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125 Cards in this Set

  • Front
  • Back
Autoimmunity leads to what?
Serious chronic and acute diseases.
What is "horror autotoxicus"?
It is the original name for autoimmune diseases coined by Paul Erlich.
What does autoimmunity result from?
Results from failure of host's humoral and cell-mediated immune system to distinguish self from non-self.
What is tolerance?
The mxms that exist to protect us from self-reactive lymphocytes. A state of responsiveness to an Ag either internal or external. It is very specific to a particular Ag.
What is a tolerogen?
Ags that induce tolerance. The same chemical compound can be both an immunogen and a tolerogen depending on how it is presented to the immune system.
In the establishment and maintenance of tolerance mechanisms of tolerance ?.
What results in anergy?
This is involved in the est. and maintenance of tolerance. When an Ag presented to T-cells without appropriate costimulation results in anergy. For ex. no B7, CD28, etc)
When presented with good costimulation the same Ag can become a ? ?.
Can become a potent immunogen.
What are the two types of tolerance?
1. Central tolerance

2. Peripheral tolerance (Back-up mxm)
What does central tolerance delete?
T or B-cell clones before they are allowed to mature if they possess receptors that recognize self-Ags with greater than a low threshold affinity. Negative selection results in apoptosis.
In central tolerance negative selection results in what?
Where does central tolerance occur?
In the primary lymphoid organs, bond marrow or thymus.
Central tolerance is not a ? process. Explain?
It is not a foolproof process. Some self-reactive lymphocytes find their way into the secondary lymphoid tissues.
What does peripheral tolerance provide?
Back-up for lymphocytes that 'escape' central tolerance.
What does peripheral tolerance render lymphocytes?
It renders lymphocytes in secondary lymphoid tissues inactive or anergic.
Define anergic?
Unresponsive to antigen
What can peripheral tolerance be induced by?
Treg cells. A unique subset of CD4+. Express high levels of IL-2R-alpha chain (CD25)
In peripheral tolerance if you are lacking Fas or Fasl what might happen?
Cells may not be killed because these are a part of apoptosis.
Where are Treg cells generated from?
Treg cells are generated from thymocytes during negative selection.
Which thymocytes are deleted? Which are selected and released?
Thymocytes with high affinity for self Ags are deleted (apoptosis). Thymocytes with low affinity are positively selected and released.
What happens to thymocytes with intermediate affinity for Ags?
Thymocytes with intermediate affinity for Ags up-regulate Foxp3 to become Treg cells.
What is Foxp3?
A transcription factor.
If central and peripheral tolerance were always perfect what would happen?
If perfect nobody would have autoimmune disease.
In spite of central and peripheral tolerance what might 'escape'?
In spite of central and peripheral tolerance some self-reactive lymphocytes 'escape' surveillance.
What can autoimmune diseases cause?
Serious damage to cells and organs and can sometimes be fatal.
What causes the damage in autoimmune disease?
1. Abs (recognize self)

2. T-cells (go after self)
What is ALPS?
'Autoimmune Lymph Proliferative Syndrome'. It is an autoimmune disease that results in multiple organ failure. This is because of a failure to tolerance.
What is APECED?
It is a polyendocrine disorder. It is an autoimmune disorder. It results in total organ failure. Involves problems in ectodermal candidas.
List 12 organ-specific autoimmune diseases?
1. Addison's disease

2. Autoimmune hemolytic anemia

3. Goodpasteur's syndrome

4. Hashimoto's thyroiditis

5. Idiopathic thrombocyopenia purpura

6. Insulin-dependent diabetes mellitus

7. Myasthenia gravis

8. Myocardial infarction

9. Pernicious anemia

10. Poststreptococcal glomerulonephritis

11. Spontaneous infertility

12. Grave's syndrome
What is the self-ag involved in Addison's disease? What is the immune response?
Self Antigen = Adrenal cells

Immune response = Auto-antibodies
What is the self-ag involved in autoimmune hemolytic anemia? What is the immune response?
Self Antigen = RBC membrane proteins

Immune response = Auto-antibodies
What is the self-ag involved in Goodpasture's syndrome? What is the immune response?
Self-antigen = Renal and lung basement membranes

Immune response = Auto-antibodies
What is the self-ag involved in Grave's disease? What is the immune response?
Self-Antigen = Thyroid-stimulating hormone receptor

