L12: Autoimmunity

Question 1

What is autoimmunity? What mechanisms must be breached?

Answer 1

• Immune response against self antigens as a result of central and peripheral tolerance mechanisms being breached.

Question 2

What causes tissue damage in autoimmunity?

Answer 2

• Autoreactive CTLs
• Circulating autoantibodies
• Immune complexes

Question 3

Theories underlying autoimmunity

Answer 3

1. ) Inflammation and upregulation of co-stimulatory molecules by DCs leads to self-reactive T cells
2. ) Microbial protein homology with human proteins (molecular mimicry)
3. ) Inappropriate expression of MHC proteins (linked to other genes that make one susceptible?) – cells that don’t normally express MHC molecules may do so and activate T lymphocytes, also during T cell selection binding to elicit negative selection might not be strong enough

Question 4

HLA allele associated with ankylosing spondylitis

Answer 4

• B27

Question 5

Examples of organ-specific autoimmune diseases

Answer 5

1. ) autoimmune hemolytic anemia
2. ) Goodpasture’s syndrome
3. ) Pernicious anemia
4. ) Hashimoto’s thyroiditis
5. ) Idiopathic thrombocytopenia purpura (ITP)
6. ) Vitiligo
7. ) Grave’s disease
8. ) Myasthenia gravis
9. ) Type 1A diabetes
10. ) Multiple sclerosis

Question 6

What is autoimmune hemolytic anemia?

Answer 6

• RBC abs produced against RBC membrane proteins leads to
  a. ) intravascular hemolysis via cell lysis in bloodstream – anemia
  b. ) extravascular hemolysis in spleen by phagocytosis via opsonization

Question 7

What is Goodpasture’s syndrome?

Answer 7

• Autoabs to type IV collagen in BM of alveoli and kidney leads to complement activation and therefore kidney damage, pulmonary hemorrhage and death within a few months (~ 2 months)

Question 8

What is pernicious anemia?

Answer 8

• Autoabs to intrinsic factor / or gastric parietal cells producing intrinsic factor leading to decreased absorption of vit B12 and therefore abnormal erythropoiesis and anemia

Question 9

What is Hashimoto’s thyroiditis?

Answer 9

• Autoabs and autoreactive T cells to thyroid gland proteins leading to hypothyroidism

Question 10

What is ITP?

Answer 10

• Idiopathic thrombocytopenia purpura is a disease characterized by autoabs to platelets resulting in destruction. Leads to purple skin lesions as a result of epidermal hemorrhage (purpura).

Question 11

What is vitiligo?

Answer 11

• Autoimmune dz whereby skin is depigmented by destruction of melanocytes

Question 12

What is Grave’s disease?

Answer 12

• Autoantibodies against TSH leads to hyperthyroidism and increased production of T3/4

Question 13

What is myasthenia gravis?

Answer 13

• Autoabs to chain of nicotinic ACh receptor on skeletal muscle at NMJ. Blockage of NM transmission occurs leading to weakness and paralysis

Question 14

True / False. Type 1A diabetes is characterized as a state of glucose intolerance and hyperglycemia through immune-mediated destruction of insulin-secreting beta cells in pancreas. This occurs through humoral-mediated destruction.

Answer 14

• False. Autoreactive T cells mediate destruction of beta cells

Question 15

What is MS?

Answer 15

• MS is an autoimmune demyelinating disease of CNS. TH1 and TH17 cells specific for myelin antigens become activated, which drives macrophage activation and subsequent damage to myelin-containing nerve cells.

Question 16

Examples of systemic autoimmune disease

Answer 16

1. ) SLE
2. ) RA
3. ) Sjögrens syndrome
4. ) Scleroderma (progressive systemic sclerosis)
5. ) Polymyositis-dermatomyositis

Question 17

What is SLE? What is the principal concern/danger in this disease?

