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112 Cards in this Set

  • Front
  • Back
How many types of autoimmune diseases are there? What are they analogous to?
3. Hypersensitivity rxns.
First autoimmune type: Type II hypersensitivity.
2nd: Type III
3rd: Type IV
Does IgE ever cause autoimmune disorders?
No
Type II Autoimmunity
Autoimmunity against cell-surface receptors or ECM. (Type II hyper)
Type III Autoimmunity
Autoimmunity against deposited immune complexes (Type III hyper)
Type IV Autoimmunity
Autoimmunity caused by T cells (Type IV hyper)
Common type I autoimmune diseases?
Against the blood, i.e., autoimmune hemolytic anemia. Complement activated lysis.
Neutropenia
The complement-mediated phagocytosis of WBCs by the spleen in immune disorders/disease.
Can blood cells function while opsonized and covered in complement?
Sure. So one possible treatment of a WBC autoimmunity is to remove the spleen and never mind the antibody load.
What autoimmune type attacks the ECM?
Type II
Goodpasture's syndrome
Type II autoimmune disorder against a3/Type IV collagen, resulting in glomerular deposits and renal failure.
What kind of immune response is characteristic of Type II autoimmunity?
Antibody attack. Remember Type II hypersensitivity.
25% of renal failure is caused by. . .
Immune disorders. ANTIBODIES will clusterfuck the glomerular filtration membrane.
Common Type II autoimmune disorders (chart on pg.345)
Anemia, thrombocytopenia, goodpasture, pemphigus vulgaris, ARF, Graves, Myasthenia gravis, Insulin-resistant diabetes, Hypoglycemia
Common Type III (chart on pg. 345)
Bacterial endocarditis (subacute), Mixed cryoglobulinemia, lupus
Common Type IV (chart on pg. 345)
IDDM, rheumatoid arthritis, MS, Celiac
Two predisposing factors of endocrine glands to autoimmune disease?
1. Specialized fxn involves specialized proteins
2. High vascularization
Cause of endocrine autoimmune disease.
Impairment of a single type of epi cell in a given gland.
Autoimmune diseases of the thyroid gland
Hashimoto's disease, Grave's, Subacute thyroiditis, hypothyroid disorder of no apparent cause (idiopathic)
Autoimmune diseases of the pancreas
Type I and II diabetes
Autoimmune disease of the adrenal gland
Addison's disease
Pathology of Grave's disease
Autoantibodies to TSH receptors on thyroid gland cause continual T3 and T4 release, independent of pituitary control.
What is the target of autoantibodies in Grave's disease?
TSH receptor. Therefore it's a CD4 TH2 disease
Clinical presentation of Grave's disease?
Bug-eyes, heat intolerance, nervousness, weight loss, goiter
Pathology of Hashimoto's disease? (chronic thyroiditis)
Infiltration of the thyroid gland by lymphocytes (effector T and CD4 TH1), apparent conversion of thyroid follicles into secondary lymphoid tissue,.
Clinical presentation of Hashimoto's disease?
Hypothyroidism.
Short-term treatment of Hashimoto's? Graves? Long-term treatment of both?
Hashi: synthroid
Graves: thyroid suppressive drugs
Both: Kill the thyroid with radioactive iodine and then use synthroid.
Is Grave's congenital?
It can be, but then the maternal autoantibodies to the TSH receptors can be removed by plasmapheresis and the baby is fine.
Plasmapheresis
Total exchange of blood plasma. A very good way of getting rid of bad maternal antibodies from a newborn.
Are Type IV autoimmune diseases congenital?
No. T cells from mom cannot get into the baby.
Can autoimmune disorder-causing T cells be injected into another animal to test for effect?
Nope. Remember how ridiculously specific (and species-specific) the thymus selection process is.
Review: What makes what in the pancreas?
Alpha: Glucagon
Beta: Insulin
Gamma: Somatostatin
Pathology of IDDM
1.CD8 cells will physically kill Beta cells
2. Lymphocyte infiltration: insulitis
3.
Why is even Type I diabetes disease onset delayed?
