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)
Discuss the different modes of therapy for allergic rhinitis.
Environmental controls: indoor allergens
Mediator antagonists
o Antihistamines = effectively relieve sneezing and itching but not congestion
o Topical anticholinergic medication = relives rhinorrhea
o Leukotriene inhibitors/antagonists = some relief (primarily used for asthma)
o Decongestants
Anti-inflammatory agents
o Topical corticosteroids = reduce inflammation, relieve nasal congestion
• Use with caution in eye (potential side effects)
Anti-allergic medications
o Cromolyn sodium
o Lodoxamide
Immunotherapy
o If resistant to treatment
o Gradually changes T cell response to decrease TH2 cytokine secretions
o Adverse effects: local swelling (common) and anaphylaxis (rare)
Describe the pathogenesis of allergic asthma
Asthma = allergic inflammation: o Bronchial smooth muscle constriction o Airway inflammation o Edema o Mucus o Remodeling: • Smooth muscle hyperplasia/hypertrophy • Mucus gland hyperplasia and hypersectretion • Angiogenesis • Collagen deposition
Impairment due to asthma: o Current symptoms o Nighttime awakenings o Limitations of normal activities o Use of rescue inhaler o Lung function measurement
Risk
o Exacerbations requiring steroids
o Loss of lung function
Define the following terms: atopy and allergen.
- Atopy: genetic predisposition to the formation of increased levels of IgE Ab
- Allergen: antigen capable of eliciting an IgE Ab response
Differentiate food allergy and food intolerance.
Allergy: immunologic mechanism
Type I hypersensitivity reaction (mast cell activation)
• Occurs quickly (seconds/minutes to 1-2 hrs) after food ingestion
• Can be life-threatening
• Occurs reproducibly
• Can occur with tiny amounts of food protein exposure (250 mcg)
• Demonstrable food-specific IgE
Other mechanisms:
• Celiac disease
• “allergic” proctocolitis
• Food-induced enterocolitis syndrome
Food intolerance: non-immunologic o Pharmacologic (caffeine, histamine) o Toxic (food poisoning) o Metabolic (lactase deficiency) o Idiopathic
Discuss the clinical manifestations of food allergy
Skin o Hives (urticaria) o Angioedema o Atopic dermatitis (eczema) o Generalized pruritus
Respiratory o Throat tightness o Hayfever symptoms o Asthma, wheezing o Itching of tongue o Rhinoconjunctivitis = itching, rhinorrhea, congestion
Gut
o Itching or edema of mouth or tongue
o Nausea, vomiting, diarrhea
o Abdominal pain
Anaphylaxis
Neurologic manifestations
o Migraines, seizures (rare)
o Behavioral problems = no link!
o Feeling of dread
Common allergens:
Children: milk, eggs, peanuts, soy, wheat
• Most outgrow milk, egg, soy, and wheat allergy
• Less common to outgrow peanut or tree nuts
Adults: tree nuts, peanuts, seafood, shellfish
• Seafood allergies often develop in adults and persist
• Allergies that start in adults are unlikely to resolve
Oral allergy syndrome:
o Mucosal or cutaneous symptoms with fresh but not cooked foods
o Anaphylaxis unusual (celery)
o Fresh fruits and vegetables cross-react with pollen allergens
• Ex: birch and apple
• Ex: ragweed and melon
o Diagnose: skin tests with fresh juices
Differentiate drug allergy from other adverse reactions to drugs.
• An unpredictable reaction = only occurs in small subset of population
o Idiosyncratic reactions: pharmacogenetics, G6PD deficiency
Immunologic: (types I and IV most common)
• Type I: IgE or mast cell; anaphylaxis
• Type II: antibody mediated; rare
• Type III: Immune complexes of IgG and antigen; rare; ex: serum sickness
• Type IV: Delayed type; contact dermatitis, DTH reaction
Paradoxical reactions: antihistamines → hyprkinetic behavior in children
Genetic defects
• G6PD deficiency → hemolytic anemia with reducing agents
Treatment:
o Stop drug
o Pick alternative drug, avoiding same drug family if possible
o Symptom relief: antihistamines (itching), NSAIDs (joint swelling), epinephrine (anaphylaxis) or corticosteroids
o Patient education
Describe the clinical manifestations of anaphylaxis.
Manifestations:
o Urticarial, angioedema, nausea, vomiting, diarrhea, wheezing, SOB, arrhythmias, hypotension, death
Inciting agents: Food • IgE mediated Medications: • IgE mediated: penicillin • Non-IgE mediated: NSAIDs Physical (exercise): • Usually non-IgE mediated • Can potentiate effects of IgE mediated allergy Autoimmune: • Rare • Ab to FcεRI on mast cells and basophils
Describe the treatment of anaphylaxis (to include drug/dose/route).
Epinephrine
o Epi: 1:1000 dilution, 0.01 mL/kg IM (max 0.3 mL)
• Repeat every 5-10 minutes as needed
• Effect: constricts blood vessels, prevents mast cell degranulation, relaxes smooth muscles in airway, promotes cardiac contractility
o Oxygen
o IV fluids
o Glucocorticosteroids (prevent late phase reaction)
o H1 and H2 antihistamines
o Pressors (if not responding to epinephrine)
