Term
| What is the difference between "Peripheral" and "Central" Tolerance? |
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Definition
Both have B and T cell components.
1) Peripheral
T cells- Ignorance, Anergy (lack of IL-2), deletion by Fas/FasL, Inhibition by CTLA-4, Treg suppresion
B cells- impaired migration (neglect of outcompeted B cells in germinal centers), anergy and apoptosis via Fas/FasL, and germinal center deletion (somatic hypermutation can produce self-reactive BCRs).
2) Central
T Cells- Thymus: recognition of self-MHC (positive selection) and deletion of strong-binding to self (negative selection). Process is imperfect.
B Cells- Occurs in bone marrow. Includes clonal selection (self antigens cross-link IgM on B cells, causing deletion), receptor editing (LC V:J recombination to avoid self-reactivity) and anergy (soluble self-molecules). |
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Term
| What is "molecular mimicry" as it relates to autoimmunity? |
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Definition
When a foreign protein from a microorganism is similar to a native self-protein
Example is EBV infection, where viral-induced antibodies can cross-react with self-peptides that share epitopes. |
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Term
| How can EBV infection induce autoimmunity? |
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Definition
Infects B cells leading to non-specific activation of auto-reactive B cells.
Release of INF-y during infection may also increase MHC-II expression, and cause too much antigen presentation leading to autoimmunity (this is the case for many viruses) |
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Term
| Why might increased BAFF expression be of clinical concern? |
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Definition
This is a cytokine that promotes B/T cell development and survival. Can lead to autoimmunity in SLE.
Myeloid cells produce BAFF, which binds either BR3 (transcribes NFkB-2 leading to BCL-2-related survival) or TACI (transcribes NFkB-1 and causes class-switching and T-cell dependent responses) |
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Term
| What are "neo/cryptic" antigens and how are they generated? |
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Definition
Novel antigens that can induce autoimmunity. Generated by apoptosis, PTM, paraneoplastic syndromes and viral proteolysis.
1) Apoptosis (protealytic cleavage of antigens in apoptotic "blebs" via granzyme B and caspases produce auto-antigens- May be related to SLE)
2) PTM (deimination of arginien to citrulline, causing anti-CCP Ab as seen in RA). May promote epitope spreading and B cell cross reactivity to native and novel forms
3) Paraneoplastic autoimmunity (cross-reaction of anti-tumor antibodies)
4) Cleavage by viral proteases |
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Term
| What does complement have to do with autoimmunity? |
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Definition
Complement is necessary for clearance of apoptotic bodies and self-proteins.
Without it, you can get autoimmunity (SLE) |
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Term
| What are the 7 basic mechanisms of autoimmunity? |
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Definition
1) Molecular Mimicry
2) Release of sequestered antigens (by lymphocytes)
3) MHC-II Up-regulation (due to IFN-y or something similar)
4) Polycloncal B cell activation (Viral mediated often)
5) Altered cytokine milieu
6) Neo/cryptic antigens
7) Defect clearance (complement-mediated) |
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Term
| What are the 4 major triggers of Autoimmune responses? |
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Definition
1) Environment- geography (african vs. US for MS), UV light (SLE), Smoking (RA)
2) Infections- molecular mimicry (rheumatic fever and Guillain Barre), antigen release (myositis) and Viral (EBV) polyclonal B cell activation (activated B cells proliferate in context of infection).
3) Tissue Damage- Statin-induced myopathy and Exercise/crush injuries (myositis)
4) Drugs and proteins- TNF antagonists (SLE), Procainamide/hydralazine (drug-induced SLE) |
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Term
| What are 4 modulating factors in predicting the penetrance of autoimmunity? |
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Definition
1) Genetics (MHC variation)
2) Gender (Women at greater risk because of hormonal effects on CD4+ T cells and Ab levels)
3) Epitope spreading (the amount of Ab matters!)