The body has an excess of beta-cells
Treatment of IDDM?
Insulin injections, derived from pigs unless there's an immune response, in which case it's recombinant synthetic human insulin.
What is a systemic autoimmune disease?
A less-specific autoimmune attack against multiple tissue/cell types. I.e. Lupus
What is lupus, or SLE?
1. IgG attack against everything
2. Excess of antigen means creation and deposition of small immune complexes
3. Rheumatoid depositions that lead to further complications.
4. Systemic deposition of complexes=bad to worse.
Pathology of lupus
Systemic inflammatory cycles followed by a chilling out period. Chronic and fatal via renal or brain failure.
Clinical presentation of lupus
Wolf's head rash caused by Type III style immune deposition in the skin of the face. Affects Asians and Africans, women. 90% present with arthritis
Pathology of rheumatoid arthritis
1. B cells make IgG, IgM, and IgA antibodies to Fc IgG, called Rheumatoid Factor
2. Every leukocyte and Rheumatoid factor gets into joint synovium.
3. Inflammation city
4. Neutrophils release lysozyme, further damaging synovium
5.
Do immune complexes create rheumatoid arthritis?
No, but they will exacerbate it?
Treatment for rheumatoid arthritis?
Anti-inflammatory, immunosuppresive drugs. Antibody against TNF.
Pathology of MS
Autoimmune (type IV) against PBP or MBP of the myelin sheath by CD4 TH1 cells and macrophages release IFN-gamma. Destruction of sheath causes sclerotic plaques in white matter of CNS.
Onset of MS?
Late 20s early 30s.
Clinical presentation of MS?
Nervous system: spasticity, weakness, uncoordinated movement. Brain degeneration and death.
Treatment of MS
1. Injections of IFN-beta
2. Immunosuppressive drugs.
Pathology of Myasthenia Gravis
1. Antibodies to acetylcholine receptor cause receptor uptake and digestion
Clinical presentation of myasthenia gravis
Muscle weakness, drooping eyelids and double vision, breathing difficulty, death.
Treatment of myasthenia gravis
1. Pyridostigmine: stops AcH degradation, enable competition with antibody
2. Azathioprine: autoantibody suppressant.
Are antibodies to insulin receptors antagonistic or agonistic?
Either, causing different disease presentations.
Graves disease: antagonistic or agonistic?
Agonist
Myas G: antagonistic or agonistic?
Antagonistic
Role of infections in active autoimmune disorders?
Bad bad, stimulate an immune response which is already problematic for the patient.
What is the first step in prevention of autoreactive B cells?
Exposure to cell surface antigens in marrow and plasma. However, this does not prevent potential auto-reaction to antigens not present.
Effect of T cell tolerance of B cells.
The autoreactive B cell, already bound to an autoantigen will not get "help" from CD4 TH2 (because they can't see the autoantigen themselves), fail to get out of the lymph node or follicle, and die.
Anergy
The intracellular "shutting-off" of a potentially self-reactive B cell.
Does a break in B cell tolerance cause autoimmune disorders?
No. Self-reactive B cells still need assistance from T cells. ALL AUTOIMMUNE DISORDERS INVOLVE A "BREAK" IN T CELL TOLERANCE.
What is the AIRE gene?
It creates a transcription factor protein that enables systemic gene transcription to take place specially in the thymus, for negative selection
What happens in homozygous defective AIRE inheritance in Iranian Jews, Finns, Sardinians, etc?
APECED. Autoimmune polyendocrinopathy-candidiasis ectodermal-dystrophy.
Clinical presentation of APECED.
Candiasis infection, bad teeth and hair, hypoparathyroidism, ovarian failure, adrenal failure, etc.
Is APECED fatal?
Sure, ultimately, but you survive a lot longer than you might think.
Why do autoreactive T cells that escape the thymus not immediately cause a reaction?
Normal cells don't express B7 (costimulatory factor)
What holds the reins on T cell costimulation (via B7)? Therefore, what's one way increased susceptibility to autoimmune disease occurs?