Immune response = Auto-antibody (stimulating)
What is the self-ag involved in Hashimoto's thyroiditis? What is the immune response?
Self-antigen = Thyroid proteins and cells

Immune response = Th1 cells, auto-antibodies
What is the self-ag involved in Idiopathic thrombocytopenia purpura? What is the immune response?
Self-antigen = Platelet membrane proteins

Immune response = Auto-antibodies
What is the self-ag involved in insulin-dependent diabetes mellitus? What is the immune response?
Self antigen = Pancreatic B-cells

Immune response = Th1 cells, auto-antibodies
What is the self-ag involved in myasthenia gravis? What is the immune response?
Self-antigen = acetylcholine

Immune response = Auto-antibody (blocking)
What is the self-ag involved in myocardial infarction? What is the immune response?
Self-antigen = heart

Immune response = Auto-antibodies
What is the self-ag involved in pernicious anemia? What is the immune response?
Self-antigen = gastric parietal cells; intrinsic factor

Immune response = autoantibody
What is the self-ag involved in poststreptococcal glomerulonephritis? What is the immune response?
Self-antigen = kidney

Immune response = antigen-antibody complexes
What is the self-ag involved in spontaneous infertility? What is the immune response?
Self ag = sperm

Immune response = auto-antibodies
List 6 systemic autoimmune diseases?
1. Ankylosing spondylitis

2. Multiple sclerosis

3. Rheumatoid arthritis

4. Scleroderma

5. Sjorgen's syndrome

6. Systemic lupus erythematous (SLE)
What is the self-ag involved in vertebrae? What is the immune response?
Self Ag = vertebrae

Immune response = Immune complexes
What is the self-ag involved in multiple sclerosis? What is the immune response?
Self-antigen = brain or white matter

Immune response = Th1 cells and Tc cells, auto-antibodies
What is the self-ag involved in rheumatoid arthritis? What is the immune response?
Self Ag = connective tissues, IgG

Immune response = Auto-antibodies, immune complexes
What is the self-ag involved in scleroderma? What is the immune response?
Self antigen = nuclei, heart, lungs, gi tract, kidney

Immune response = autoantibodies
What is the self-ag involved in Sjogren syndrome? What is the immune response?
Self Ag = Salivary gland, liver, kidney, thyroid

Immune response = autoantibodies
What is the self-ag involved in systemic lupus erythematous (SLE)? What is the immune response?
Self Ag = DNA, nuclear protein, RBC and pltlt membranes

Immune response = auto-antibodies, immune complexes
List 5 factors promoting tolerance? How were these discovered?
1. High doses of Ag

2. Persistence of Ag in the host

3. IV or PO induction

4. Absence of adjuvants

5. Low levels of costimulators

(Evidence from animal studies)
Some autoimmune diseases are mediated by ? ? damage.
Some autoimmune diseases are mediated by direct cellular damage.
When are autoimmune disease mediated by direct cellular damage?
Occurs when lymphocytes or Abs bind to cell membrane Ags. Observed cell lysis and/or inflammation. Observe replacement of healthy tissue with fibroid tissue which results in declining organ function.
Hashimoto's thyroiditis is a form of what?
In what population is Hashimoto's Thyroiditis frequently seen?
Most frequently occurs in middle-aged women. Some of the symptoms are also associated with menopause so this disease may be overlooked. (symptoms: cold, hair thinning, tired, weight gain, anemic)
What is produced during Hashimoto's disease?
Production of auto-abs and sensitized Th1 cells specific for thyroid Ags. Abs form to thyroglobulin and thyroid peroxidase (which both bring in iodine).
What kind of response is seen in Hashimoto's thyroiditis and how is it characterized?
DTH (type IV) response characterized by infiltration of thyroid by lymphocytes, macrophages and plasma cells which form lymphocytic follicles and germinal centers.
The inflammatory response during Hashimoto's thyroiditis causes what?
It causes a goiter (swelling) and decreased hormone production.
Is Hashimoto's syndrome treatable? How?
It is highly treatable by giveng Synthroid.
List 3 autoimmune anemias?
1. Pernicious anemia