4) Tissue distribution (Abnormal location of antigen is key) |
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Term
| What are 3 classification schemes for autoimmune diseases? |
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Definition
1) Organ vs. Systemic
2) B cell vs. T cell
3) Mechanistic |
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Term
| What are 2 examples of Type III reactions in autoimmune conditions? |
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Definition
Immune complex mediated
1) Serum sickness (Arthurs reaction)
2) SLE |
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Term
| What type of hypersensitivity reaction is associated with hemolytic anemia, Grave's disease and myasthenia gravis? |
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Definition
| Type II, Antibody-medaited cytotoxic responses |
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Term
A patient presents with crescentic glomerulonephritis with renal insufficiency (proteinuria and red cell clasts), and hemoptis (coughing up blood).
You know that your patient is a heavy smoker and has had past pulmonary infections.
What might be going on? |
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Definition
Goodpasture's (Type II)= lung and kidney
Attack of the glomerulis basement membrane collagen!
Associated with HLA-DR15 and DR4 and leads to development of anti-GBM autoantibodies (type IV collagen). |
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Term
| Differentiate between "warm agglutinins" and "cold agglutinins" in Autoimmune hemolytic anemia. |
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Definition
Both manifest with Type II hypersensitivity reactions and present with Exertional dyspnea, fatigue and pallor
1) Warm agglutinins involves IgG and is associated with viral infections, autoimmune disorders (SLE), malignancies, drugs and prior transfusions
(+) Coom's test with complement- or phagocytic-mediated destruction of IgG-bound RBCs
2) Cold agglutinins is associated with infections and malignancies and V(H)4-34, detected by mAb against 9G4.
complement-mediated RBC destruction (occurs within 2 weeks of infection and then resolves/ made worse by colder temperatures) |
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Term
A 50 year old patient has presented with recurrent episodes of angioedema and skin swelling. She also has a malignancy in her left lymph node. She has also been taking anti-C1 INH.
What type of autoimmune condition might this be? |
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Definition
Acquired angioedema (anti-C1INH) (blocking or Type IV)
Taking too much anti-C1-INH can lead to over-activation of the classical complement pathway.
Autoantibodies against C1-INH protein lead to Bradykin overproduction (too much vasodilation and loss of BP) . |
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Term
A patient presents with weakness in ocular, bulbar, limb and respiratory muscles, as well as thymoma (hyperplasia)
You run an edrophonium (Tensilon) test and it comes back abnormal.
What could be going on? |
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Definition
Myasthenia gravis (blocking and type II)
Autoantibodes block Ach receptor (most common and block nerve impulses, or to muscle specific receptor tyrosine kinase (MuSK) (type II)
The test is abnormal, because normally the AchE inhibitor would lead to decreased strength, but in this case, patient's appear STRONGER.
Treat by removing the Thymus |
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Term
| What is the difference between Goitrous and Atrophic autoimmune thyroiditis in Hashimoto's thyroiditis? |
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Definition
Both are "blocking" reactions and Goitrous precedes Atrophic.
1) Goitrous includes goiter, HYPERthyroidism, tachycardia, mania, heat sensitivity and weight loss).
2) Atrophic is HYPOthyroidism, slowing of metabolic processes and weight gain, depression, sensitivity to cold, bradycardia
Autoantibodies against thyroid peroxidase lead to hypothyroidism and T-cell infiltration of thyroid. |
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Term
A patient presents with Hyperthyroidism, Goiter, myxedema and Orbitopathy (see whites of eyes between lid and lens). You perform a blood test and it is negative for anti-thyroid peroxidase antibodies, but positive for anti-TSHR.
What is going on? |
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Definition
Grave's Disease
The antibodies ACTIVATE the receptor, stimulating thyroid hormone synthesis and secretion.
Remember, thyroid peroxidse antibodies are for Hashimoto's. |
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Term
A patient presents with Bullous skin lesions, Dermal-epierdmal skin blisters.
What do you think is going on? |
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Definition
Pemphigus Vulgaris (Type II reaction)
Epidermal/Dermal location is site of auto-Ab binding
anti desmoglein-1 (skin) and 3 (mucous membranes) antibodies act through multiple mechanisms (steric hindrance, complement, disrupted intracellular signaling) |
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Term
| Which Organ-based autoimmune diseases involve Type II hypersensitivity reactions (Antibody mediated) |
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Definition
1) Goodpasture's (anti-GBM against collagen IV in kidney)
2) Autoimmune hemolytic anemia (warm- IgG-coated RBCs and cold-IgM (anti-V(H)4-34) antibody leading to complement-mediated destruction.
