Section 4: Tissue and Organ specific autoimmunity Flashcards
What are the three most common autoimmune diseases that affect the endocrine system?
- Graves disease (hyperthyroidism)
- Hashimoto’s thyroiditis (hypothyroidism)
- Type I diabetes (pancreases)
-generally an autoimmune response to a secretory gland results in a decrease of function and hormone production (exception is graves’ disease)
Graves disease epidemiology
-1,259 of every 100,000 people in the US
-4 to 5 times more prevalent in women than men
-symptoms commonly occur in middle age 30-40
Graves disease: key symptoms
-weight loss
-enlarged thyroid
-anxiety, nervousness, irritability
-heat intolerance
-exophthalmos- bulging of the eye
Graves disease pathogenicity
-autoantibodies to the thyroid stimulating hormone (TSH) receptor results in hyperthyroidism
-autoimmune response is biased to a CD4 TH2 response
-HLA-DR3 linked to genetic risk
-antibody stimulation of the TSH receptor results in chronic overproduction of thyroid hormones that are uncontrolled by TSH and insensitive to metabolic needs
Graves disease treatment
controlling of: blood pressure, elevated heart rate, thyroid hormone production (drug suppression)
-definitive therapy, surgical resection or radioablation with 131 iodine followed by hormone replacement
-30% resolve spontaneously within 2 years of diagnosis
Graves disease: diagnostic testing
TSH and thyroid hormone levels
-TSH decreased
-Thyroid hormones increased
Antibodies
-antithyroglobulin
-thyroperoxidase
Graves disease and pregnancy
-temporary symptoms of antibody-mediated autoimmune diseases can be passed down from affected mother to their newborn babies
1. mother with graves disease makes anti-TSHR antibodies
2. during pregnancy the antibodies cross the placenta into the fetus
3. newborn infant also suffers from graves disease
4. plasmapheresis removes maternal anti-TSHR antibodies and cures the infant disease
Hashimoto’s disease (chronic thyroiditis) Epidemiology
-1,324 out of 100,000 people in the US
- 4-5 times more common in women
- symptoms can be present in children and adults
Hashimoto’s disease: key symptoms
-goiter or enlarged thyroid gland
-low energy levels
-weight gain
-cold intolerance
Hashimoto’s disease pathogenesis
CD4 Th1 response
-antibodies and effector T cells (CD8) specific for thyroid antigens
-lymphocyte infiltration of thyroid progressive destruction of the thyroid tissue
-these lymphocytes organize into structures that atomically resemble the microstructure of secondary lymphoid organs
-contain T and B cell areas, dendritic cells, follicular DC and macrophages (ectopic lymphoid tissues)
ectopic lymphoid tissues
-are not encapsulated
-lack lymphatics
-exposed to inflammatory environment plus all the other functions characteristics of secondary lymphoid tissues (Ag stimulation, somatic hypermutation, isotype switching
Hashimoto’s disease treatment
-hormone replacement therapy (synthetic- thyroxine)
Hashimoto’s disease: diagnostic testing
TSH and thyroid hormone levels
-TSH increased
-Thyroid hormone decreased
Positive thyroid antibodies
myasthenia gravis epidemiology
-20 out of 100,000 people in the US (RARE)
-equal prevalence between males and females
-symptoms can occur acutely or over a long period of time
Myasthenia gravis: key symptoms
-progressive muscle weakening
-early symptoms: droopy eyelids and double vision
-late symptoms: worsening facial and chest muscle weakness (impaired breathing)
myasthenia gravis pathogenicity
gravis (severe)- myo (muscle)- asthenia (weakness)
-signaling across the nerve-muscle junction is impaired
-autoantibodies are produced that bind to acetylcholine receptors on muscle cells (induces endocytosis and intracellular degradation)
-the loss of cell-surface acetylcholine receptors makes muscle less sensitive to neuronal stimulation
myasthenia gravis- treatment
pyridostigmine- an inhibitor of the enzyme cholinesterase, increases levels of acetylcholine
azathioprine (glucocorticoid) - immunosuppressive
myasthenia gravis: diagnostic testing
-radioimmunoassay for the anti-acetylcholine receptor antibody or semiquantitative flow cytometry
-85% positive for AChR Ab (binding, blocking, modulating, versions of Ab)
multiple sclerosis (MS) epidemiology
the prevalence varies by geographical area
-highest in the western hemisphere
-lowest in equatorial regions
-0.8-150 out of 100,000 depending on the location
-more common in women ages 30-40 years
-often associated with the presence of other autoimmune diseases (autoimmune thyroid disease and inflammatory bowel disease)
multiple sclerosis (MS): etiology
unknown
MS pathogenesis
-autoimmune response against the myelin sheath of nerve cells resulting in sclerotic plaques of demyelinated tissue in the white matter of the CNS
-Th1 CD4 cells and IFN-y implicated disease (enriched in CSF and blood)
-activated macrophages present in sclerotic plaques release proteases and cytokines that result in demyelination
-90% of MS patients have plasma cells in sclerotic plaques that secrete oligoclonal IgG into the CSF (myelin basic protein, proteolipid protein, and myelin oligodendrocyte glycoprotein)
Multiple Sclerosis: graph
- mice injected with myelin basic protein and complete Freund’s adjuvant develop EAE and are paralyzed
- the disease is mediated by myelin basic protein-specific Th1 and or Th17 cells
- disease can be transmitted by the transfer of T cells from the affected animal
- unknown trigger sets up the initial focus of inflammation in the brain and the blood-brain barrier becomes locally permeable to leukocytes and blood proteins
- T cells specific for CHS antigens and activated in peripheral lymphoid tissues reencounter antigens presented on microglia or dendritic cells in the brain.
- inflammatory reaction in brain due to mast-cell activation, complement activation, antibodies, and cytokines
- demyelination of neurons
5.
MS treatment
-subcutaneous injection with IFN-B1 reduced flare-ups and the appearance of sclerotic plaques
-high doses of immunosuppressive drugs
MS: diagnostic testing
-no lab test is usually needed (ex: autoantibodies) because clinical symptoms and MRI are sufficient
What are the three most common diseases in the US?
- Hashimoto’s thyroiditis
- Graves’ disease
- Rheumatoid arthritis
Graves’ disease: antigen
thyroid stimulating hormone receptor
Graves’ disease: antibody
agonist
Graves disease: consequence
hyperthyroidism
Myasthenia gravis: Antigen
acetylcholine receptor
Myasthenia gravis: antibody
antagonist
Myasthenia gravis: consequence
progressive muscle weakness
Insulin-resistant diabetes: antigen
insulin receptor
Insulin-resistant diabetes antibody
antagonist
Insulin-resistant diabetes: consequence
hyperglycemia, ketoacidosis
Hypoglycemia: antigen
insulin receptor
Hypoglycemia: antibody
agonist
Hypoglycemia: consequence
-hypoglycemia