2. Autoimmune hemolytic anemia

3. Drug-induced hemolytic anemia
What characterizes pernicious anemia?
Low B12. Auto-abs to intrinsic factor (which is necessary for the absorption of B12).
What characterizes autoimmune hemolytic anemia?
Auto-Ab to RBC Ags triggers complement mediated lysis or Ab-mediated opsonization.
What characterizes Drug-induced hemolytic anemia?
Includes such examples as penicillin or methyldopa interacts with reacting with RBCs making them antigenic (so immune system thinks RBCs are foriegn)(so penicillin or methyldopa induced).
What test is involved in the detection of drug-induced hemolytic anemia?
Coombs test for IgG autoantibodies.
Which gender tends to be inflicted by Goodpasteur's syndrom?
One of the few that effects both men and women.
What autoantibodies are observed in Goodpasteur's syndrome?
Auto-abs for certain basement membrane Ags of kidney glomeruli and lung alveoli. Glomeruli is important for filtration and regulation of blood pressure. This results in protein in urine and increased blood pressure.
What does Goodpasteur's syndrome leads to?
Goodpasteur's syndrome leads to complement activation and cell damage from inflammation. This results in progressive kidney damage and pulmonary hemorrhage.
What is observed in an autopsy of a victim of Goodpasteur's syndrome?
IgG and C3b noted along basement membranes.
Insulin dependent diabetes mellitus is which type?
Type I
Type I diabetes affects what percentage of the population?
Insulin dependent diabetes mellitus affects 0.2% of population.
Type I diabetes involves what kind of 'attack'?
Attack of insulin-secreting beta-cells of pancreas.
Describe the attack of insulin-secreting beta-cells of pancreas in type I diabetes.
1. Activated CTLs migrate into islet and activate macrophages causing insulinitis

2. Production of INF-gamma and alpha, and IL-1

3. DTH response
In type I diabetes there is an overwhelming what observed?
An overwhelming inflammation of pancreatic islets.
Some autoimmune diseases result from ? or ? auto-abs?
From stimulated or blocked auto-abs.
What do Abs do in autoimmune diseases when they act like Agonists?
They bind to hormone receptors and stimulate inappropriate activity.
What do auto-abs do when they act like antagonists in autoimmune diseases?
They bind to hormone receptors so the natural ligand can't bind.
In Grave's Disease what autoantibodies are observed?
Autoantibodies against the TSH receptor on thyroid cells. TSH (thyroid stim hormone) is secreted by the pituitary adn tells the pit. to make T3 or T4.
The autoantibodies produced in grave's disease mimic the function of ? but are not subject to what?
Mimics function of TSH but not subject to negative feedback control so there will be unregulated overproduction of thyroid hormones.
What are LATS?
Long-Acting thyroid stimulating abs. They are autoantibodies that physicians observe in Grave's disease.
What are the symptom's of Grave's disease?
Eat and don't gain wt, diarrhea, tremors, exopthalmus (bulging eyes that do not respond to tx)
How do you tx Grave's disease?
Take the thyroid out and then treat the resulting hypothyroidism which is very treatable with Synthroid.
What are two symptoms of Myasthenia Gravis?
Difficulty swallowing and motor coordination.
In Myasthenia Gravis there is a production of autoantibodies against what?
Autoantibodies against the acetylcholine receptor on motor end plates of muscles. This blocks the binding of ACh and induces complement mediated lysis of cells leading to progressive muscle weakness. The disease is manageable.
Systemic autoimmune diseases are characterized by what?
Characterized by a broad range of target Ags.
Systemic autoimmune diseases involves a number of what?
Involves a number of organs and tissues. Widespread tissue damage.
Systemic autoimmune disease represents what kind of defect?
Represents a general defect in immune regulation.
Systemic autoimmune disease results in what?
It results in hyperactive T and B-cells.
What is SLE?
Systemic Lupus Erythematous.
Who does SLE tend to affect?
SLE affects mostly women between ages of 20-40. It is more frequent in African American and Hispanics. Ratio of women to men is 10:1.
What is SLE characterized by?
Fever, weakness, arthritis, skin rashes, pleurisy, and kidney dysfunction.
What autoantibodies are present in SLE? These are involved in ? ? lysis.
Autoantibodies to DNA, histones, RBCs, and platelets. These are involved in complement mediated lysis (C3a and C5a). Hemolytic anemia and thrombocytopenia.
What do lab diagnoses of SLE focus on?
Antinuclear Abs.
What type of hypersensitivity can develop in SLE? What is observed>
Type III hypersensitivity can develop. Vasculitis and glomerulonephritis. This causes the physical damage which includes inflamed blood vessels and inflamed kidneys.
Why might autoimmune disease be more associated with women then men?
Because women have the 'ultimate tissue graft'--pregnancy.
Multiple sclerosis (MS)symptoms range from ? to ?.
Multiple sclerosis symptoms range from mild to severe.
When is it common for those with multiple sclerosis to be diagnosed? Where is it most common?
Around age 20-40. Most common in the Northern hemisphere (north of the 37th parallel)(so maybe there is an environmental component)
In MS the production of autoreactive T-cells causes what?
Causes inflammatory lesions along myelin.
In multiple sclerosis what does the CSF contain?
Activated T-cells which infiltrate the brain and destroy myelin.
In rheuatoid arthritis there is severe deformation of what?
Bones and joints.
Who does rheumatoid arthritis primariliy affect?
Women ages 40-60.
Rheumatoid arthritis is characterized by chronic ? ?.
By chronic joint inflammation.
What rheumatoid factors are produced in pts with rheumatoid arthritis? What do these factors activate?
IgM/IgG complexes that activate complement cascade causing a Type III hypersensitivity.
What are the two types of animal models of autoimmunity?
1. Spontaneous

