Type I Hypersensitivity

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Type I Hypersensitivity
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Definition of Hypersensitivity

• An immunologic reaction which produces tissue
  damage on reexposure 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)

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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)

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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

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Type I Hypersensitivity Diseases

• Allergic rhinoconjunctivitis (hay fever)
• Asthma
• Eczema (atopic dermatitis)
• Acute urticaria
• Anaphylaxis

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J. M. Oliver et al.
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Mast Cell Mediators

• Preformed
• Vasoactive amines histamine
• Neutral proteases tryptase, chymase
• Acid hydrolases b-hexoseaminidase
• Proteoglycans heparin, chondroitin sulfate
• Newly formed
• Eicosanoids PGD2, LTC4
• Cytokines TNFa, 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 have
  total tryptase levels that are elevated (gt 20
  ng/ml) and are at least 10-fold greater than
  their ? tryptase level.

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Histamine

• Produced almost exclusively by basophils and 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 the Skin The Triple
Response

• Local erythema - H1 (and some H2)-mediated
  arteriolar dilatation
• More widespread flare from antidromic release of
  Substance P from sensory nerves
• Wheal produced by increased vascular permeability

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Acute Phase Allergic Reaction

• Occurs within seconds to minutes of IgE receptor
  activation (mast cell mediator release) and
  resolving within 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 at 4-8
  hrs and persisting up to 24 hrs) following an
  intense acute phase reaction
• Skin erythema, induration, burning
• Lungs airway obstruction poorly responsive to
  bronchodilators
• Nose/eyes erythema, congestion, burning
• Histology mast cell degranulation followed by
  influx of first neutrophils and eosinophils
  followed by mononuclear cells
• Major portion of effects replicated by TNFa

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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

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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)

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Type II Hypersensitivity ReactionsMechanisms 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 ReactionsExamples of
Diseases

• Transfusion reactions
• Hemolytic disease of the newborn
  (Rh incompatibility)
• Hyperacute graft rejection
• Drug-induced hemolytic anemia

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Transfusion Reactions
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Hemolytic Disease of the Newborn
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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 IV (Delayed-type hypersensitivity)

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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 enzymes and cytokines into the
  local microenvironment

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Type III HypersensitivityExamples of Diseases

• Arthus reaction
• Hypersensitivity pneumonitis
• Immune complex-mediated glomerulonephritis
• Serum sickness

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The Arthus Reaction

• Occurs with introduction of antigen into an
  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 Pneumonitis Syndromes and
Associated Antigens

• Farmers lung (thermophilic actinomycetes)
• Malt workers lung (Aspergillus spores)
• Pigeon fanciers disease (avian proteins)
• Cheese washers lung (Penicillium spores)
• Furriers lung (fox fur)
• Laboratory technicians lung (rat urine proteins)

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A Dominant Role for Mast Cell Fc Receptors in the
Arthus Reaction
Sylvestre et al, 1996, Immunity 5387
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A Control ?-/- B Control ?/ C Control
W/Wv D W/Wv reconstituted with ?-/- mast cells
or E ?/ mast cells
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Serum Sickness

• Fever, rash, joint pain, lymphadenopathy,
  occasionally glomerulonephritis
• Timecourse days to weeks after introduction of
  foreign antigen
• Causes allogeneic serum, drugs, infections,
  autoimmune disorders

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Serum Sickness Reactions
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Serum Sickness Reactions
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Common Locations of Vascular Involvement
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Autoimmune Glomerulo-nephritis
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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)

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