Type I Hypersensitivity Reaction (Immediate Hypersensitivity)

Overview: Sequence of Events

Step 1: Sensitization Phase (First Exposure)

1. Antigen presentation: Dendritic cells process and present allergen peptides to naive CD4+ T cells. Epithelial cytokines - IL-25, IL-33, and TSLP - promote a type 2 immune environment.
2. Th2 differentiation: Naive T cells differentiate into Th2 cells and T follicular helper (Tfh) cells, which produce IL-4 and IL-13.
3. IgE class switching: IL-4 and IL-13 drive B cells to undergo class-switch recombination, producing allergen-specific IgE from plasma cells.
4. Mast cell sensitization: IgE binds via its Fc portion to high-affinity FcεRI receptors on mast cells and basophils. These IgE-coated cells are now "sensitized" and ready to react.

• Cellular and Molecular Immunology, p. 1303-1307

Key point: No clinical symptoms occur at this stage. The individual has no adverse reaction on first exposure (with rare exceptions).

Step 2: Elicitation Phase (Re-exposure - "Challenge")

• The allergen (being multivalent) cross-links adjacent IgE antibodies on the mast cell surface.
• This brings the underlying FcεRI receptors together, triggering intracellular signal transduction cascades.
• The result: mast cell activation and degranulation - release of preformed and newly synthesized mediators.

"IgE-coated mast cells are said to be sensitized because they react to subsequent encounters with antigen. If the antigen is multivalent, it binds to and cross-links adjacent IgE antibodies, bringing the underlying Fce receptors together." - Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 200

Mast Cell Mediators

A. Preformed Granule Mediators (Released within seconds)

Plasma histamine peaks ~10 minutes after anaphylaxis onset; returns to normal within 1 hour. Serum tryptase is elevated in anaphylaxis (and chronically elevated in systemic mastocytosis). Urinary histamine may remain elevated for 24 hours. - Quick Compendium of Clinical Pathology

B. Newly Synthesized Lipid Mediators (Produced within minutes)

• Cyclooxygenase pathway → Prostaglandin D2 (PGD2): Most abundant mast cell cyclooxygenase product; causes intense bronchospasm and increases mucus secretion.
• 5-Lipoxygenase pathway → Leukotrienes:
  • LTC4 and LTD4: Most potent vasoactive and spasmogenic agents known; thousands of times more active than histamine on a molar basis in causing bronchospasm and increasing vascular permeability.
  • LTB4: Highly chemotactic for neutrophils, eosinophils, and monocytes.
• Platelet-activating factor (PAF): Derived directly from membrane phospholipids; contributes to vascular and bronchospastic effects.
• Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 200-201

C. Cytokines (Produced over hours)

Phase Breakdown: Immediate vs. Late-Phase Reaction

Immediate Reaction (seconds to ~1 hour)

• Driven by histamine, LTC4, LTD4, PGD2
• Manifestations: vasodilation, vascular leakage, smooth muscle spasm, mucus secretion
• Clinically: bronchospasm, urticaria, rhinorrhea, anaphylaxis

Late-Phase Reaction (2-24 hours after allergen exposure)

• Leukocytes (especially eosinophils) are recruited by eotaxin and mast cell-derived chemokines.
• IL-5 from Th2 cells activates eosinophils, which release:
  • Proteolytic enzymes
  • Major basic protein (MBP) and eosinophil cationic protein - cause tissue damage
  • Galectin-10 - forms Charcot-Leyden crystals (seen in sputum of asthmatics)
• The late-phase reaction is a major driver of symptoms in asthma - this is why antihistamines alone are insufficient for asthma; corticosteroids are required.
• Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 201

Atopy and Genetic Predisposition

• Elevated serum IgE levels
• More IL-4-producing Th2 cells than general population
• Positive family history in ~50% of atopic individuals
• Genetic linkage to polymorphisms in IL-3, IL-4, IL-5, IL-9, IL-13, GM-CSF genes, and HLA loci on chromosome 6
• The atopic triad (atopic march): atopic dermatitis (infancy) → allergic rhinitis → asthma (childhood)

"A positive family history of allergy is found in almost 50% of atopic individuals." - Robbins, Cotran & Kumar Pathologic Basis of Disease

Nature of Allergens

• Molecular weight: 5-70 kD
• Stable, glycosylated, soluble in body fluids
• Many are enzymes (e.g., cysteine protease of house dust mite, PLA2 in bee venom)
• T cell-independent antigens (polysaccharides) cannot elicit type I reactions unless protein-conjugated
• Cellular and Molecular Immunology, p. 1306

Clinical Manifestations

"In the most extreme systemic form, called anaphylaxis, mast cell-derived mediators can restrict airways to the point of asphyxiation and produce cardiovascular collapse leading to shock, which together may result in death." - Cellular and Molecular Immunology, p. 1303

Non-IgE-Mediated (Nonatopic) Triggers

• Temperature extremes (heat, cold)
• Exercise
• Drugs (codeine, morphine, contrast media)
• Complement anaphylatoxins (C3a, C5a)
• Bee venom components (melittin)

Note: Anaphylactoid reactions and hereditary angioedema are NOT classified as Type I hypersensitivity reactions. - Quick Compendium of Clinical Pathology

Diagnosis

• Tietz Textbook of Laboratory Medicine, p. 3972

Treatment

"The best prevention relies on the identification of the antigen (detected by skin test or IgE antibody serology) and subsequent avoidance." - Jawetz, Melnick & Adelberg's Medical Microbiology

Th2 Cytokines and Their Role

Summary

1. Sensitization: First allergen exposure → Th2/IgE production → mast cell sensitization (no symptoms)
2. Elicitation: Re-exposure → IgE cross-linking → mast cell degranulation → immediate reaction (histamine, leukotrienes) + late-phase reaction (eosinophils, cytokines)