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94 Cards in this Set
- Front
- Back
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How is the immune system a double edged sword?
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Elimination of infectious agents and foreign antigens
May bring exagerrated (hypersensitive) response to innocuous Ag and produce disease leading to anaphylaxis |
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What is a hypersensitivity disease?
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Normal immune mechanisms directed against innocuous Ag
->Result in tissue injury -> Cause serious disease |
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What happens in type I sensitivity?
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Sensitization and IgE production
Genetic and environmental factors Effective mechanisms in allergic reaction |
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What are the types of hypersensitivity? (4)
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Type I: Immediate hypersensitivity (mediated by IgE). Occurs in minutes
Type II: Ab-dependent Cell dependent Cytotoxicity (ADCC)L mediated by IgG, IgM. Cytoplasmic r cell surface Ag Type III: Immune complex mediated (mediated IgM, IgG). Soluble antigen Type IV: Delayed type (mediated T-cell mediated) |
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Which is the most common type of misdirected response ofthe immune system?
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Type I: immediate hypersensitivity
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What induces an allergic reaction?
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Specific antigen (allergen)
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Do you have an allergic reaction the first time you're exposed to a given allergen?
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NO
-> Allergic reaction provoked by re-exposure to the same antigen |
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Which Ab mediate Type 1?
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IgE
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Where are IgE found?
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Tissue Mast Cells
Circulating basophils |
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Which inflammatory mediators are released following the binding of the IgE to an allergen, cross-linking of the Ab, receptor conform. change and it activation?
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Inflammatory mediators released:
LTC4 PGD2 LTB4 PAF IL-3/4/5/6 GM-CSF Eotaxin Histamine Serotonin -> These can have a local or systemic effect |
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What are the types of allergic diseases seen in the population?
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Systemic Anaphylaxis: allergic to medication
Acute Urtcaria (hives): usually allergic to animals Hayfever (allergic Rhinitis): allergic to pollen Asthma: allergic to pets/pollen Food allergy |
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What are the routes of entry?
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Skin (animal scratch)
Injection (IV/drug/bee stings) Ingestions (medication) Inhalation (pollens/pet damder) |
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Which Ig are involved in ADCC (type II)?
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IgM and IgG
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What are these Ig's made against?
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Intrinsic Ag (normal self Ag)
->Failure in immune tolerance -> Cross reactivity of foreign antigen with self molecule on the surface of host cell Extrinsic Ag -> Absorbed on host cell's surface -> penicillin at the surface of RBC |
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What happens when the Ab bind the surface of host cells? (e: can have Ab vs your RBCs and must get rid of them)
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Opsonization
Complement Activation ADCC (NK cell) Activation/blockage of important cell receptors |
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What does opsonization do in type II hypersensitivity?
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Opsonization of host cells (phagocytosis):
Monocytes/macrophages have receptors for the IgG Ab and by doing this, monocytes/macrophages will phagocytose these RBCs ->leads to hemolytic anemia |
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What does ADCC do in type II hypersensitivity?
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ADCC destruction of host cells:
-NK cell attach to Fc portion of IgG (have receptors) - target cell that is coated in IgG binds receptor of NK which secretes Perforins (makes pores) and Granzymes (go throught pores and attack machinery of target cell -> apoptosis) |
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What does actvation/blockage of important cell receptors do in type II hypersensitivity?
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Seen in myatenina gravis
->these patients have Ab vs ACh receptors -> If Ab attaches here, ACh can't bind its receptor, .: you get progressive muscular weakness, leading to respiratory fatigue --> Death |
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What are the diseases that are mediated by ADCC?
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ABO and RB blood group incompatabilities (Transfusional reactions)
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What are the autoimmune diseases ass't with Type II hypersensitivity?
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Idiopathic thrombocytopenic purpura
Myasthenia gravis Goodpasture's: kidneys attacked by immune system Graves: Thyroid attacked by immune system Also have some drug reactions |
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What causes immune complex mediated (type III) hypersensitivity?
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When Ag-Ab complexes form in Ag excess
-usually we form immune complexes but get rid of them regularly -In type III: these complexes are formed in large amounts in the circulation and our body can't always get rid of them ->these complexes deposit in varous tissues |
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Where do these immune complexes deposit?