2. Induced
What are some of the components of spontaneous animal models of autoimmunity?
They share important clinical and pathophysiology aspects with human disease.

ex. NZB = Lupus

ex. NOD = Diabetes
What are some components of induced animal models of autoimmunity?
Experimentally acquired.

ex. EAE = model for encephalitis

ex. EAT = thyroiditis
In the experimental animal models diseases are transferred by ?.
T cells
? underly autoimmunity.
Each animal model indicates what as the primary mediator?
What has been acquired from all the animal models?
Autoimmune T-cell clones
In autoimmunity what balance affects outcomes?
Th1/Th2 balance
Autoimmunity is likely not the result of ? ? ?.
Autoimmunity is likely not the result of one single event.
Autoimmunity susceptibility differs between ?.
Differs between sexes.
What is MBP?
Myelin Basic Protein. It is a protein NORMALLY sequestered from immune system by the BBB. (but when protein is unsequestered you become prone to attack)
In the EAE animal model (encephalitis model) what are the animals injected with?
The animals are injected directly with MBP + adjuvent.
What can release sequestered Ag into circulation?
Trauma to tissues (accident) or viral/bacterial infection can release sequestered Ag into circulation.
Molecular ? can contribute to autoimmunity.
Molecular mimicry can contribute to autoimmunity. (very rare)
With molecular mimicry what may a pathogen express?
A pathogen may express a protein epitope that resembles a particular self-component.
List some conditions associated with molecular mimicry.
1. Post-rabies encephalitis

2. MPB and viral peptides

3. Herpes stromal keratinitis (HSK)
What is the goal in the treatment of autoimmune diseases?
To reduce the autoimmune response and leave the rest of the immune system intact. (not very successful at txing this goal)
Describe the current therapies for autoimmune diseases?
Palliatives (tx symptoms not cures); so goal is not attained. Includes:

1. immunosuppresive drugs

2. removal of thymus

3. biologics (these are fairly new and hard to develop)
Targeting inflammation has several ?.
Targeting inflammation has several stages.
Describe how cytokine release in inflammation may be targeted?
1. Often injectables with several side effects (ie, lymphoma).

2. TNF-alpha inhibition (Enbrel, Remicade, Humira)

3. IL-1R antagonism for rheumatoid arthritis

4. Anti-IL6 and Anti-IL-15 Abs for RA
Recruitment of leukocytes involves what?
Why would statins be used to tx autoimmune diseases?
They are normally used for hyperlipidemia but Dr.s noticed they seemed to also help autoimmune diseases.
Name a drug involved with monoclonal antibodies?
What are the goals when targeting activated T-cells?
1. Blockade of Ag-activated Th cells only

2. Monoclonal Ab against alpha subunit of high affinity IL-2R (expressed only by Ag-activated Th cells)
What do oral Ags induce? Where was this seen?
Tolerance (for some unknown reason). This was seen in animal models. For example, mice fed MBP (myelin base protein) fail to develop EAE (multiple sclerosis). Human studies are not as convincing. equivalent)