Section 4: Tissue and Organ specific autoimmunity

Question 1

What are the three most common autoimmune diseases that affect the endocrine system?

Answer 1

1. Graves disease (hyperthyroidism)
2. Hashimoto’s thyroiditis (hypothyroidism)
3. 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)

Question 2

Graves disease epidemiology

Answer 2

-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

Question 3

Graves disease: key symptoms

Answer 3

-weight loss
-enlarged thyroid
-anxiety, nervousness, irritability
-heat intolerance
-exophthalmos- bulging of the eye

Question 4

Graves disease pathogenicity

Answer 4

-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

Question 5

Graves disease treatment

Answer 5

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

Question 6

Graves disease: diagnostic testing

Answer 6

TSH and thyroid hormone levels
-TSH decreased
-Thyroid hormones increased

Antibodies
-antithyroglobulin
-thyroperoxidase

Question 7

Graves disease and pregnancy

Answer 7

-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

Question 8

Hashimoto’s disease (chronic thyroiditis) Epidemiology

Answer 8

-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

Question 9

Hashimoto’s disease: key symptoms

Answer 9

-goiter or enlarged thyroid gland
-low energy levels
-weight gain
-cold intolerance

Question 10

Hashimoto’s disease pathogenesis

Answer 10

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)

Question 11

ectopic lymphoid tissues

Answer 11

-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

Question 12

Hashimoto’s disease treatment

Answer 12

-hormone replacement therapy (synthetic- thyroxine)

Question 13

Hashimoto’s disease: diagnostic testing

Answer 13

TSH and thyroid hormone levels
-TSH increased
-Thyroid hormone decreased
Positive thyroid antibodies

Question 14

myasthenia gravis epidemiology

Answer 14

-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

Question 15

Myasthenia gravis: key symptoms

Answer 15

-progressive muscle weakening
-early symptoms: droopy eyelids and double vision
-late symptoms: worsening facial and chest muscle weakness (impaired breathing)

Question 16

myasthenia gravis pathogenicity

Answer 16

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

Question 17

myasthenia gravis- treatment

Answer 17

pyridostigmine- an inhibitor of the enzyme cholinesterase, increases levels of acetylcholine
azathioprine (glucocorticoid) - immunosuppressive

Question 18

myasthenia gravis: diagnostic testing

Answer 18

-radioimmunoassay for the anti-acetylcholine receptor antibody or semiquantitative flow cytometry
-85% positive for AChR Ab (binding, blocking, modulating, versions of Ab)

Question 19

multiple sclerosis (MS) epidemiology

Answer 19

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)

Question 20

multiple sclerosis (MS): etiology

Answer 20

unknown

Question 21

MS pathogenesis

Answer 21

-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)

Question 22

Multiple Sclerosis: graph

Answer 22

1. mice injected with myelin basic protein and complete Freund’s adjuvant develop EAE and are paralyzed
2. the disease is mediated by myelin basic protein-specific Th1 and or Th17 cells
3. disease can be transmitted by the transfer of T cells from the affected animal
4. 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
5. T cells specific for CHS antigens and activated in peripheral lymphoid tissues reencounter antigens presented on microglia or dendritic cells in the brain.
6. inflammatory reaction in brain due to mast-cell activation, complement activation, antibodies, and cytokines
7. demyelination of neurons
   5.

Question 23

MS treatment

Answer 23

-subcutaneous injection with IFN-B1 reduced flare-ups and the appearance of sclerotic plaques
-high doses of immunosuppressive drugs

Question 24

MS: diagnostic testing

Answer 24

-no lab test is usually needed (ex: autoantibodies) because clinical symptoms and MRI are sufficient

Question 25

What are the three most common diseases in the US?

Answer 25

1. Hashimoto’s thyroiditis
2. Graves’ disease
3. Rheumatoid arthritis

Question 26

Graves’ disease: antigen

Answer 26

thyroid stimulating hormone receptor

Question 27

Graves’ disease: antibody

Answer 27

agonist

Question 28

Graves disease: consequence

Answer 28

hyperthyroidism

Question 29

Myasthenia gravis: Antigen

Answer 29

acetylcholine receptor

Question 30

Myasthenia gravis: antibody

Answer 30

antagonist

Question 31

Myasthenia gravis: consequence

Answer 31

progressive muscle weakness

Question 32

Insulin-resistant diabetes: antigen

Answer 32

insulin receptor

Question 33

Insulin-resistant diabetes antibody

Answer 33

antagonist

Question 34

Insulin-resistant diabetes: consequence

Answer 34

hyperglycemia, ketoacidosis

Question 35

Hypoglycemia: antigen

Answer 35

insulin receptor

Question 36

Hypoglycemia: antibody

Answer 36

agonist

Question 37

Hypoglycemia: consequence

Answer 37

-hypoglycemia