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46 Cards in this Set
- Front
- Back
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Describe the 4 types of hypersensitivity
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Type 1 - Immediate-type hypersensitivity. Anaphylaxis. IgE, mast cell and basophil; Type 2 - Antibody-dependent cellular cytotoxicity. IgG, macrophage, complement and NK cells; Type 3 - Serum sickness. IgG and complement; Type 4 - Delayed type. Lymphocytes and macrophages
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Type 1 Hypersensitivity steps
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First antigen exposure --> Activation of Th2 cells and stimulation of IgE class switching in B cells --> Production of IgE --> Binding of IgE to FceRI on mast cells (Sensitization) --> Repeated exposure to Allergen --> Activation of mast cell; release of mediators --> 1. Vasoactive amines, lipid mediators (--> immediate hypersensitivity rxn, minutes after exposure); 2. Cytokines (--> late phase reaction, 2-4 hours after repeat exposure to allergen)
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Allergens vs. Irritants
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Allergens (IgE mediated disease, require sensitization, Affects only those that are sensitized to the allergen, NOT usually dose dependent). Irritants (not mediated through IgE, dose dependent response, will affect everyone at high enough dose)
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What are the major effector cells in Type I hypersensitivity response?
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Mast cells and Basophils
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What cells express the high affinity receptor IgE, FceRI?
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Mast cells and basophils. Also found on dendritic cells and activated eosinophils
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Mast cell toxic immediators (in Type 1 HS)
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Histamine: has a short half-life in the serum (gone within min.). only produced by mast cells adn basophils. Has at least 3 receptors (H1R, H2R, H3R). Via the H1 and H2R --> toxic to parasites, increases vascular permeability, causes smooth m. contraction / Heparin (similar effects as histamine)
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What does Histamine do? (mediator of Type 1 HS)
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Histamine: has a short half-life in the serum (gone within min.). only produced by mast cells adn basophils. Has at least 3 receptors (H1R, H2R, H3R). Via the H1 and H2R --> toxic to parasites, increases vascular permeability, causes smooth m. contraction / related to Anaphylaxis: H1 (smooth muscle contraction, increase vascular permeability), H2 (increased vascular permeability), H1+H2 (vasodilatation, pruiritus)
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Reactions that the following mediators lead to? 1. Biogenic amines (histamines), lipid mediators (PGD2, PAF, LTC4); 2. Cytokines (TNF), lipid mediators; 3. Enzymes (tryptase)
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1. vascular leak, broncho-constriction, intestinal hypermotility; 2. Inflammation; 3. tissue damage
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Type 1 HS - skin testing (Wheal and flare)
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picture?
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Does the following lower or increase release threshold of Histamine? Corticosteroids, Antihistamines, Cromolyn (in vitro)
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Release threshold is increased (= likelihood of dz decreased)
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What is the single best marker of mast cell activation?
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Tryptase
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Tryptase?
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Released by Mast cell. 2 forms (alpha-tryptase - constitutively released form / beta-tryptase - form only released with mast cell activation). Remains identifiable in the serum for up to 4 hours after release. Only mast cells make this protein. Single best marker of mast cell activation. Leads to remodeling of connective tissue matrix.
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Chymase?
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Mast cell mediator - lead to remodeling of CT matrices
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Cathepsin G?
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Mast cell mediator - lead to remodeling of CT matrices
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Carboxypeptidase?
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Mast cell mediator - lead to remodeling of CT matrices
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Mast cell mediators (Type 1 HS) - name cytokines
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Release delayed (4-6 hours) after degranulation because it has to be made. IL-4, IL-13 / IL-3, IL-5, and GM-CSF / TNF
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IL-4, IL-13?
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Associated with Th2 cells and lead to Ig class switching in B cells to the production of IgE
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IL-3, IL-5, and GM-CSF
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Promote the survival and activation of eosinophils
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TNF
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Activated endothelium and leads to adhesion molecule expression. Some exists as preformed mediator.
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What are the mediators that are released immediately in Mast cell immediate reactions (Type I HS)
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Tryptase and Chymase, Cathepsin G, Carboxypeptidase
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(CCL3) MIP-1alpha
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Chemotactic for monocytes/macrophages/neutrophils/T cells eosinophils (Mast cell mediators).
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CCL5 (RANTES)
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Mast cell mediators - Regulated and normal T cells expressed and exposed) Chemotactic for T cells and eosinophils; binds to CCR3 (as well as CCR1 adn CCR5)
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Name Chemokines in Mast cell mediators of Type 1 HS rxn?
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CCL3, CCL5 (RANTES), CCL11
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Leukotrienes C4, D4, and E4
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(Mast cell mediators in Type 1 HS) - Lead to eosinophil migration, smooth muscle contraction, vascular permeability, and mucus hypersecretion / (related to Anaphylaxis as mediators) - smooth muscle contraction, increased vascular permeability and dilatation.
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PAF
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(Platelet activatin factor) Attracts eosinophils and other leukocytes. Activates eosinophils, neutrophils, and platelets. Increases production of lipid mediators. / Bronchoconstriction
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Zileuton?
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Inhibits Arachidonic acid --> 5-PETE (--> LTA4) in Leukotriene production of mast cells)
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Zafirlukast/montelukast
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Inhibit LTB4, LTD4, LTE4 --> LTC/C/D receptor (in leukotriene production of mast cells)
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Elevated eosinophil count results from?
