17. Autoimmune Diseases Flashcards
(40 cards)
1
Q
Autoimmune Hemolytic Anemia
A
Characterized by destruction of RBCs caused by IgG and IgM Abs directed at Ag on RBCs
2
Q
Pernicious Anemia
A
Self Abs to “intrinsic factor”, which facilitates vitamin B12 uptake; Ab blocks absorption of B12 which negatively affects hematopoiesis reducing production of RBCs
3
Q
What disease affects ~21000 children in the US?
A
Type 1 Diabetes Mellitus
4
Q
What causes Type 1 Diabetes Mellitus?
A
autoimmune attack against insulin-producing beta cells in the pancreas
5
Q
What are the key mediators of Type 1 Diabetes Mellitus?
A
Th1 cells and auto-Abs
6
Q
What are the symptoms of Grave’s Disease?
A
weight loss, heat intolerance, “bug eyes”, goiter, anxiety, irritability, sweating, insomnia, irregular heartbeat
7
Q
What are the 3 steps of Type I Diabetes Mellitus?
A
- Th1 cells infiltrate the pancreas to activate macrophages
- cytokine release and production of autoantibodies, which can activate complement and ADCC activities by NK cells
- Eventual DTH response releases destructive enzymes
8
Q
What causes Insulin-Dependent Diabetes Mellitus?
A
Loss of insulin leading to uncontrolled blood glucose levels (diabetic)
9
Q
Insulin-Dependent Diabetes Mellitus symptoms include:
A
ketosis, increased urine production (early) and coma, death, blindness, kidney failure, gangrene, impeded vascular flow (late)
10
Q
What causes Grave’s Disease?
A
Abs that react with muscles of the eye – reason unknown
11
Q
Grave’s Disease affects what percent of the population?
A
0.5 % population
12
Q
Disease in which signaling from nerve to muscle across neuromuscular junction is impaired.
A
Myasthenia Gravis
13
Q
Early signs of Myasthenia Gravis include:
A
Drooping eyelids, double vision, difficulty swallowing, progressive weakening of muscles, chest muscle failure → difficulty breathing, respiratory infections
14
Q
Explain Myasthenia Gravis in 4 steps.
A
- Abs to acetylcholine receptors – blocks ligand binding – muscle cells can’t contract
- Receptors are also receptor mediated endocytosis
- Also get complement mediated lysis of cells – so definitely a type II
- Acetylcholine (neurotransmitter) binding activates activates G protein opening K+ channel (leading to Na+ Influx) leading to muscle contraction
15
Q
What are the treatments for Myasthenia Gravis?
A
corticosteroids, cholinerase inhibitors to prolong Acetylcholine – not very good therapies
16
Q
Systemic Lupus Erythematosus (SLE) symptoms include:
A
butterfly rash, fever, weakness, arthritis (first symptom), pleurisy, kidney dysfunction
17
Q
Lupus (Description)
A
- 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
18
Q
Lupus (Diagnosis)
A
- 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)
19
Q
IgG Autoantibodies
A
- DNA
- Histones → Immune complexes → vasculitis, arthritis, glomerulonephritis
- RNA
- Nuclear proteins
- Ribosomes
- RBCs → hemolytic anemia
- Platelets→ thrombocytopenia (low platelet count)
- Clotting factors
20
Q
Double Stranded DNA as Ag
A
- 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)
21
Q
Multiple Sclerosis (MS) – inflammatory disease of central nervous system
A
- 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)
22
Q
How do T cells cross the blood brain barrier? (a possible scenario)
A
- 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
23
Q
Rheumatoid Arthritis (RA)
A
- 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
24
Q
Environmental factors favoring the development of autoimmune disease include:
A
o Diet differences may lead to gut microflora differences
o Different geographic areas may have different endemic diseases
25
The Roles of Genes in susceptibility to Autoimmunity
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)
26
TCR restriction suggests that...
a single epitope might induce the clonal expansion of a small number of pathogenic T cells
27
In MS, observe that particular TCR are preferentially expressed. This is called _____________.
TCR restriction
28
Example of Release of Sequestered Ag
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
29
Molecular Mimicry for Induction of Autoimmunity
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
30
Inappropriate Expression of MHC II Molecules as Mechanism for Autoimmunity
* 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)
31
Autoimmunity: Treatment Approaches
* 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
32
Strategies that target specific cell types
* 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
33
Therapies that block steps in the inflammatory process
* 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
34
Name four types of autoimmune treatments:
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
35
Strategies that interfere with co-stimulation
* 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
36
Glatiramer acetate has been used to treat ________.
MS (multiple sclerosis)
37
What is the only FDA approved antigen specific treatment currently available for autoimmune disease?
glatiramer
38
Ag specific immunotherapy
* 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
39
Why are women more susceptible to autoimmunity?
* ~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)
40
Example: T Cells obtained from EAE mice (MS model) tend to have a Th1 bias
* 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
