Lecture 33 - Autoimmunity Flashcards
What are the three key components required for autoimmunity?
- Genetic susceptibility
- Environmental exposure
- Loss of self-tolerance
Describe how tolerance is generated in lymphocytes
Negative selection in primary lymphoid tissues during development
Self Ag is presented.
Any lymphocytes that bind strongly to this antigen will be removed
Will circulating auto-reactive lymphocytes always bring about autoimmunity?
No, they may not be activated
- Antigen not available
- Absence of Signal 2
• DCs not activated to express co-stimulatory molecules
• DC activation through PRR:PAMP signalling (i.e. Danger signals needed for co-stimulatory molecule expression) - Auto-reactive B cells don’t get proper stimulation
• Need T cell help to become activated
• Lack of corresponding auto-reactive CD4+ T cell help
What is meant by ‘loss of self-tolerance’?
Loss of self-tolerance signifies:
Activation of self-reactive lymphocytes in the periphery
Presence of the (inactivated) auto reactive lymphocytes does not constitute loss of self-tolerance
Compare these two terms:
• Autoimmune response
• Autoimmune disease
What is the overlap?
Autoimmune response:
• Do not always result in autoimmune diseases
• Isolated damage due to auto-reactive cells does not constitute an autoimmune disease
Autoimmune disease:
• Continued tissue damage mediated by autoimmune response
• Always involve autoimmune responses
Describe normal effector mechanisms in response to self-antigens in:
• B cells
• CD4 and CD8 T cells
• Macrophages
B cells:
Hyper-sensitivities
• Type II (ligand mediated reactions)
• Type III (immune complex deposition)
CD4 and CD8 T cells:
• DTH responses
• CTL killing of stromal cells (e.g. Type 1 diabetes)
• Provision of B cell help
Macrophages:
• NO
• Proteases
• Oxidative radicals
Compare Organ specific and systemic autoimmune disease
Give examples of each
1. Organ specific • Confined to particular organs or cell types • Antigens involved are organ specific Examples • Hashimoto thyroiditis • Islet cells (type I diabetes) • Gastric parietal cells • Multiple sclerosis
2. Systemic • Multiple tissues of the body targeted • Antigens involved are more ubiquitous Examples • Rheumatoid arthritis • SLE
List examples of B cell mediated autoimmune diseases
- Graves disease
- Myasthenia gravis
- SLE
What is Graves disease?
Give the general features
Describe the pathogenesis
What is the effect on the Pituitary gland?
- Organ specific (thyroid gland)
- B cell mediated
Pathogenesis:
- Ab against TSH receptor on thyroid cells
- Ab stimulates the receptor
- Enhanced production of thyroid hormones
- Hyperthyroidism
NB Pituitary function inhibited due to the high levels of thyroid hormone, but there is still activation of the thyroid
Give and overview of thyroid function
- Pituitary gland releases TSH (Thyroid stimulating hormone)
- TSH induces thyroid hormone release from thyroid
- Thyroid hormones feedback negatively on pituitary to stop TSH release
- Thyroid hormones essential for regulation of metabolism
What is Myasthenia gravis?
Outline the general features
Describe the Pathogenesis
- Ab mediated
- Ab inhibits receptor function
Pathogenesis:
- Auto-Ab against AChR on motor end plate
- AChR internalised and degraded
- ACh released from lower motor neurons unable to bring about muscle contraction
What is SLE?
Outline the general features
Clinical features
(Systemic Lupus Erythematosis)
- B cell mediated
- Systemic
Clinical features: • Multiple body systems are involved • Circulating anti-DNA autoantibodies • Immune complex deposition in kidney → glomerulonephritis • Lupoid rash
Describe glomerulonephritis in SLE
- Immune complex deposition in basement membrane in glomeruli
- Activation of C’ cascade
- Leukocyte activation and inflammation in glomerulus
List examples of T cell mediated autoimmunity
- Insulin dependent diabetes mellitus (IDDM)
- Multiple sclerosis
- Coeliac disease
What is Type 1 insulin dependent diabetes mellitus?
Outline the general features
aka Juvenile onset diabetes
aka Type 1 diabetes
- Organ specific
- T cell mediated (CD4+ and CD8+)
Pathogenesis:
- Autoreactive T cells specific for islet proteins
- T cell mediated destruction of pancreatic β-islet cells
- Infiltration of lymphocytes into pancreatic islets
- Gradual loss of insulin secretion ( → insulin dependence)
Th1 cell involvement:
Production of:
1. Chemokines
• Macrophage recruitment into islets
- Cytokines
• IFN-γ: macrophage activation
• IL-3: monocyte production in BM stimulated
• GM-CSF: monocyte production in BM stimulated - Cytotoxins
• TNF-β: tissue destruction, inflammatory cell infiltrate
What is the genetic basis of IDDM?
(Insulin dependent diabetes mellitus)
Certain HLA molecules:
• HLA DR3-DQ2
• HLA DR4-DQ8
What happens to insulin production in IDDM?
Why?
Gradual loss of insulin production
Due to the progressive loss of insulin producing β-islet cells