Immunology
Allergy Response
IgE-mediated type I hypersensitivity — from sensitization to anaphylaxis
Allergy is the immune system mistaking a harmless protein for a threat. Type I hypersensitivity begins with sensitization: a Th2-skewed response makes B cells class-switch to IgE, which coats mast cells via the FcεRI receptor. On re-exposure, antigen cross-links these IgE molecules, triggering degranulation in seconds. Histamine, tryptase, leukotrienes, and prostaglandin D2 cause vasodilation, smooth muscle contraction, and mucus production. The clinical spectrum runs from sneezing to fatal anaphylaxis, and treatment ranges from antihistamines to intramuscular epinephrine.
- Mediator classIgE-coated mast cell degranulation
- OnsetSeconds to minutes after exposure
- Key mediatorHistamine (H1 and H2 receptors)
- First-line for anaphylaxisIM epinephrine 0.3-0.5 mg adult
- Biphasic reactionRecurs in 1-72 hours in ~5%
- Tryptase peak1-2 hours post-event
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Why allergy response matters
- Emergency medicine. Anaphylaxis is a time-critical diagnosis where minutes to epinephrine determine survival.
- Anesthesia. Neuromuscular blockers, antibiotics, and latex are the leading causes of perioperative anaphylaxis.
- Pediatrics. Food allergy now affects ~8% of children and shapes school nutrition policy and epinephrine access laws.
- Pharmacology. Beta-blockers blunt response to epinephrine; ACE inhibitors potentiate angioedema and complicate management.
- Pulmonology. Allergic asthma overlaps mechanistically; ICS and biologics like omalizumab target shared IgE pathways.
- Dermatology. Chronic urticaria and atopic dermatitis share mast cell and Th2 biology; dupilumab transformed treatment.
- Public health. Hygiene hypothesis links rising allergy prevalence to reduced microbial exposure during immune development.
Common misconceptions
- "Antihistamines treat anaphylaxis." They treat hives and itch; only epinephrine reverses airway and circulatory collapse.
- "You can outgrow all food allergies." Milk and egg allergies often resolve; peanut, tree nut, and shellfish usually persist for life.
- "A mild reaction last time predicts mild next time." Severity escalates unpredictably; prior mild reactions do not protect against future anaphylaxis.
- "Penicillin allergy is permanent." About 90% of labeled penicillin allergies are not real on testing; over-labeling drives broader-spectrum prescribing and resistance.
- "Steroids work fast." IV steroids take 4-6 hours to act; they prevent late-phase reactions but do not rescue acute symptoms.
- "Epinephrine is dangerous in young or healthy patients." IM epinephrine in the lateral thigh has an excellent safety margin; underuse kills, overuse rarely does.
Frequently asked questions
How does sensitization occur?
First exposure activates dendritic cells that present antigen to naive CD4 T cells. In allergy-prone individuals, the cytokine milieu (IL-4, IL-13) drives Th2 differentiation. Th2 cells signal B cells to class-switch from IgM to IgE. The IgE binds the high-affinity FcεRI receptor on tissue mast cells and circulating basophils, where it can persist for weeks. The patient is now sensitized but asymptomatic — symptoms only appear on re-exposure.
What happens during the reaction?
When allergen cross-links two adjacent IgE molecules on a mast cell, intracellular signaling triggers immediate degranulation. Preformed histamine, tryptase, and heparin are released within seconds. Newly synthesized leukotrienes C4, D4, E4 and prostaglandin D2 follow within minutes. Cytokines like TNF and IL-4 propagate inflammation over hours. Histamine causes vasodilation, increased permeability, bronchospasm, and itch through H1 receptors.
Why is anaphylaxis fatal?
Massive systemic mediator release causes simultaneous airway obstruction (laryngeal edema, bronchospasm), distributive shock (vasodilation, capillary leak — up to 35% of plasma volume can shift into tissue within 10 minutes), and arrhythmias. Death is usually from asphyxia or cardiovascular collapse. Untreated anaphylaxis has a mortality of about 1%, but delayed epinephrine is the single largest preventable factor.
Why epinephrine first, not antihistamines?
Epinephrine reverses the dangerous physiology directly. Alpha-1 agonism constricts vessels and reverses hypotension. Beta-2 agonism opens airways. Beta-1 agonism supports cardiac output. Mast cell stabilization at higher levels reduces ongoing release. Antihistamines and steroids only blunt secondary symptoms and have no role in reversing shock or upper airway edema. Delay in epinephrine is associated with fatality.
What is a biphasic reaction?
About 5-20% of anaphylaxis patients experience a recurrence 1-72 hours after the initial event, even without re-exposure. This reflects the late-phase response — recruited eosinophils and basophils releasing additional mediators. It is unpredictable and can be severe, which is why observation periods of 4-6 hours and prescription of an epinephrine autoinjector at discharge are standard.
How is allergy diagnosed?
Clinical history is primary. Skin prick testing introduces tiny amounts of allergen and reads a wheal-and-flare in 15 minutes; sensitivity is high but specificity moderate. Serum specific IgE (formerly RAST) quantifies antibody to specific allergens. Tryptase drawn 1-2 hours after a suspected anaphylactic event supports the diagnosis. Oral food challenges remain the gold standard for food allergy when results are equivocal.
What is desensitization?
Allergen immunotherapy delivers escalating doses of allergen subcutaneously or sublingually, shifting the immune response from Th2 to Treg/Th1, generating IgG4 blocking antibodies, and reducing mast cell reactivity. Effective for venom, environmental, and increasingly food allergy (oral immunotherapy for peanut). Treatment runs 3-5 years for durable benefit. Biologics like omalizumab (anti-IgE) and dupilumab (anti-IL4Rα) supplement therapy in refractory disease.