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Type I Hypersensitivity

Definition of Hypersensitivity

An immunologic reaction whichproduces tissue damage onreexposure to antigen.

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Gell and Coombs Classification

• Type I (IgE-mediated)• Type II (Fc and complement-mediated)• Type III (Immune complex-mediated)• Type IV (Delayed-type hypersensitivity)

Gell and Coombs Classification

•• Type I (IgE-mediated)Type I (IgE-mediated)• Type II (Fc and complement-mediated)• Type III (Immune complex-mediated)• Type IV (Delayed-type hypersensitivity)

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Type I Hypersensitivity:History of Discoveries

• Anaphylaxis: Portier and Richet, 1902• Histamine: Dale and Laidlaw, 1911• Transfer of sensitivity: Prausnitz &

Küstner• Mast cells as main tissue source of

histamine: Riley and West, 1952• IgE immunoglobulin: Ishizaka and

Ishizaka, 1966

Type I Hypersensitivity Diseases

• Allergic rhinoconjunctivitis (hayfever)

• Asthma• Eczema (atopic dermatitis)• Acute urticaria• Anaphylaxis

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Mast Cell Mediators

• Preformed– Vasoactive amines: histamine– Neutral proteases: tryptase, chymase– Acid hydrolases: β-hexoseaminidase– Proteoglycans: heparin, chondroitin sulfate

• Newly formed– Eicosanoids: PGD2, LTC4– Cytokines: TNFα, IL-4, IL-5, IL-6

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Mast Cell Tryptase

• Tetrameric serine protease• Found only in mast cells, not basophils• Peaks in 1 hour and remains elevated 4-6 hours in

serum following release in anaphylaxis• Alpha isoform is predominant in blood: most

mastocytosis patients with systemic disease havetotal tryptase levels that are elevated (> 20 ng/ml)and are at least 10-fold greater than their βtryptase level.

Histamine

• Produced almost exclusively by basophilsand mast cells (3-8 pg/cell)

• Immediate pharmacologic effects:– pruritus (H1)– ↑ vascular permeability/vasodilatation (H1)– smooth muscle contraction (H1)– gastric acid secretion (H2)

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Injection of Histamine in theSkin: The Triple Response

• Local erythema - H1 (and some H2)-mediated arteriolar dilatation

• More widespread flare from antidromicrelease of Substance P from sensorynerves

• Wheal produced by increased vascularpermeability

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Acute Phase Allergic Reaction:

• Occurs within seconds to minutes ofIgE receptor activation (mast cellmediator release) and resolvingwithin an hour

• Intense pruritus, edema, erythema• Almost all effects can be replicated

with histamine

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Late Phase Allergic Reaction:

• A delayed inflammatory response (peaking at4-8 hrs and persisting up to 24 hrs) followingan intense acute phase reaction– Skin: erythema, induration, burning– Lungs: airway obstruction poorly responsive to

bronchodilators– Nose/eyes: erythema, congestion, burning

• Histology: mast cell degranulation followedby influx of first neutrophils and eosinophilsfollowed by mononuclear cells

• Major portion of effects replicated by TNFα

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Therapy of Allergic Disease

• Inhibition of IgE synthesis: Immunotherapy• Inhibition of IgE binding to receptor:

– Monoclonal anti-IgE (Xolair (Omalizumab)• Inhibition of mast cell mediator release:

– Topical corticosteroids– Cromolyn, nedocromil

• Inhibition of mediator action:– Antihistamines– Leukotriene receptor antagonists– Topical and systemic corticosteroids

Gell and Coombs Classification

• Type I (IgE-mediated)•• Type II (Fc and complement-mediated)Type II (Fc and complement-mediated)• Type III (Immune complex-mediated)• Type IV (Delayed-type hypersensitivity)

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Type II Hypersensitivity Reactions:Mechanisms of Tissue Damage

• Complement-mediated cytolysis• Antibody-dependent cell-mediated

cytotoxicity (ADCC)

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Type II

Reactions

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Type II Hypersensitivity Reactions:Examples of Diseases

• Transfusion reactions• Hemolytic disease of the newborn

(Rh incompatibility)• Hyperacute graft rejection• Drug-induced hemolytic anemia

Transfusion

Reactions

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Hemolytic Disease of the Newborn

Hemolytic Disease of the Newborn

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Mechanisms

Of Drug

Hypersensitivity

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Gell and Coombs Classification

• Type I (IgE-mediated)• Type II (Fc and complement-mediated)•• Type III (Immune complex-mediated)Type III (Immune complex-mediated)• Type IV (Delayed-type hypersensitivity)

Type III HypersensitivityMechanisms of Tissue Injury

• In situ activation of complement• Anaphylatoxin-mediated activation of

mast cells and phagocytes• Complex-mediated phagocytosis and

release of phagocyte granule enzymesand cytokines into the localmicroenvironment

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Type III HypersensitivityExamples of Diseases

• Arthus reaction• Hypersensitivity pneumonitis• Immune complex-mediated

glomerulonephritis• Serum sickness

The Arthus Reaction

• Occurs with introduction of antigen intoan individual with high titer antibody

• Requires both complement & phagocytes• Peaks at 3-6 hours after exposure• Histology: massive influx of neutrophils,

edema, sometimes necrosis

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Hypersensitivity PneumonitisSyndromes and Associated Antigens

• Farmer’s lung (thermophilic actinomycetes)• Malt worker’s lung (Aspergillus spores)• Pigeon fancier’s disease (avian proteins)• Cheese washer’s lung (Penicillium spores)• Furrier’s lung (fox fur)• Laboratory technician’s lung (rat urine

proteins)

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Serum Sickness

• Fever, rash, joint pain, lymphadenopathy,occasionally glomerulonephritis

• Timecourse: days to weeks afterintroduction of foreign antigen

• Causes: allogeneic serum, drugs, infections,autoimmune disorders

SerumSicknessReactions

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SerumSicknessReactions

CommonLocations of

VascularInvolvement

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AutoimmuneGlomerulo-nephritis

Gell and Coombs Classification

• Type I (IgE-mediated)• Type II (Fc and complement-mediated)• Type III (Immune complex-mediated)•• Type IV (Delayed-type hypersensitivity)Type IV (Delayed-type hypersensitivity)

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Type IV Hypersensitivity Reactions

• Contact dermatitis• Foreign body reaction• Infection-associated

– Mycobacterial– Fungal– Viral

• Chronic graft rejection

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Ocular Allergy

• Allergic conjunctivitis• Vernal conjunctivitis• Atopic keratoconjunctivitis• Giant papillary conjunctivitis• Contact allergy

Ocular Contact Allergy: Causes

• Topical medications• Cosmetics, eyeliner, mascara• Hair products• Creams• Nail polish• Soaps, detergents• Numerous others

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Ocular Contact Allergy:Clinical Features

• Frequently a complication of topicaleye medications

• Conjunctival injection, chemosis,watery discharge

• Eczema of periorbital skin

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Ocular Contact Allergy:Therapy

• Remove offending agent• Cold compresses• Topical or systemic steroids

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