17. Autoimmune Diseases

Question 1

Autoimmune Hemolytic Anemia

Answer 1

Characterized by destruction of RBCs caused by IgG and IgM Abs directed at Ag on RBCs

Question 2

Pernicious Anemia

Answer 2

Self Abs to “intrinsic factor”, which facilitates vitamin B12 uptake; Ab blocks absorption of B12 which negatively affects hematopoiesis reducing production of RBCs

Question 3

What disease affects ~21000 children in the US?

Answer 3

Type 1 Diabetes Mellitus

Question 4

What causes Type 1 Diabetes Mellitus?

Answer 4

autoimmune attack against insulin-producing beta cells in the pancreas

Question 5

What are the key mediators of Type 1 Diabetes Mellitus?

Answer 5

Th1 cells and auto-Abs

Question 6

What are the symptoms of Grave’s Disease?

Answer 6

weight loss, heat intolerance, “bug eyes”, goiter, anxiety, irritability, sweating, insomnia, irregular heartbeat

Question 7

What are the 3 steps of Type I Diabetes Mellitus?

Answer 7

1. Th1 cells infiltrate the pancreas to activate macrophages
2. cytokine release and production of autoantibodies, which can activate complement and ADCC activities by NK cells
3. Eventual DTH response releases destructive enzymes

Question 8

What causes Insulin-Dependent Diabetes Mellitus?

Answer 8

Loss of insulin leading to uncontrolled blood glucose levels (diabetic)

Question 9

Insulin-Dependent Diabetes Mellitus symptoms include:

Answer 9

ketosis, increased urine production (early) and coma, death, blindness, kidney failure, gangrene, impeded vascular flow (late)

Question 10

What causes Grave’s Disease?

Answer 10

Abs that react with muscles of the eye – reason unknown

Question 11

Grave’s Disease affects what percent of the population?

Answer 11

0.5 % population

Question 12

Disease in which signaling from nerve to muscle across neuromuscular junction is impaired.

Answer 12

Myasthenia Gravis

Question 13

Early signs of Myasthenia Gravis include:

Answer 13

Drooping eyelids, double vision, difficulty swallowing, progressive weakening of muscles, chest muscle failure → difficulty breathing, respiratory infections

Question 14

Explain Myasthenia Gravis in 4 steps.

Answer 14

1. Abs to acetylcholine receptors – blocks ligand binding – muscle cells can’t contract
2. Receptors are also receptor mediated endocytosis
3. Also get complement mediated lysis of cells – so definitely a type II
4. Acetylcholine (neurotransmitter) binding activates activates G protein opening K+ channel (leading to Na+ Influx) leading to muscle contraction

Question 15

What are the treatments for Myasthenia Gravis?

Answer 15

corticosteroids, cholinerase inhibitors to prolong Acetylcholine – not very good therapies

Question 16

Systemic Lupus Erythematosus (SLE) symptoms include:

Answer 16

butterfly rash, fever, weakness, arthritis (first symptom), pleurisy, kidney dysfunction

Question 17

Lupus (Description)

Answer 17

• More common in women (9:1 ratio)
• Symptom onset typically between 20–40 years
• More frequent in African American/Hispanic women than Caucasians
• Auto-Ab against DNA, histones, other self-molecules
• Symptoms result from specificity of Ab produced, and can include:
  o Fever, weakness, arthritis, skin rashes, and kidney dysfunction
  o Type III mechanism induces damage
• Relapsing – remitting disease
• Patients can ultimately die due to failure of vital organs – especially kidney failure

Question 18

Lupus (Diagnosis)

Answer 18

• Often difficult to diagnosis
• Average 7 years to diagnosis
• ANA clinical test (anti-nuclear Ab)
• Detects Ab to DNA, histones, nuclear envelop proteins, RNA polymerase, RNAs, etc.
• Sensitive test for SLE
• But specificity is low (also found in rheumatic diseases, viral infection, autoimmune liver disease, and at low titers in some healthy individuals)

Question 19

IgG Autoantibodies

Answer 19

• DNA
• Histones → Immune complexes → vasculitis, arthritis, glomerulonephritis
• RNA
• Nuclear proteins
• Ribosomes
• RBCs → hemolytic anemia
• Platelets→ thrombocytopenia (low platelet count)
• Clotting factors