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Skin
Joints Kidneys |
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What happens when immune complexes are deposited in these tissues?
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They lodge in the capillaries and get the activation of classical complement path by the immune complexes
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What can this deposition cause?
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MAC lysis
Aggregation of platelets Influx of neutrophils Massive inflammation, depending on where the complexes deposit |
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What are the signs of inflammation?
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Heat
Redness Swelling Pain Loss of fct |
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What are the pathologies ass't with Type III hypersensitivity?
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Arthus Rxn: local reaction, resulting from subcutaneous injection of any soluble Ag for which the host has a significant IgG titre
Serum Sickness: systemic reaction Immune complex Glomerulonphrititis Extrinsic Allergic Alveolitis (Farmer's lung) |
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What happens in the Arthus Reaction?
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Local reaction
Results from subcutaneous injection of any soluble Ag for which the host has a significant IgG titre Excess Ag reacts with Ab in the extracellular spaces Activating complement and phagocytic cels Producing local inflammatory response at site of infection If no Ab, would see nothing at site of infectioin |
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What is serum sickness?
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Systemin reaction
-In pre-antibiotic era, antiserum was made by immunizing horses used to treat pneumonia -But horse ptns caused an immune response -Results in systemoic type III hypersensitivity reaction 7-10 days after injection of the horse serum -leads to chills, fever, rash, arthritis and sometimes glomerulonephrititis -Ppl would get sick again with the same bacteria, were given the same A, but the 2nd time around, have stronger response against the horse serum, leading to worse conditions |
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What mediates Delayed tye hypersensitivity (type IV)?
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T-cell mediated
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Which test is used to see the typical type IV reaction?
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Tuberculin test (purrified ptn derivatives (PPD) test)
->to determine previous exposure to M. tuberculosis |
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Descobe the tuberculin (PDD) test.
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Takes ptns from dead TB and gives to patients
The APC around injection site would present peptides to TH1 cells **Recognize complexes of peptide: MHC II on APCs** Release INF-y and TNF-B Stimulate expression of adhesion molec on endothelium and increase local blood vessel permeability Attract, retain and activate macrophages, allowing plasma and accessory cells to enter the site causing visible swelling -After 24-72 hours: get swelling and redness |
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What happens in contact dermatitis with poison ivy?
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Response to a achemical in the posion ivy lea (lipid soluble cmpd that can cross the cell mb)
-Once they get in, bind to intracellular self-peptides, changing the shape -This is presented by MHC I to CD8 T-cells, causing an exaggerated response) -Poison ivy also expresses compounds that bind to extracellular self-ptns, which are taken up by APC, presenting them by MHC II to Th1 cells, leading to a response |
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What produces IgE?
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Plasma cells
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Where is IgE predominantly located?
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Tissues
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When is IgE tightly bound to Fc-Epsiloin-RI?
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On Tissue mast cells
Circulating Basophils Activated Eosinophils |
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What are the 2 types of Fc-Epsilon R?
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Fc-Epsilon-RI: HIGH affinity receptor for IgE, binds IgE on mast cells, basophils and activated eosinophils
CD23 (Fc-eps-RII): LOW affinity receptor for IgE, enhancing the Ab response to a specific Ag |
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What is the typical sequence of events following exposure to an allergen?
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-Exposure to antigen (allergen) for the 1st time (i.e. pollen, inhaled)
- These pollens cross the epithelial barrier and taken up by the APC and peptides are presentsed through APC to Th2 -Activation of Th2 and helper B cells produce IgE vs pollen -Upon re-exposure, the IgE on te surface of these receptors get polarized to one pole of the mast cell and lead to cross-linking of the receptors -> This sends an activation signal, causing the release of pro-inflammatory mediators and leading to dev'p of Type I hypersensitivity |
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What are the different effects produced when mast cells release mediators?
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GIT: diarrhea, vomiting
Respiratory system: coughing, wheezing, mucus productionk Blood vessels: hypertension, arrythmias |
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How can type I be tested?
