Lecture 33 - Immunopathology II Flashcards
Three things needed for autoimmunity
1) Genetic susceptibility
2) Environmental factors
3) Loss of self-tolerance
Where are rates of autoimmune diseases the highest?
Western countries
Why are circulating auto-reactive lymphocytes not always activated?
1)
2)
3)
1) Antigen not available
2) Lack of signal 2 (DCs don’t receive PAMP or DAMP activation)
3) Auto-reactive B cells don’t have auto-reactive T cells for activation
Why mightn’t an auto-reactive T cell come into contact with cognate autoantigen?
Autoantigen might be in the periphery, while the auto-reactive antibody is in a lymph node
Difference between autoimmune response and autoimmune disease
An autoimmune response is where an autoreactive lymphocyte attacks an autoantigen.
An autoimmune disease entails chronic autoimmune response with sustained tissue damage (lack of tissue repair, or regulation of autoreactive lymphocytes)
B cell autoimmune disease types
1)
2)
1) Type II (including ligand-mediated interactions)
2) Type III (immune complex formation)
T cell autoimmune disease types
1)
2)
3)
1) Delayed-type hypersensitivity (Th1 activates macrophages, cytokine production, pro-inflammatory mediator release)
2) CTL killing of stromal cells (EG: type I diabetes)
3) Th help of autoreactive B cells
Two types of autoimmune disease
1) Systemic
2) Organ-specific
Systemic autoimmune disease
1)
2)
1) Recognised antigens are more ubiquitous
2) Multiple organs affected
Organ-specific autoimmune disease
Antigens recognised are organ-specific
Examples of systemic autoimmune disease
1)
2)
Systemic lupus erythematosus
Rheumatoid arthritis
Examples of B cell mediated autoimmunity
1)
2)
3)
1) Grave’s disease
2) Myasthenia gravis
3) Systemic lupus erythematosus
Grave's disease 1) 2) 3) 4)
1) Pituitary gland releases thyroid stimulating hormone
2) Thyroid normally releases hormones to suppress pituitary gland (negative feedback)
3) In Grave’s disease, autoantibodies bind to TSH receptors in thyroid, stimulate release of thyroid hormones
4) Hyperthyroidism results. Pituitary gland releases no more TSH, but this has no effect on Ab production
Type of autoimmune disease that is Grave’s disease
B cell mediated, organ-specific
Myasthenia gravis
1)
2)
3)
1) B cells produce autoantibodies that bind to nicotinic ACh receptors in neuromuscular junction
2) Results in internalisation, degradation of ACh receptors
3) No Na+ influx, no muscle contraction
How can Grave’s disease be transmitted?
Through placenta, from mother to child
Systemic lupus erythematosus 1) 2) 3) 4) 5)
1) Unknown aetiology
2) B cell hyper-reactivity observed
3) DNA autoantibodies produced
4) Immune complexes deposited in kidneys
5) Numerous autoantibodies produced, multiple organ systems affected
Pathogenesis of systemic lupus erythematosus
1)
2)
3)
1) Immune complex deposition in basement membrane of kidney
2) This activates complement cascade
3) Tissue damage from leukocyte activation and inflammation
Examples of T cell-mediated autoimmunity
1)
2)
3)
1) Type I diabetes mellitus
2) Multiple sclerosis
3) Coeliac disease
Type I diabetes
1)
2)
3)
1) Organ-specific, T cell mediated (CD4+ and CD8+)
2) Autoimmune destruction of beta cells in pancreatic islets (alpha and delta cells are spared)
3) Characterised by lymphocyte infiltration, weak autoantibody response, T cell reactivity with islet proteins
HLA type that type I diabetes is more common with
1)
2)
1) DR3-DQ2
2) DR4-DQ8
How do Th1 cells contribute to type I diabetes? 1) 2) 3) 4)
1) Chemokines recruit macrophages to pancreas
2) IFNg causes macrophages to release inflammatory mediators
3) TNF causes tissue destruction, expression of adhesion molecules on blood vessels
4) IL-3, GM-CSF cause bone-marrow production of macrophages
Multiple sclerosis 1) 2) 3) 4) 5)
1) Polygenic degenerative disorder of the CNS
2) Episodes of paralysis in early stages, chronic paralysis in later stages
3) CD4+ specific to myelin antigens degrade myelin
4) Th1, Th17 associated with inflammation.
5) Th2 associated with recovery
HLA types associated with multiple sclerosis
1)
2)
1) DR15
2) DQ6
Is coeliac disease an autoimmune disease?
No
It is a type IV hypersensitivity
Antigen is a food antigen, not a self antigen
Coeliac disease incidence in Europe
1/300
HLA associated with coeliac disease
1)
2)
3)
1) Over 95% of patients are DQ2 positive
2) Some DQ8 positive
3) Homozygous for DQ2 leads to higher risk of disease
Coeliac disease
Type IV hypersensitivity to gliadins and gliadin-like molecules in wheat, barley and rye
Effects of coeliac disease
Villous atrophy in jejunum
What is gluten?
A complex mix of glutamine and proline rich polypeptides
How might DQ2 and DQ8 interact with gluten?
1) Tissue transglutaminase converts glutamine in gluten to glutamic acid, which is negatively charged
2) HLA-DQ2 and DQ8 bind negatively charged residues (gliadins) more avidly
3) This results in T cell activation
4) Innate system can be triggered via unknown mechanisms. release of IL-15,
What are gliadins?
A large portion of gluten proteins
How can autoreactive antibodies be generated?
1)
2)
3)
1) Circulating B cell binds self antigens released by damaged cells
2) B cell presents antigen, cognate T cell activates B cell
3) B cell maturation, proliferation
Good animal model for type I diabetes
Non-obese diabetic mouse
Role of infection in autoimmunity
Infection can activate DCs presenting autoantigen, lead to activation of autoreactive T cells