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NAACP - neoplasia, allergies, asthma, connective tissue disease, parasitic disease
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CCL11 (Eotaxtin)
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Chemotactic for T cells and eosinophils (Mast cell mediators). found at sites of allergic inflammation
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CCR3
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only known receptor for Eotaxin (CCL11).
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Steroids - funcion related to eosinophils
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induce rapid apoptosis of eosinophils. Also inhibit the production of IL-5, leading to decreased release from the marrow as well as increased apoptosis. This effect is mediated by steroid binding to GR-alpha and inhibiting AP-1 and NFkB
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IL-5 - 1. produced by?; 2. effect on eosinophils in vitro; 3. effect on eosinophils in vivo
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1. Produced by Th2 lymphocytes and other cells; 2. in vitro) prolongs survival, enhances leukotriene production adn cytotoxicity for parasites. Conversion to the hypodense phenotype. Augments beta2 integrin-mediated adhesion and transendothelial migration.; 3. in vivo) Infusion causes eosinophilia. Levels increased in some diseases with eosinophilia. Level increased in fluids obtained from sites of experimental allergic late phase reactions
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Eosinophil - structure (basic/acidic components? secretory products? other products?
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Crystalloid granule proteins - MBP (major basic protein) at CORE (very basic proteins that burn holes into...); Secretory products - IL-5, GM-CSF, Charcol-Leyden crystal protein.; It has core, matrix, and crystalloid granules
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Eosinophil roles: 1. Cationic granule proteins (MBP, eosinophil cationic protein); 2. Enzymes (eosinophil peroxidase)
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1. killing of parasites and host cells; 2. tissue damage
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Type I hypersensitivity - 4 clinical aspects
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Allergic Rhinitis, Asthma, Anaphylaxis, Urticaria
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Case: 7 yr old male previously hospitalized as an infant with a severe viral infection. He now presents with spring time nasal congestion, rhinorrhea, rhnitis, and conjuctivitis. When his syptoms are really bad he finds it difficult to sleep, often awakening with a cough or chest tightness. PE - pale nasal mucosa, swollen turbinates and a clear discharge bilaterally.
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Allergic Rhinitis adn Asthma
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Case: 7 yr old male previously hospitalized as an infant with a severe viral infection. He now presents with spring time nasal congestion, rhinorrhea, rhnitis, and conjuctivitis. When his syptoms are really bad he finds it difficult to sleep, often awakening with a cough or chest tightness. PE - pale nasal mucosa, swollen turbinates and a clear discharge bilaterally. Question: 1. Is the hospitalization for a viral infection important?; 2. From an immunologic perspective, why does he sneeze? 3. Why would his syptoms be worse in the spring? 4. Would this history be different if JR was a girl? 5. Does his nasal disease have anything to do with his chest breathing problems? 6. Against what mediators should his treatment be designed?
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1. Yes. High risk of developing asthma & allergic dz; 2. already allergic to something --> IgE on Mast cell produces IgE when encountered with allergen; 3. tree pollen; 4. Asthma occurance rate is boys> girls prepuberty and girls>boys after puberty (overall same); 5. yes. when nose is bad materials can trickle down to lungs; 6. Histamine, Leukotrienes, IgE (could give steroids)
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Allergic Rhinitis - %, cause
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up to 20% of population suffers from AR. Symptoms are due to cross-linking of IgE in the nasal mucosa and ocular conjunctiva with specific antigen exposure (Nasal pruritis, rhinorrhea, rhinitis, congestion, ocular pruritis, conjunctivitis). Systemic symptoms are rare. May have associated asthma.
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Rhinorrhea?
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runny nose
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Rhinitis?
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sneezing
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Asthma - % population, cause, pathophysiology
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Around 5% of the population suffers from asthma. Symptoms are due in part to IgE mediated disease in the lower airways (wheezing, shortness of breath due to increased airway constriction - prevents exhalation. Increased mucus secretion and production - mucus plugging)/ Inflammatory cell infiltrate consists of mainly of eosinophils and lymphocytes. "sudden death" asthma associated with an infiltrate of neutrophils. Denudation of airway epithelium. Mucus gland hyperplasia and hypersecretion. Smooth muscle cell hyperplasia. Submucosal edema and vascular dilatation. ribrin deposition/airway remodeling
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What is the Inflammatory cell infiltrate of Asthma mostly consists of? What is "sudden death" of asthma associated with?
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1. eosinophils and lymphocytes; 2. neutrophils
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Ashtma - pathologic airway changed induced in asthma
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Mucous gland hypertrophy, edema, mucus, thickening of basement membrane, epithelial damage, airway smooth muscle, inflammatory cell infiltration, vascular dilatation
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Case: Anaphylactic shock -- use epinephrine. Questions; 1. was this the first time he had been stung by a bee? 2. Why does epinephrine work? 3. Would steroids be of benefit in acute anaphylaxis? 4. What mast cell product could you measure to verify anaphylaxis? 5. Could you skin test him immediately after the anaphylacitc event?
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1. No. should have been exposed to bee venome at least once before 2. Epinephrine causes vasoconstriction 3. No. it doesn't cause vasoconstriction. may block late phase reaction but not helpful in acute response. 4. Tryptase within 4 hours; 5. NO - if it was a large response, then would have used up all IgE. shold wait 6-8 weeks
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Name Anaphylaxis Mediators (3)
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Histamine, leukotrienes, NO
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Nitric oxide
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Anaphylaxis Mediator. Smooth muscle relaxation. increased permeability and dilatation
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