3) Myasthenia gravis (Anti MuSK) (blocking if anti-AchR) leading to muscle weakness)
4) Pemphigus Vulgaris (Anti-desmoglein 1 (mucous membrane) and 2 (skin) leading to skin blistering)
5) Type 1 Diabetes (Antibodies against pancreatic B cells) |
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Term
| What are the different forms of SLE? |
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Definition
1) Anti-dsDNA and nephritis (type III)
2) anti-glutamate receptor, hemolytic anemia (Type II)
3) Neonatal SLE (anti-SSA/B) (type II)
** also known as Ro/La** |
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Term
| What are the 4 defining features of many systemic autoimmune conditions? |
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Definition
1) Genetics and HLA associations (HLA-DRB1 for RA and HLA-B27 for seronegative spondyloarthropathies- AS)
2) Autoantibodies (EXCEPT IBD)
3) Responsive to corticosteroids and immunosuppressives (almost "diagnostic")
(EXCEPTION Systemic sclerosis)
4) Environmental triggers/modulators |
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Term
| What are 5 ways by which peripheral T cell tolerance is maintained? |
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Definition
1) Ignorance (Anatomical barrier to foreign peptide)
2) Anergy (lack of IL-2 production prevents proliferation of activated T-cells)
3) Deletion (Fas on T cell binds FasL on APC and initiated apoptosis)- ALPS is a Fas defect
4) Inhibition (CTLA-4)
5) Suppression by Tregs (IL-10 and TGF-b) |
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Term
| What are 3 ways by which peripheral B cell tolerance is maintained? |
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Definition
1) Impaired migration (B cells enter the follicular zone of LN through HEVs and compete with another for binding of MHC- those that don't win cannot leave).
2) Anergy and apoptosis vis FAS/FASL
3) Germinal center deletion (somatic hypermutation in germinal centers can generate self-reactive B cells which are deleted). |
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Term
| What are the 7 basic mechanisms of Autoimmunity? |
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Definition
1) Molecular Mimicry (cross-reactivity of viral-induced Ab)
2) Release of sequestered antigens (trauma, drug-induced)
3) Up-regulation of MHC-II (viral infection cause INF-y release and MHC-II expression on APCs)
4) Polyclonal B activation (EBV infection leads to non-specific activation of auto-reactive B cells- could link to lupus)
5) Cytokine (BAFF promotes B/T cell development and bypasses tolerance)
6) Neo/cryptic antigens (Apoptosis, PTM, Paraneoplastic, Viral protease- promote epitope spreading)
7) Defective clearance (CLq, C2, C4 in SLE)
7) |
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Term
| What is the relationship between DM/PM (myositis) and Malignancy? |
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Definition
| Tumors express altered auto-antgens in pro-inflammatory environments (such as adenocarcinoma), which can lead to the production of auto-antibodies as seen in DM/PM |
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Term
| What is the relationship between complement expression and SLE? |
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Definition
Complement goes down
1) Loss of C1q (90%), C2 (33%) and C4 (75%) seen in many patients with active SLE |
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Term
| How can smoking increase risk for RA? |
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Definition
Smoking leads to pleural inflammation
1) Inflammation activates PAD, which recognizes citrullinization in patients with HLA-DR SE (binds citrulinated peptides particularly well).
2) These recognized self-peptides can cause autoimmune reactions, and even though the inflammation arose in the lungs, an infection of the joints will now affect citrulinated proteins.
2) Even thought the inflammation arose in the lungs |
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Term
| Why should patients with HLA-DR4 SE be particularly careful with smoking? |
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Definition
This subtype is very good at binding citrulinated peptides, which can present with post-translational modifications occurring as a result of smoking.
You may get RA! |
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Term
| What are the 3 important HLA types to remember for autoimmune diseases? |
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Definition
B27- AS
RA- DR4 (subset of DRB1)
SLE- DR3
also, MS- DR2 |
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Term
| How can epitope spreading result in altered penetrance of autoimmune conditions? |
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Definition
Ro/La signaling.
APC presents La (nuclear protein) to T-cell, which is also expressing a self-protein to a B cells (also "seeing" La).
That B-cell can be activated and produce anti-La Abs.