Question 20

Double Stranded DNA as Ag

Answer 20

• Abs against dsDNA correlate with renal involvement – high specificity
• Small DNA-Ab immune complexes may become trapped in glomerular basement membrane of kidney through electrostatic interactions (DNA negatively charged, basement membrane positively charged)

Question 21

Multiple Sclerosis (MS) – inflammatory disease of central nervous system

Answer 21

• Auto-reactive T cells to myelin
• Myelin forms an insulating sheath around nerve fibers
• Activated Th1 cells infiltrate the brain
• Recruit Macs
• Inflammation destroys myelin
• Neurologic dysfunction
• Multiple scars form
• Scar location determines nerves are affected
• Relapsing remitting disease or chronic progressive
• Most common cause of neurologic disability in Western countries
• MS means multiple scars
• Can follow a steady course or relapsing remitting
• Resembles DTH response
• Affects more women than men (~3X)
• Usually diagnosed between 20-30 yr of age
• ~ 1 in 1000 chance of developing MS
• Increases to 1 in 50 if close relative has MS
• Suggests a genetic component
• MS more prevalent in Northern hemisphere
• Most prevalent in US
• 2X incidence if live north of 37th parallel
• A Southern person assumes this risk if moves above 37th parallel before 15 yrs of age
• Theories? Possible viral molecular mimicry
• Unknown environmental factor? This relates to theory called “molecular mimicry”
• Childhood virus exposure might be important (measles)
• Symptoms may be mild (numbness in limbs) to severe (spasticity, paralysis, loss of vision)

Question 22

How do T cells cross the blood brain barrier? (a possible scenario)

Answer 22

• Activated T cells express integrins allowing adhesion to vessels near brain
• Activated T cells make MMP (matrix metalloproteinase) which degrades collagen in basal lamina
• Breach of blood brain barrier
• Once T cells gain entry into the brain they are restimulated by Ag presented by microglial cells (APC)
• Chemokines recruit Macs and WBCs
• Exacerbations tend to follow viral infections

Question 23

Rheumatoid Arthritis (RA)

Answer 23

• Systemic disease
  o Often diagnosed between 40-60 years of age
  o More frequent in women 3X
  o Major symptom is chronic inflammation in joints
   Rheumatoid factors are oftn produced
• Auto Ab reacts to Fc region of IgG “rheumatoid factor”
• Form immune complexes and activate complement cascade (Type III mechanism)
  o Treatments include nonspecific anti-inflammatory drugs and corticosteroids
   More specific anti-cytokine antibodies are useful: Enbrel, Humera (anti-TNF Abs)
• Synovium normally just one cell thick
• Becomes so infiltrated with WBCs that mimics lymphoid tissue and forms new blood vessels
• DC, Macs, T, B, NK, and plasma cells
• Release TNF, IL-1, prostaglandins, and degradative enzymes that destroy cartilage
• After repeated bouts of inflammation:
• Cartilage is replaced by fibrous tissue
• Joint fuse (ankylosis)
• FYI: rheumatoid factor is marker for more aggressive disease, but not a common initiator since 30% of RA patients don’t have detectable levels

Question 24

Environmental factors favoring the development of autoimmune disease include:

Answer 24

o Diet differences may lead to gut microflora differences
o Different geographic areas may have different endemic diseases

Question 25

The Roles of Genes in susceptibility to Autoimmunity

Answer 25

o Certain MHC genes linked to specific autoimmune disorders
 HLA-B27 expression = 90 more likely to develop ankylosing spondylitis, an inflammatory disease of vertebral joints
 Mutations in aire and FoxP3 genes result in particular immunodeficiencies that affect central and peripheral tolerance
* Th1/Th2 balance plays important role in autoimmunity (at least in animal models)

Question 26

TCR restriction suggests that…

Answer 26

a single epitope might induce the clonal expansion of a small number of pathogenic T cells

Question 27

In MS, observe that particular TCR are preferentially expressed. This is called _____________.