CTLA-4, which competes with CD28. If there isn't enough CTLA-4 soluble around, you have increased likelihood of Graves, Hashimotos, IDDM, etc.
Regulatory T cells
1. Look like naive but express CD25.
2. When bound to an MHC II with antigen will suppress the proliferation of other naive t cells that bind.
3. Requires actual contact and IL-4, IL-10, TGF-B to suppress.
4. CTLA-4 binds B-7 on a rT cell, but CD28 binds B-7 on a naive T cell
5. If something's wrong with CTLA-4, suppression may not work.
FoxP3
A regulatory T cell ONLY transcription repressor, which if it goes wrong (X-Linked) causes IPEX. - Totally fatal. The body attacks the body and there is no regulatory suppression.
Treatment of IPEX
Bone marrow transplant from HLA match.
3 gene families that, when defective, confer susceptibility to autoimmune disorders
AIRE, CTLA-4, FOXP3. - But these by themselves do NOT cause disease!
Role of HLA in autoimmune disease.
VERY important- determines almost 50% of genetic predisposition to disease. i.e. homologous HLA segregation in siblings is correlated to IDDM.
Error in HLA-B27
Ankylosing Spondylitis
Linkage disequilibrium
The preferential (weirdly) associating of certain alleles beyond that of statistical chance. The genes cannot be separated to analyze the contribution of individual alleles.
Why do white people get more autoimmune diseases?
The 8.1 haplotype
What is the relationship of HLA types to IDDM?
HLA-DQ is a stronger influence, but not without linking from HLA-DR
Common HLA-DQ haplotypes in IDDM?
DQ-2 and DQ-8. If you have both, the susceptibility is much greater.
The genotypic name for the DQ allele that predisposes to IDDM? What's the relationship of this allele to DR-4
DQA1*03:DQB1*0201.

Linkage with DR4 will, depending on slight amino acid variations in a highly conserved LRAV sequence, confer either protection or increased susceptibility.
Is protection from IDDM, say, from DQ-6, dominant or recessive? What about DQ-7?
Dominant. Which is rare for disease. Recessive.
Theoretical model for T-cell tolerance breakage?
Disease allelic HLA molecule present autopeptides to a CD4 T cell and so starts the shitstorm.
What's the max frequency that someone with a genetic predisposition will develop an autoimmune disease?
20%. Environmental factors play a big role.
Sympathetic opthalmia
The autoimmune rxn to proteins in an undamaged eye when the other eye has been damaged. Reversible with removal of the damaged organ and immunosuppression.
Linkage disequilibrium
The preferential (weirdly) associating of certain alleles beyond that of statistical chance. The genes cannot be separated to analyze the contribution of individual alleles.
Why do white people get more autoimmune diseases?
The 8.1 haplotype
What is the relationship of HLA types to IDDM?
HLA-DQ is a stronger influence, but not without linking from HLA-DR
Common HLA-DQ haplotypes in IDDM?
DQ-2 and DQ-8. If you have both, the susceptibility is much greater.
The genotypic name for the DQ allele that predisposes to IDDM? What's the relationship of this allele to DR-4
DQA1*03:DQB1*0201.

Linkage with DR4 will, depending on slight amino acid variations in a highly conserved LRAV sequence, confer either protection or increased susceptibility.
Is protection from IDDM, say, from DQ-6, dominant or recessive? What about DQ-7?
Dominant. Which is rare for disease. Recessive.
Theoretical model for T-cell tolerance breakage?
Disease allelic HLA molecule present autopeptides to a CD4 T cell and so starts the shitstorm.
What's the max frequency that someone with a genetic predisposition will develop an autoimmune disease?
20%. Environmental factors play a big role.
Sympathetic opthalmia
The autoimmune rxn to proteins in an undamaged eye when the other eye has been damaged. Reversible with removal of the damaged organ and immunosuppression.
How does oral tolerance diminish the potential for gut inflammation?
By producing IgA and TH2, which do not stimulate inflammatory cytokines
What is celiac disease?