Ro and La (also SSA/SSB) coexist on the same nuclear region and pair |
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Term
| What is the difference between a direct and indirect "Coomb's" test? |
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Definition
Direct
Used to diagnose warm agglutinins in Autoimmune hemolytic anemia (type II)
You use a humanized antibody with a fluorescent tag and see whether it binds to RBCs (which would indicate that they are coated in IgG)
2) Indirect
Used in blood typing for transfusions
Look to see if a recipients serum contains autoantibodies against a donor's blood (positive test means no transfusion) |
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Term
| You know that your patient has an HLA type of HLA-DR15 and DR4. Why are you particularly concerned with their smoking? |
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Definition
This HLA type is associated with smoking-induced Goodpasture's syndrome (anti-GBM attacks collagen 4 in basement membrane of lung and kidney cells)
DR4 is also associated with RA. |
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Term
| Why does cold agglutinins resolve after 2 weeks while warm agglutinins persists? |
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Definition
The cold form of Autoimmune hemolytic anemia involves IgM, which is lost by activated B-cells.
The warm form involves IgG, which increases with B-cell activation. |
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Term
| Why might you run a Tensilon test? |
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Definition
Myasthenia gravis (II and blocking)
If a patient presents with total (including ocular/bulbar) muscle weakness (if it is peripheral and proximal, you might look at Myositis).
If the patient has MG, this test will be "abnormal," because normally the AchE inhibitor would lead to decreased strength, but in this case, patients appear STRONGER. |
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Term
| Why mighty you see Bradykin in Acquired angioedema? |
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Definition
| Anti-C1 INH antibodies will cause too much complement activation, raising Bradykin production and leading to vasodilation and loss of BP. |
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Term
| Which Organ-based autoimmune diseases involve blocking hypersensitivity reactions (Antibody mediated) |
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Definition
1) Acquired angioedema (anti-C1 INH leading to Bradykin overproduction
2) Myasthenia gravis (AchR) (type II if MuSK)
3) Hashimoto's Thyroiditis (thyroid peroxidase) |
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Term
| Which Organ-based autoimmune diseases involve Type IV reactions |
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Definition
| Multiple Sclerosis and Type 1 Diabetes (also type II in terms of autoantibodies) |
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Term
| Which Organ-based autoimmune diseases involve "activating" reactions? |
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Definition
Only Grave's Disease!
You get anti-TSHR antibody that is activating (basically, a TSH analog). |
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Term
A patient presents with granulomatus vasculitis affecting the upper/lower airways and the kidney and you draw a (+) c-ANCA test.
Upon taking a full history, you discover he has been exposed to Silica on a repeated basis.
What is your diagnosis? |
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Definition
Wegener's
The cyt-ANCA test is characteristic and binds EtOH-fixed PMNs. The EtOH makes the PMNs bind more tightly to endothelial cells, allowing them to generate inflammation.
It can be caused by Silica exposure and Staph infection. |
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Term
A patient presents with peripheral muscle weakness in the proximal regions of the musculature. You also draw a (+) anti-JO1 antibody test.
What is your diagnosis? |
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Definition
Myositis (PM or DM)
The peripheral/proximal weakness is a key to reject Myasthenia Gravis and the anti-JO1 test is characteristic of myositis. |
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Term
| What are 7 common organ-specific autoimmune conditions? |
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Definition
1) Autoimmune hemolytic anemia (warm and cold agglutinins)
2) Myasthenia Gravis (AchR or MuSK)
3) Acquired angioedema (anti-C1 INH)
4) Grave's Disease (anti-TSHR- activating)
5) Hashimoto's thryroiditis (anti-thryoid peroxidase)
6) Goodpasture's (anti-GBM/ collagen IV in lungs and kidney)
7) Pemphigus Vulgaris (anti-dsg1 (skin) and -dsg3 (mucous membrane) |
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Term
| What are 8 important systemic autoimmune diseases? |
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Definition
1) SLE (dsDNA (III), hemolytic anemia (II), Neonatal (II))
2) Vasculitis- Wegener's (ANCA) (II)
3) Sjogren's (IV)
4) SSc
5) RA (III and IV)
6) Seronegative spondyloarthropathies (IV)
7) IBD (IV)
8) PM/DM (IV) |
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