Answer 27

TCR restriction

Question 28

Example of Release of Sequestered Ag

Answer 28

MBP (myelin basic protein) is normally sequestered from the immune system via the blood brain barrier; physical trauma, or a viral or bacterial infection may expose Ag to the immune system

Question 29

Molecular Mimicry for Induction of Autoimmunity

Answer 29

A viral or bacterial pathogen expresses a region of protein that resembles a particular self-protein; Abs made against pathogen can later react with self-protein

Question 30

Inappropriate Expression of MHC II Molecules as Mechanism for Autoimmunity

Answer 30

• Pancreatic beta cells in IDDM express high levels of Class I and Class II MHC
• Pancreatic beta cells in normal subjects express lower levels of Class I and Class II MHC
• Inappropriate MHC II expression may sensitize Th cells to peptides from beta cells
• Thyroid cells from individual’s with Grave’s disease also express MHC II
• Possible IFN-gamma produced by viral infection allows this to happen
• This could allow Th cell activation to occur with autoimmune consequences
• Acinar cells
• IFN may be the signal that causes this (from another inflammatory response)

Question 31

Autoimmunity: Treatment Approaches

Answer 31

• Corticosteroids – general immune suppressor
• A slightly more selective approach involves Cyclosporin A – blocks T cell activation
• Methotrexate – slows cell proliferation (also used a cancer therapeutic -kills rapidly dividing cells at high doses)
  o General toxicity is a negative side-effect
  o Also predisposes individuals to uncontrolled infections
  o Can promote development of cancer by removing anti-tumor T and NK cells
• Grave’s disease – remove/destroy thyroid and replace with synthetic thyroid hormones
• Hashimoto’s – synthetic thyroid hormones
• Other approaches – plasmapheresis to remove immune complexes

Question 32

Strategies that target specific cell types

Answer 32

• If the disease is caused by immune complexes, targeting B cells can be effective
  o Monoclonal Ab against CD20 used in RA cases
• T-cell targeting therapies are used more often because the cells are usually directly pathogenic or provide help to B cells
  o Early efforts targeting CD3 molecules proved ineffective, but other drugs targeting TCR signaling work well

Question 33

Therapies that block steps in the inflammatory process

Answer 33

• Drugs that block TNF-α are used to treat RA, psoriasis, and Crohn’s disease
• IL-1 receptor antagonist can be used against RA
• Compounds that block chemokine or adhesion molecule signals prevent movement of lymphocytes into areas of inflammation

Question 34

Name four types of autoimmune treatments:

Answer 34

1. strategies that targe specific cell types
2. therapies that block steps in the inflammatory process
3. strategies that interfere with co-stimulation
4. Ag specific immunotherapy

Question 35

Strategies that interfere with co-stimulation

Answer 35

• Formation of a fusion protein
  o Extracellular domain of CTLA-4 and human IgG1 constant region
   Abatacept (Orencia) approved for RA treatment
  o Binds to CD80/86
  o Blocks CD28-CD80/86 interactions

Question 36

Glatiramer acetate has been used to treat ________.

Answer 36

MS (multiple sclerosis)

Question 37

What is the only FDA approved antigen specific treatment currently available for autoimmune disease?

Answer 37

glatiramer

Question 38

Ag specific immunotherapy

Answer 38

• The holy grail―stimulate tolerance to the auto-Ag, restoring balance
• But what if you make the response worse instead of better?
• Glatiramer acetate has been used to treat MS
• Polymer of 4 basic amino acids found in MBP
• Selectively increases TREG cells
• Could make disease worse by introducing the toleragen

Question 39

Why are women more susceptible to autoimmunity?

Answer 39

• ~78% of people with autoimmune disease are women
• Sex hormones thought to have a role
• Lupus
  o More flares during pregnancy (high estrogen)
  o More remission after menopause (low estrogen) MS
• Androgens (male hormones) can suppress MS in rodent models
• Th1/Th2 balance
  o Female mice more likely to develop Th1 response
  o Females also tend to mount more vigorous immune responses in general
• During Pregnancy
  o Hormone balance changes
  o Critical that mother’s immune system tolerate the fetus, which is type of foreign semi-allograft
  o Women mount more of a Th2 response (less pro-inflammatory than Th1)
  o SLE can worsen
  o MS can go into remission
  o Fetal cells in the maternal circulation – state of microchimerism
  o Fetal cells can persist in the mother for decades!
  o Exchange of cells can be bidirectional (cells of mother can appear in fetal circulatory system)

Question 40

Example: T Cells obtained from EAE mice (MS model) tend to have a Th1 bias

Answer 40

• Transfer of these Th1 cells to a syngeneic healthy mouse transfers disease
• Injection of 1st mouse with myelin specific Th2 cells causes disease remission or protects from disease
• IL-4 administered same time as immunization with myelin/adjuvant INHIBITS EAE
• IL-12 administered same time as immunization with myelin/adjuvant PROMOTES EAE