A condition where CD4 T cells in the gut activate macrophages, and therefore inflammation, in response to gluten-containing foods. Eventually the villi will atrophy, chronic diahrrea and malnutrition are evident.
80% of celiac disease sufferers have what HLA allotype?
HLA-DQ2, the rest have DQ8. In the gut of celiacs there are TH1 cells capable of seeing those allotypes, and causing inflammation.
What 2 antibodies do celic sufferers make?
1. Tissue transglutaminase
2. Anti-gliadin antibodies
Where is the polymorphism that give susceptibility to IDDM?
Residue 57 of HLA-DQ Beta chain. I don't really understand this.
Pathological mechanism of celiac
1. Gluten is only partially degraded
2. Resistant fragment enters gut and is deaminated
3. HLA-DQ2 presents deaminated fragment and T cells freak out.
How is autoimmunity stimulated in test subjects?
Mixing of self-products with microbial products capable of stimulating inflammation.
Autoimmune disease that is a response to a simple infection?
Rheumatic fever from strep pyogenes.
Why does rheumatic fever develop?
The antigens of strep pyogenes mimic our self-antigens and therefore the antibodies we make to strep will attack other tissues.
Why is rheumatic fever self-limiting?
The autoantigenic response does not stimulate CD4 cells to make additional antibodies.
T cell activation
Only occurs in the presence of inflammation, and therefore infection.
Diseases associated with HLA-B27 expression and common chlamydial/enterobacterial infections?
Arthritis, whether reactive or Reiter's syndrome.
Disease associated with Borrelia burgdorferi and HLA-DR2/DR4 expression?
Chronic Lyme disease arthritis
Disease associated with HLA-DQ2/DQ8/DR4 and picornaviridae?
IDDM
2 mechanisms of T cell autoimmune activation?
1. Nonspecific: i.e. an infection will disturb the regulatory balance, causing suppressed or anergized T cells to be activated.
2. Specific: cross-reactive T cell receptors to multiple antigens, or same antigen specificity for multiple T cell receptors.
The SIMPLISTIC explanation of T cell autoreactive activation
You have a pathogenic peptide and a self-peptide bound to MHC. Normally, the self-peptide complex does not bind STRONGLY enough to a T cell receptor to activate it. But, the pathogen-complex does. So, once activated, the T cell receptor can see lower-binding affinities, can see the self-peptide complex, and react against it.
What's the problem with an autoreactive ACTIVATED T cell?
It can get into any tissue.
When is a tissue most likely to be the target of an autoimmune reaction by activated T cells?
When interferon-gamma forces cells that do not express MHC complexes to express them . . . like say thyroid cells or pancreatic B cells. Sound familiar?
Why are dendritic cells totally unhelpful when it comes to autoimmunity?
Dendritic cells will pick up peptides from the carnage caused by autoreactive T cells, traipse into a lymph node, and stimulate the formation of more autoreactive T cells.
Pemphigus vulgaris and pemphigus foliaceus?
Autoantibodies for desmogleins, the adhesion molecules responsible for binding keratinocytes together. Your skin will fall off.
Intramolecular epitope spreading
When an autoimmune disease begins by attacking only selective epitopes of a certain molecule and then acquires more over the course of the disease. I.e. pemphigus foliaceus begins with EC5 on desmoglein
Does intramolecular epitope spreading occur with T cell reponses in autoimmunity?
Yes, normally to low-expressed, cryptic (normally hidden) epitopes.
Intermolecular epitope spreading
B-cells bound to one epitope can digest the entire molecule, digest, and present multiple epitopes to the T cell. In this way, T cells can co-mount a response to other parts of the same molecule.
Do HIV infected cells continue to present antigens?
Sure, except that it's antigens from our own body, not viral antigens.
How does the body compensate for the involution of the thymus, and therefore a decrease in naive T cell production?
1. Expanding clone lines
2. Changing CD28 and KIR expression so that T cells are less susceptible to apoptosis.
Process of T cell activation in rheumatoid arthritis
Even though older T cells cannot be costimulated (they lack CD28), they can be stimulated via KIR to mass-produced interferon-gamma, hence causing inflammation.