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7 mechanisms of developing autoimmunity:
1.Th cells and MHC
2. Special TCR
3. IFN-y
4. Sequestered Antigen Release
5. Molecular Mimicry by Pathogens
6. Inappropriate Class 2 MHC expression
7. Polyclonal B-cell activation
What is requisite of Th cells and MHC in order for there to be an autoimmune response?
Both the TcR and MHC are capable of binding SELF proteins.

The APC chew up SELF, presents it to Thelper.
What makes the TCR special in an autoimmune response?
It recognized a SELF antigen; the only way it can do so is by BYPASSING negative selection in the thymus.
What does negative selection in the thymus do to TCR?
Selects Tcells that bind self-ag with self-MHC too strongly.

Makes them die by apoptosis.

This is failed in autoimmunity.
What are "Special" TcRs?
Tcell receptors that underwent normal random gene rearrangement; it turned out to be reactive to self antigen. After release into circulation, binds its antigen.
How does IFN-y contribute to autoimmunity?
IFN-y promotes the production/secretion of other cytokines that upregulate MHC1/2.

In Autoimmunity, this occurs on non-APC cells; they should not be presenting Ag.
How does inappropriate expression of MHC2 contribute to autoimmunity?
If non-APCs have MHC2, they can present self-antigens that otherwise would not be presented to Tcells.

Presentation sensitizes a Tcell population and results in self-reaction.
Why is improper activation of Th cells bad?
-They are the central secretors of cytokines that turn on the whole immune response.
What is an example of cells that have inappropriate MHC2 expression?
Beta-cells in the pancreas.
How does sequestered Ag release cause autoimmunity?
During T-cell matuation, the naieve cells are not exposed to sperm/brain cells.

If injury/surgery allows release of the sequestered antigens, they'll be seen as non-self.
How does molecular mimicry by pathogens cause autoimmunity?
Some bacteria resemble brain or cardiac cells.
Their epitope size/chemical structure resembles self-proteins.
This causes cross-linking and sensitizing of Tcells.
Why is polyclonal Bcell activation bad?
Polyclonal activation of Bcells is nonspecific and unregulated; the Bcells will express mainly IgM, and some can bind self proteins.
How does polyclonal Bcell activation cause autoimmunity?
DUring the activation/proliferation, some Bcells are activated that bind self-Ag.
What causes polyclonal Bcell activation in humans?
-Epstein-barr virus for mono
-SLE - lupus
What is Autoimmunity CAUSED BY?
the activation of self-reactive T and B cells.
What are the two types of autoimmunity?
-Organ specific

4 types of organ-specific autoimmunity:
Hashimoto's disease
Autoimmune anemias
Goodpasture's syndrome
Insulin dependent diabetes mellitus
in Hashimoto's Thyroiditis, what are:
-their effects
-the result
Th cells and antibody sensitized to thyroid-produced proteins.

Effect: DTH, inflammatory response, germinal centers, granulomas.

Result: Hyperthyroidism - not enough proteins put out
2 types of autoimmune anemias,

What happens?
Pernicious - Ab to intrinsic factor forms; can't take up Vitamin B12

Hemolytic - Ab forms to RBC surface antigens; activates complement and causes RBC lysis.
What happens in Goodpasture's Syndrome
Mediators: antibody to basement membrane cells in kidney and lung

Effect: activate complement, inflammatory response.

Result: renal failure and hemorrhage in lungs.
What happens in IDDM?
Antibodies form to Beta-cells of the pancreas - these cells produce insulin.

-Cytokine TH1 subset release; DTH, inflammation, complement, ADCC - everything.

-Result: low insulin production, high blood glucose levels, pancreas damage.
2 contrasting ways of causing autoimmunity with antibody:
-Activating antibody (activates a certain molecule or tissue)

-Blocking (prevents a certain function).
What is an example of an "Activating Ab" autoimmune disease?

Grave's disease

-An antibody that mimics TSH is produced.
-Ab binds TSH receptor on thyroid; this Ab is not regulated like normal TSH; causes overproduction of Thyroid hormones.

What is an example of a "Blocking Ab" autoimmune disease?

Myasthenia Gravis

-Antibodies to acetylcholine receptors.
-Bind in place of real acetylcholine; block the activation for muscle movement.

-Can result in muscle atrophy, loss of even autonomic muscular functions -breathing.
What is Systemic Autoimmunity?
A general lack of immune regulation

-Hyperactive T and B cells.
3 examples of Systemic autoimmune disorders:
-Systemic Lupus Erythematosus
-Multiple Sclerosis
-Rheumatoid arthritis
What is the main mediator of the disease, SLE (lupus)?

Main effects:
-A general production of auto-antibodies to a vast array of tissue antigens, including RBCs and DNA.

Ag-Ab complexes are depositied in tissue and cause Serum Sickness - Type 3 hypersensitivity.
Main symptoms of Lupus:

Complement-mediated effects - inflammation and lysis of self sells
What is vasculitis?
occlusions in small blood vessels - result of neutrophils attaching to them in lupus.
Multiple Sclerosis
Mediators: Tcells reactive to myelin sheaths around nervous tissue in CNS.

Effects: lesions on the CNS tissue

Results: neurologic dysfunction.
What is Rheumatoid arthritis?
mediators: auto antibodies to Ig-G

effect: form complexes with Ig-M, deposited in joints.

Result: chronic inflammation of joints. Pain.
2 very General treatment strategies for autoimmunity:
-Remove the thymus

-Give corticosteroids
What is Plasmapheresis?
Taking plasma out of patients with lupus, centrifugin, and returning only the blood cells.

The Ag-ab complexes causing serum sickness are removed with the plasma and lessen the disease symptoms.
What are 2 more-specific treatment options for autoimmune disease?
-Cyclosporin -> blocks signal transduction mediated by the Tcell receptor, prevents proliferation of only ACTIVATED cells.

-Monoclonal Ab (humanized) to the alpha subunit of high-affinity IL-2R; prevents proliferation/activation of the sensitized Tcells that have constitutive high-levels.
How can Tolerance aid in preventing autoimmunity?
Oral eating of antigen induces tolerance, immunologic unresponsiveness.

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