoimmune disease
2 examples of HLA allotypes associated with autoimmune diseases...
- HLA-27 for ankylodising spondylosis (90x) and Goodpasture's syndrome (10x)
- HLA-DR2 for Goodpasture's (16x)
example of amino acid chain conferring susceptibility to an autoimmune disease
- Position 57 in HLA-DQbeta
- asp is protective (charged, forms electrostatic attractions)
- ser/ala/val is susceptible (hydrophobic)
- affects binding of diabetogenic peptides?
2 factors other than genetic which can alter susceptibility to autoimmune disease (with examples)
percentage contributions to susceptibility to T1D
- 50% environment
- 25% HLA
- 25%? other genes?
2 triggers of autoimmunity
- Release of sequestered antigen: eg autoimmune sympathetic opthalmia - damage to one eye leads to attack of the other
- T cell tolerance bypass: in 3 ways
- Molecular mimickry: pathogen epitope similar to self epitope
- Inflammation: activates pAPCs: may activate anergic autoreactive T cells
- Modification: neoantigen eg pathogen binding to self
2 types of animal models of autoimmunity
- Spontaneous: genetic inbreeding eg Ob mouse
- Induced: eg injecting with MBP and CFA to produce EAE (Experimental autoimmune encephalmyelitis)
3 drug types for autoimmune diseases
- organ specific: thryoxine for Grave's disease
- immunosuppressive (blunt!): cyclosporin, rapamycin, steroids
- anti-TNF etc
Role of Th17 cells
Produce IL17. Recruit neutrophils to sites of infection.
Role of Tfh cells
Activate B cells in B cell follicles.