Introduction to Hypersensitivity & Allergy
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Transcript of Introduction to Hypersensitivity & Allergy
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Hypersensitivities
• Immune responses to innocent antigens or self antigens that lead to symptoms or tissue
damage
• Term “hypersensitivity” originally used to denote acquired immune response, as was
“allergy”
• “Hypersensitivity” and Allergy” most commonly refer to responses to innocent
antigens
• But autoimmune diseases are sometimes subset of hypersensitivity
• Atopy is term used to describe condition of general likelihood of responding with allergic
reaction
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Classified by mechanism (Gel and Coombs 1963)
• Type I, Immediate: IgE antibody triggering mast cells and eosinophils
• Type II, Antibody Mediated: IgGantibody reacting with cell surface or
matrix antigens
• Type III, Immune Complex Mediated: antigen-antibody
complexes
• Type IV: T cell mediated
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Type I: allergies. IgE and mast cells
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Usefulness of “Type I” IgE responses:
eliminating parasites, like helminths
Propulsive smooth muscle contraction,
mucus prevent infiltration of epithelium by parasites
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About 20% of people in US have some form of allergy
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• CD4 TH2 T cells cytokine profile leads to isotype switching to IgE
Sensitization phase:
• IgE triggers Mast cell degranulation
Effectorphase:
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Sequence of events in Type I, “immediate hypersensitivity”
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Eosinophils & Basophiles contribute to the chronic allergic reaction releasing similar chemicals mediators to IgE binding to FceeRI (which is induced in eosinophils by inflammation)
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• Helper T cells (TH2) that secrete IL-4, IL-5, and IL-13 are
responsible for inducing allergen specific IgEproduction
• Non-atopic individuals also have T cells that recognize
allergens after sensitization, but in normal individuals the
T cells are kept in check by Tregs (IL-10 and TGFb) • Normal people activate TH1 helper T cells and
make IgG antibodies to same antigens
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• Four distinct susceptibility genes identified so far
– G-protein coupled receptor expressed in inflamed tissue
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8% of children under 3, 4% of US adults Leading cause of
anaphylaxis outside of hospitals, 30,K ER cases per year
May lead to IgE or cell mediated responses, and be expressed any of atopic sites (gut, skin, bronchi,
systemic)
Gut largest immunologic organ for Food allergy
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•Systemic antigen, like bee sting
Systemic response of
IgE cross linking
receptors on connective tissue mast
cells and circulating basophils
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• Desensitization with protein or peptide antigens, with or without adjuvant
• Anti-IgE antibody • – Xolair approved in 03 for asthma, but not yet
tested for peanut allergy (Genentech)
• – TNX-901 very effective in clinical trials but removed
from testing by biotech squabbling (Tanox/Genentech
legal battle)
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• – Peanut allergy treated with treated with peptide plusHeatKilled Listeria, to induce TH1 response (in dogs, Frick 05)
• E.g., Arah 1,2, and 3 are peanut
proteins
• – Peptide epitopes recognized by CD4 TCRs have been determined
• – Therapy with Fel d 1 peptides increases TH1 T cellsrather then T reg T cells (Alexander 05)
Fel d 1 is component
of cat dander
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generation of IgG antibodies
that prevent
allergic antigen from reaching
IgE coated mast cells
Desensitization may also be due to
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Hygiene hypothesis
• Asthma and allergies increasing dramatically in recent years in
developed countries
• Exposure to pathogens (larger families, day care, farms) lowers
incidence of allergies
• Suggested that TH1 responses limit TH2responses, but TH1 and TH2
are not solely antagonistic, and basis of hygiene effects are notyet clear