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Scratch test
->take peanut ptn, scratch it on the skin -> if the mast cell has IgE for the ptn, would get release of mediators at site of the test and get swelling and redness at site of scratch 10 minutes late ->this person has IgE vs the peanut ptn ->If test is negative (no redness/swelling), no IgE vs the peanut ptn and .: probly didn't react to peanut |
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What determines whether the ymptoms are localized or systemic?
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Nature/quantity ofthe allergen
Route of introduction of allergen Other host factors: i.e. PAF -> if high, have higher risk of anaphylactic shock |
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How do B cells produce IgE?
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Need 2 signals to switch from IgM to IgE
Signal 1: costimulator ligand CD40L on surface of T-cell to CD40 on B-cell (needed for any type of class switching) Signal 2: Secretion of IL4/13, which have receptors on surface of B cells -> produced by Th2, basophils and mast cells -> IL4 and 13 have similar receptors, both are heterodimers (IL-4R alpha are common btw both of them, while the other chain is not similar) |
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What appens when IL4/13 binds its receptor?
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Leads to activation of TF STAT-6, which mediates production of IgE (why they can use either IL)
-> When STAT 6 is activated goes to nucleus of B-cell and binds to the STAT6 Responsive element, to get T of the epsilon region ->Once have CD40-CD40L and either IL4 or IL13. the B-cell produces IgE |
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Why is IL4/13 important?
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Because STAT6 is important
->a lot of STAT 6, a lot of IgE -> KO STAT 6, no IgE, but still have production of other Ab |
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How do mast cells exert a positive feedback loop on IgE?
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Mast cells express IgE0receptors on their surface
When they bind IgE, they upregulate expression of CD40-L and can also PRODUCE IL4 -> gives both signal 1 and 2 .: positive fdbk loop, so that once mast cell recognizes Ag, provides signals 1 and 2 to produce more IgE |
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What does it mean if someone is atopic?
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Have allergies/ prdisposition to produce IgE and have + skin test
-increased tendency to mount IgE response to innocuous Ag Has strong familial basis |
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What are the genetic loci identified in atopic families?
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-Polymorphism in IL-4, would have increased amount of IL4 produced nd these ppl more likely to become allergic
-Gain of fct mutation of IL-4 receptor alpha constitutively activated, will predispose persone to be more prone t allergies -Some haplotypes of MHC II which better present pollens to Th2 |
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What is the Filaggrin gene?
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Encodes a ptn important in the skin barrier integrity
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What happens if there is a loss of fct mutation in the filaggrin gene?
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Get defective skin barrier
->These ppl are predisposed to get Eczema (Atopic dermatitis) -> Skin barrier isn't intact, allergens can enter, are rec'z by APCs, who process these allergens, present them to Th2, lead to the production of IgE |
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What are filaggrin mutations important risk factors for?
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Asthma in ass't with atopic dermatitis
(not asthma in the absence og atopic dermatitis) ->supports the hypothesis that the breakdown of the epidermal skin barrier will lwad to allergens able to penetrate the skin to make contact with APCs, eventually leading to IgE production |
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Where is there a higher risk of allergies?
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Economically advanced regions of the world (40% of ppl here have allergies)
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What happens to patients that have a genetic susceptibility (predisposition) and live in environments that are hygienic (few microbes)?
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Prone to have allergic diseases
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What happens to ppl who have low genetic susceptibility and live in unhygienic areas?
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Less likely to become allergic
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Describe the Hygiene Hypothesis.
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Less hygienic environent (predisposing to infections) protect vs atopic diseases
Bias towards Th2 response in neonates Infections that evoke Th1 response early in life might reduce the likelihood of Th2 response later in life (less allergic) and vice cersa (more allergic diseases) If you have a lot of exposure to microbes, have more Th1 (underdev'l countries) and see less allergic diseases |
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What is the problem with this hypothesis?
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In the past few decades, there was a decrease in some infectious diseases with an increase in allergic diseases, but also see an increases in different diseases nediated by Th1 (MS, diabetes, Crohn's disease)
.:seeing both mediated allergy diseases an TH1 mediated diseases |
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What is the modified Hygiene hypothesis?
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Maybe Th1 and Th2 aren't just balance
Have another set of Th cells (reg'l cells: TH3) that regulate process -Infections might protect vs developing atopy by driving the production of regulatory Th3 cytokines (IL10, TGF-beta) |
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What kind of T cell is present at the beginning of life?
