Type I Hypersensitivity Reaction - Mechanism

Phase 1: Sensitization (First Exposure)

1. Allergen entry: Allergens (pollen, house dust mite proteins, food proteins, drugs) enter via mucosal surfaces and are captured by dendritic cells (DCs).
2. T cell polarization: DCs present allergen peptides to naive T cells, which differentiate into Th2 cells (and T follicular helper [Tfh] cells). Th2/Tfh cells produce IL-4 and IL-13.
3. IgE class switching: IL-4 and IL-13 act on allergen-specific B cells, promoting class-switch recombination from IgM/IgG to IgE production. Plasma cells then secrete large amounts of IgE.
4. Mast cell sensitization: IgE binds with extremely high affinity to FcεRI (Fc epsilon receptor type I) on tissue mast cells and circulating basophils. The mast cells are now "armed" - this is sensitization.

At this point the person is sensitized but asymptomatic.

Phase 2: Effector Phase (Re-exposure / Elicitation)

1. Allergen cross-linking: The allergen binds to and cross-links two or more adjacent IgE molecules on the mast cell surface. This aggregates the FcεRI receptors.
2. Mast cell activation: Cross-linking of FcεRI activates intracellular signaling (Lyn kinase → Syk kinase → downstream phospholipase C pathway), leading to:
   • Rise in intracellular Ca²+
   • Degranulation - preformed granule contents released within seconds to minutes

Mediators Released

• Cellular and Molecular Immunology, Table 20.2

Immediate vs. Late-Phase Reactions

• Immediate reaction (within minutes): Driven by vasoactive amines (histamine) and lipid mediators - causes rapid vasodilation, bronchoconstriction, and mucus secretion.
• Late-phase reaction (2-4 hours after re-exposure): Driven by cytokines (especially IL-4, IL-5, TNF) released by mast cells. These recruit eosinophils, neutrophils, and more Th2 cells, causing a prolonged inflammatory response.

Clinical Manifestations

• Systemic - Anaphylaxis (most severe - airway restriction + cardiovascular collapse)
• Respiratory - Allergic asthma, allergic rhinitis (hay fever)
• Skin - Urticaria (hives), angioedema, atopic dermatitis
• GI - Food allergy symptoms (abdominal pain, diarrhea)
• Eyes - Allergic conjunctivitis

• Serum tryptase - elevated in anaphylaxis (peaks at ~1 hour; also chronically elevated in systemic mastocytosis)
• Plasma histamine - peaks rapidly (~10 minutes), returns to normal within 1 hour
• Urinary histamine - may remain elevated for 24 hours

• Katzung's Basic and Clinical Pharmacology, 16th Ed., pp. 1524-1525
• Cellular and Molecular Immunology (Abbas), 10th Ed., pp. 1302-1308
• Quick Compendium of Clinical Pathology, 5th Ed., p. 4360

Why NOT Type I: Important Distinctions

• Anaphylactoid reactions - clinically similar to anaphylaxis but NOT IgE-mediated (direct mast cell degranulation by drugs like morphine, radiocontrast media) - not true Type I hypersensitivity
• Hereditary angioedema - complement-mediated (C1 inhibitor deficiency) - not Type I
• Type II - antibody-mediated cytotoxicity (IgG/IgM on cell surfaces)
• Type III - immune complex-mediated (IgG + antigen complexes + complement)
• Type IV - delayed-type (T cell and macrophage mediated, 48-72 hrs)

Haptens

Definition

"Immunization with free hapten produces no antibodies to the hapten. However, immunization with hapten groups linked to a protein carrier generates antibodies that react with high affinity to hapten alone or linked to a molecule other than the carrier."

• Roitt's Essential Immunology

The Classic Demonstration

• Injecting a free hapten (e.g., m-aminobenzene sulfonate) alone → no antibody produced
• Injecting hapten conjugated to a carrier protein (e.g., ovalbumin) → produces anti-hapten AND anti-carrier antibodies
• The antibodies produced can then react with the free hapten in vitro

Why Haptens Alone Cannot Induce an Immune Response

Three Key Rules of the Hapten-Carrier Effect (Abbas, Cellular & Molecular Immunology)

1. Both hapten-specific B cells AND carrier-specific T helper cells are required - the response is T cell-dependent
2. Hapten and carrier must be physically linked - administering them separately cannot induce an anti-hapten response. The hapten is responsible for the efficient internalization of the carrier protein into the B cell
3. The interaction is MHC class II-restricted - helper T cells cooperate only with B cells that express the same class II MHC molecules involved in the initial T cell activation by dendritic cells

Mechanism Step-by-Step

1. Hapten-carrier conjugate enters the body
2. Hapten-specific B cell binds the conjugate via its BCR (recognizing the hapten epitope)
3. The B cell endocytoses the entire hapten-carrier conjugate
4. The carrier protein is proteolytically processed inside the B cell into linear peptides
5. These peptides are loaded onto class II MHC molecules and displayed on the B cell surface
6. A carrier-specific CD4+ T cell (Th cell) recognizes the class II MHC-peptide complex
7. T cell delivers help via CD40L-CD40 interaction + cytokines (IL-4, IL-21)
8. B cell activates, proliferates, undergoes isotype switching, and differentiates into plasma cells secreting anti-hapten antibodies

Clinical Relevance

• Drugs like penicillin bind to RBC membranes (haptenize them)
• Anti-drug IgG antibodies then coat the RBCs → complement activation → hemolysis (Type II hypersensitivity)

Application: Conjugate Vaccines

• Polysaccharide capsule antigens (equivalent to haptens - recognized by B cells but T cell-independent and weak in infants) are covalently linked to carrier proteins (e.g., tetanus toxoid, CRM197)
• This converts the weak T-independent polysaccharide response into a strong T-dependent response with isotype switching, affinity maturation, and immunologic memory
• Examples: Hib (H. influenzae type b), PCV (pneumococcal), MCV (meningococcal) vaccines

• Cellular and Molecular Immunology (Abbas), 10th Ed., pp. 769-771
• Roitt's Essential Immunology, p. 163
• The Washington Manual of Medical Therapeutics, p. 1215