Allergic Disorders Flashcards
IgE antibody properties
- Polyclonal IgE Ab detected at 12 weeks gestation
- At birth = start to form antigen-specific Ab’s
- 18 months-2 years = aeroallergens
- Properties
- 1 heavy chain (ε) and 2 light chains (κλ)
- Long latency in skin
- Heat labile
IgE antibody production
• Naïve CD4 T cells encounter antigen in presence of IL-4 → TH2 cells
• TH2 cells release cytokines (IL-4, IL-13)
• Promote B cell switching = production of IgE instead of IgM
Other signals in class switching and proliferation:
o CD40 ligand (on T cell) binds CD40 (on B cell)
o B7 binding to CD28
Other events in IgE production:
o IL-4 receptors bind on B cells
o Activation of JAK1 and JAK3 (tyrosine kinases)
o STAT6 phosphorylation
o STAT6 binds to IL-4 promoter in nucleus
o Activation of Cε gene transcription
Allergen hypersensitivity skin testing
o Detects IgE in skin mast cells
o Most common and sensitive clinical test
o Can be early (by 1 month of age)
o Test:
• Detect IgE Ab on surface of cutaneous mast cells
• Mast cells respond to IgE cross-linking → mediator release
• Skin responds to mediator release
• Wheals form
Immunoassays
o For specific IgE in serum
o Called “RAST”
Provocation studies
o Used to see if treatment working or if food allergy has been lost
Types of IgE receptors
FcεRI
o High affinity
o Binds CH3 domain of IgE
o Present on mast cells, basophils, Langerhans cells, dendritic cells
o Structure = multi-subunit complex:
• α –chain
• Extracellular part binds Fc of IgE
• β- chain
• Involved in amplifying receptor signal
• 2 disulfide-linked γ-chains
• Signal transducing molecules
o Crosslinking of IgE receptors → mast cell/basophil activation (allergen binds 2 IgE molecules)
o Level of IgE influence number of receptors
• Increased IgE → increases number of receptors
FcεRII
o Low affinity
o Binds CH2-4
o Present on B cells, NK cells, eosinophils, macrophages, platelets
o Stimulation with antigen results in cell activation
o Unknown exact biologic significance
IgE target organ biologic effects
o Nose → rhinorrhea, itching, sneezing, congestion
o Lung → wheezing, coughing, SOB
o Skin → urticarial/angioedema, atopic dermatitis
o Eye → itching, watering, redness
o GI → food allergies
o Systemic → arrhythmia, hypotension, any of above
Mast cells vs basophils
Mast cells Origin • CD34+ progenitors from bone marrow • Mature in peripheral tissue • Growth factors: IL-3, IL-4, IL-9, IL-10, nerve growth factor, stem cell factor (c-kit ligand) Location • Present throughout CT, especially near epithelial surfaces exposed to environment • Heterogeneous cell population • Morphological differences (staining and size) • Functional differences (types mediators, pharmacologic response) Histamine content • Higher Steroid effects • None Cycoloxygenase inhibition • None AA metabolism • PGD2, LTC4, and other leukotrienes
Basophils Origin • CD34+ progenitors in bone marrow • Mature in bone marrow Location • Circulate in periphery • Differentiation based on IL-3 • Express FcεRI • Secrete sorted and Histamine content • Lower Steroid effects • Inhibit mediator release Cycoloxygenase inhibition • Augments mediator release AA metabolism • No PGD2, small amounts of leukotrienes
Describe the mechanisms and agents responsible for mast cell activation / secretion that are non-IgE mediated
Endogenous
• Complement fragments C5a (receptor mediated) and C3a
• Neuropeptides (substance P, somatostatin)
• ATP
• Adenosine (potentiates secretion)
• Neutrophil lysosomal proteins
• Eosinophil major basic protein
• Cytokines
• Histamine releasing factors
• IL-3, GM-CSF, IL-1α, and IL-1β = enhance basophil histamine release
Exogenous • Anesthetic agents (succinylcholine, d-tubocurare) • Antibiotics (polymyxin B) • Narcotics (morphine, codeine) • Iodinated contrast material
List the principal preformed and generated mast cell mediators.