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Th0
->Not prone to make one pattern of cytokines over another |
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What happens in a Th1 dominant response?
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TNF-a/B, IFN-y, IL2: they're overexpression leads to TH1 diseases
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What happens in Th2 dominant responses?
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IL4/5/13: overexpression leads to allergy
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Can the Th3 response be dominant?
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Yes, dampens TH1/2 and lead to tolerance
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What happens if your not exposed to these microbes in the first few months of life?
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Lead to topic Disease
(If exposed to the microbes at this window, get tolerance and less allergies) |
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What mediates allergic inflammatory reactions?
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Mast cells
Basophils Eosinophils |
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What happens when IgE binds to mast cells?
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Immediate release of histamine
over minutes: prostaglandins and leukotrienes hours: cytokine production (IL4 and IL13) |
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What is the mast cell like before and after meeting the antigen?
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Before: full of granules
After: mast cell is empty, all granules released |
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What are mast cell derived from?
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CD34+ progenitor cells
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Where is the major site of mast cell differentiation?
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Connective tissue
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What is the major growth factor for mast cells?
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Stem cell factor (SCF)
->acts on its receptor: C-Kit |
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What is Mast cell cytosis?
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Massive prolif of mast cells
Can be caused by gain of fct mutation in C-Kit so that mast cells are always active |
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What is the life span of mast cells?
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Week to months
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Which Fc epsilon receptor is expressed the most?
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Fc-epsilon-R1 (high leel of expression, but also have R2)
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What are the 2 major subsets of mast cells?
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Connective tissue mast cells
Mucosal mast cells (each release different enzymes) |
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What is the fundamental role of mast cells in the innate immunity?
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-Expresss multiple pattern recognition receptors
Involved in recognizinf broad classes of pathogens -Effector fct mediated by cytokines/proinflammatory mediators released upon activation |
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Where are eosinophils derived from?
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CD34+ progenitor cells
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Where is the major site of maturation for eosinophils?
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Bone marrow
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What role does IL-5 play for eosinophils?
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Production
Differentiation Survival Release from bone marrow |
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What is the eosinophil major chemotactic factor?
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Eotaxines
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What is the life span of eosinophils?
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week to months
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What happens to the level of FC-epsilon-R1?
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Low lvls of expression before activation
Upregulation after activated |
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Through what agents can eosinophils fight off infectious agents/damages to tissue
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Release of toxic granule ptns:
-Major basic ptn -eosinophil derived neurotoxin -eosinophil cationic ptn |
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Why are eoinophils important?
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Defense vs parasites
Fighting viral infections through their RNAses (contained in their granules) Source of IL4: helps polarize lymphocytes toward Th2 phenotype, ass't with IgE factor |
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What happens when the eosinophil ejects DNA of mito origin?
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Make sticky network that can produce their extra'cellular killing
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What else are eosinophils important for?
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Tissue remodelling in asthma
Promoting chronic inflammation |
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What are basophils derived from?
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CD34+ progenitor cells
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Where is the major site of differentiation for basophils?
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Bone marrow
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What influences differentiation?
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Il3/5
CM-CSF |
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Are there a lot of basophils in circulation?
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No, least common WBC
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What is the basophil life span?
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Days
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What kind of expression of Fc-epsilon R1 do basophils have?
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High level of expression befor activation
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What diseases do the basophils respond to?
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Infection with parasitic helminths
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How are basophils important in modulating secondary immune responses that lead to aumented by production and humoral memory ?
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Produce large quantities of IL4/13 and express CD40L
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What are the 2 phases allergic reactions are divided into?
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Immediate phase response (seconds)
Late phase response (up to 12 hours) |
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What is the immediate reaction following innhalation of allergen?
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Histamin, prostaglandins and other preformed rapidly synthesized mediators
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What do these mediators cause?
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Rapid increase in vascular permeability
Contraction of smooth muscle |
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What is the late phase reaction caused by?
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Synthesis/release of mediators (leukotrienes, chemokines, cytokines)
Recruit other leukocytes (eosinophils, Th2 lymphocytes) |
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Which are clinically marked more: late or immediate response?
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Late phase react less
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