Answer 17

• Multisystem disease mediated by autoantibodies (most via complexes). There is broad loss of regulatory control of self-tolerance. Autoantibodies produced against DNA, RNA, proteins and ribonucleotides. Organ systems affected include: skin, joints, kidney. Higher frequency in females
• Danger = kidney failure d/t passage of complexes through glomerulus and deposition on renal podocytes, which express CR1 that binds C3b and C4b on complexes

Question 18

What predisposes individuals to SLE?

Answer 18

• Genetic factors
• Drug-induced lupus
• B cell hyperactivity, T-cell activity increased and decrease in T reg activity

Question 19

What is RA?

Answer 19

• Progressive inflammatory disease of joints that destroys joint cartilage, leads to inflammation of synovium. Systemic involvement with pulmonary, cardiac and ocular manifestations
• Possibility of synovium being previously infected with viral infection. TH1/17, macrophages and B cells/plasma create inflammatory environment
• Also, some pts have rheumatoid factor, which is a susbstance that binds IgM/G to Fc portion of IgG leading to complex formation. TNF-alpha plays role in disease process

Question 20

Treatment of RA?

Answer 20

• Drugs to sponge up TNF-alpha
  a. ) etanercept: TNF-alpha type II receptor fused to IgG antibody
  b. ) infliximab: chimeric anti-TNF-alpha ab
  c. ) adalimubab: IgG monoclonal

Question 21

What is Sjögren’s syndrome?

Answer 21

• Autoimmune destruction of lacrimal and salivary glands (leads to dry eye and mouth). B and T cells influx into glands, but unknown whether it is cell or humoral mediated. Can occur with RA or SLE, mostly in females.

Question 22

What is scleroderma (progressive systemic sclerosis)?

Answer 22

• Disease that leads to excessive deposition of collagen in skin, kidneys, GI, heart, muscle lungs. Antinuclear abs found in 80% of cases without known roles. T cells infiltrate dermis and may have a hypersensitivity to collagen resulting in IL-1 and TNF-alpha and vicious cycle ensues

Question 23

What is polymyositis-dermatomyositis?

Answer 23

• Muscle injury brought about by CD4+ and CD8+ T lymphocytes infiltrates. Skin rash often accompanies this disease. Antibodies seen against tRNA synthetase in 25% of cases. Coxsackie B viruses could play role

Question 24

Treatment options for autoimmune disease?

Answer 24

1. ) Cortisol: anti-inflammatory effects
2. ) Azathioprine and cyclophsophamide: cytotoxic drugs that inferefere with DNA synthesis, therefore eliminating dividing lymphocytes – damage = bone marrow suppression and damage to intestinal epithelium
3. ) Cyclosporine and tracolimus: block calcineurin, blocks transcription of IL-2 (nephrotoxicity of drugs however)
4. ) Plasmapharesis: remove ab-ag complexes (short term alleviation)
5. ) Antagonists of TNF-alpha can relive symptoms of some diseases: infliximab (anti-TNF-alpha mab), etanercept (soluble TNF-alpha receptor protein), adalimubab (IgG mab to TNF-alpha)

Question 25

A 23-year old woman with a history of double vision, difficulty swallowing and weakness in her upper arms had an uneventful pregnancy and delivered a 6 lb. infant. The newborn appeared limp and had difficulty breathing. The baby was placed on a ventilator and was fed through a nasogastric tube. A blood test confirmed the suspected etiology of the infant’s condition. Within three weeks all symptoms subsided and the baby was sent home. Your diagnosis would be transient neonatal
1.botulism.
2.Grave’s disease.
3.myasthenia gravis.
4.pernicious anemia.
5.systemic lupus erythematosus.
Why was significant improvement seen in the infant’s condition after several weeks?
If the infant was given edrophonium, what result would you expect? Would this treatment distinguish between congenital and transient form of disease?

Answer 25

• 3. Myasthenia gravis (etiology: mother’s anti-ACh receptor IgG crossed placenta, confirmatory test = IgG antibodies)
• IgG antibodies catabolized (half life = ~ 21 days)
• Edrophonium is an acetylcholinesterase inhibitor, substantial improvement expected as it prolongs presence of ACh in synaptic cleft (sets up competitive inhibition situation). Would not distinguish bw congenital or transient form of disease.