Preformed Vasoactive amines • Histamine → vasopermeability, vasodilation, pruritus, mucus secretion • Serotonin (non-primates) Proteoglycans • Heparin → anticoagulant • Chondroitin sulfates Neutral proteases • Tryptase (can be measured in blood) • Chymotryptic proteases Acid hydrolases • Beta-hexosaminidase • Beta- glucuronidase Chemotactic factors for: • Eosinophils (ECF-A) • Neutrophils (NCF-A) Peroxidase and superoxide → toxic oxygen species
Generated
Arachidonic acid products
• Cyclooxygenase products
• Prostaglandins (mostly PGD2; mast cells only) → vasopermeability, bronchospasm, chemotaxis, inflammation
• Lipoxygenase products
• Leukotrienes C4, D4, E4 (slow reacting substances of anaplylaxis) → vasopermeability, bronchospasm
Platelet activating factor → chemotaxis, smooth muscle constriction, hypotension, platelet activation
Cytokines (growth and regulatory factors)
• Interleukins (IL-3, IL-4, IL-5, IL-6)
• Inflammatory factors (TGF-β, TNF-α)
• Interferon γ
• Growth factors (ex: GM-CSF)
Describe late-phase reactions.
Isolated immediate response
o Occurs in minutes
o Granule contents released: histamine, TNF-α, proteases, heparin
o Lipid mediators: leukotrienes, prostaglandins
Dual response (immediate and late reactions)
Immediate reaction
• Minutes
Late reaction
• 4-12 hours
• Reflects tissue inflammation started by mast cell activation
• Involves cytokine production (IL-4, IL-13)
o Important feature of many allergic disease
o Can lead to chronic inflammation
Compare the skin test and RAST procedures for sensitivity testing
Skin testing (immediate hypersensitivity)
o Prick-puncture technique
o Intradermal technique
o Positive test result = Classic wheal and flare response
o In vivo tests
o Most common and most sensitive test used clinically
RAST (radioallergosorbent) test
o Uses radiolabeled Iodine
o In vitro test for allergen specific to IgE
o Not widely used
ELISA assay
o Uses enzyme linked to anti-IgE
o In vitro test for allergen specific to IgE
Describe the signs and symptoms of allergic rhinitis.
Inflammatory disease of upper airways o IgE mediated o Nasal inflammation Often presents first in childhood and adolescence, tends to decrease in severity over decades o Positive family history of atopy (genetic predisposition to develop an allergic reaction and IgE overproduction) o Seasonal or perennial o Chronic or intermittent Prevalence of 10-30% in adults
Clinical manifestations o Congestion o Post-nasal drip and rhinorrhea o Pruritus (“allergic salute”) o Sneezing o Ocular congestion, redness, itching o Allergic shiners, Dennie’s lines Complication • Sinusitis • Nasal polyposis (mostly in adults) • Otitis media • Allergic conjunctivitis
Describe the pathogenesis of allergic rhinitis.
Binding of allergen to allergen-specific IgE on mast cells
Triggers mediator release
Pre-formed: histamine, proteases
De novo synthesis:
• Arachodonic acid metabolites (leukotrienes and prostaglandins)
• Cytokines = recruit and activate inflammatory cells
Late phase inflammation
• Increased expression of cell adhesion molecules by endothelium
• Local release of cytokines and chemotactic factors
• Influx of eosinophils, basophils, and activated lymphocytes
Discuss methods to diagnose allergic rhinitis.
Diagnosis o History Physical exam • Swelling of nasal mucosa with clear rhinorrhea • Boggy, pale turbinates • Conjunctival inflammation • Allergic shiners (discoloration under the eyes) • Nasal crease • Mouth breathing
Laboratory tests
• In vitro IgE (immunocap, RAST)
• Skin tests
• Nasal smear (eosinophils)
