Download Notes on Allergy

Immunology: Allergy and Hypersensitivity (Sundick)
DEFINITIONS:
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Allergy: a type of hypersensitivity reaction (type I) mediated by IgE
o Poylgenic: MHC, IL4 gene cluster, other loci
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Hypersensitivty: an exaggerated immune response to an innocuous agent that yields tissue injury and disease
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Allergen: substance that induces IgE; proteins, drugs that bind protein (penicillin); helminthic worms also stimulate
high IgE
HYPERSENSITIVTY REACTIONS:
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Type I:
Immune Reactant: IgE
Antigen: soluble Ag
Effector Mechanism: mast cell activation
Examples:
o Systemic Anaphylaxis: vascular permeability, laryngeal edema, shock; usually due to drugs, venom or
peanuts (IV/oral route)
o Rhinitis (Hay Fever): nasal edema, sneezing; usually due to pollen or dust mite feces (inhalation route)
o Asthma: bronchial constriction, mucus production; usually due to dander, pollen, or dust (inhalation)
o Food Allergy: vomiting, hives, anaphylaxis; common examples are peanuts, shellfish and eggs (oral)
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Type II:
Immune Reactant: IgG
Antigen: cell or matrix associated Ag
Effector Mechanism: activate complement, attract FcR+ cells (phagocytes, NK cells) to bind IgG; these can
damage self-cells
Examples: some drug allergies (ie. penicillin- however, can also stimulate IgE release)
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Type III:
Immune Reactant: IgG
Antigen: soluble antigen
Effector Mechanism: formation of immune complexes that activate complement and attract phagocytes,
resulting in localized tissue damage
Examples: Serum sickness (immune complexes deposit in vascular system), Arthus reaction
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Type IV:
Two Major Pathways:
o Immune Reactant TH1:
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Antigen: soluble, stimulates TH1 cells to be produced
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Effector Mechanism: TH1 cells activated macrophages (IFN-gamma), causing cytokines,
chemokines, and cytotoxins to be released
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Examples: contact dermatitis, tuberculin reaction
o Immune Reactant CD8+ T cell:
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Antigen: cell associated
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Effector Mechanism: cytotoxicity
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Examples: contact dermatitis (poison ivy)
TYPE I HYPERSENSITIVITY:
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First Phase- Sensitization: exposure to allergen induces B cells to produce IgE
IgE production requires TH2 cells (produce IL4 and IL13)
IgE is short lived in the blood but persists for months bound to mast cells in tissues and basophils in the blood;
bound via FcεRI receptors (bind Fc portion of IgE)
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Second Phase- Activation: IgE present on mast cell is crosslinked, causing activation and rapid release of granules
Allergen must be at least bivalent (in order to cross-link)
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Third Phase- Effector Phase: allergic symptoms result due to substances produced and released by mast cells
Preformed Substances:
o Histamine: major agent involved in allergic symptoms
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Binds H1 receptors on smooth muscle (bronchial constriction) and on endothelial cells
(vascular permeability); lead to systemic anaphylaxis
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Binds H2 receptors involved in mucus secretion, vascular permeability and secretion of
stomach acid
o Chemotactic factors: IL8 (PMNs) and eosinophil chemotactic factor (ECF)
o Other Cytokines: IL3, IL4, IL5, GM-CSF (attract/activated inflammatory cells)
Newly Synthesized Substances: play major roles in antihistamine-resistance astham
o Leukotrienes: cause prolonged constriction of smooth muscle
o Thromboxanes, Prostaglandins: constrict bronchi; also chemotactic for PMNs and eosinphils
o Platelet Activating Factor (PAF): cause release of histamine and thromboxanes
Late Phase Reaction to Allergens:
Eosinophils and PMNs come to site and prolong symptoms (occurs 7-8 hours after exposure)
o Eosinophils release: leukotrienes, PAF, toxins for helminths (eosinophilic cationic protein), enzymes
and chemotactic factors
o PMNs release: leukotrienes, PAF, and lysosomal enzymes
Current Treatments:
Epinephrine: systemic anaphylaxis (prevents blood vessel leakage and relaxes bronchial/tracheal smooth
muscle)
Pharmacological Agents:
Type
Agent
Effect
Clinical Use
Beta Agonists
Epinephrine
Antagonist of antihistamine
Anaphylaxis
Xanthine Derivatives
Aminophylline
Relaxes smooth muscle
Asthma
Mast Cell Membrane
Cromolyn sodium
Prevents degranulation
Ashtma
Stabilizers
Leukotriene Modifiers
Binds leukotriene R or inhibit
Ashtma
formation of leukotrienes
Antihistamines
Many
Block H1 receptors
Rhinitis, Dermatitis
Corticosteroids
Many
Anti-inflammatory
Asthma, rhinitis
Specific Desensitization: inject patient with small amount of allergen and increase the dose weekly for several
months
o Mechanism: elevates IgG Ab, which binds allergen and prevents it from reacting with IgE on mast cells;
also induces a switch from TH2 to TH1 cells; may induce Treg cells
o Useful for: allergic rhinitis, bee stings, asthma and peanut allergies (more recently)
Clinical Tests for Allergy:
Patient history
Skin tests: small amount of allergen injected; positive reaction is wheal and flare, swelling and redness (occurs in
10-15 minutes)
Radioallergosorbent Test (RAST): quantitates the amount of serum IgE for a specific allergen
Mast Cells, Eosinophils and IgE also Protect Against Parasitic Worms:
Worms stimulate IgE production
Mast cells recruit eosinophils that bind IgE on the worm and release cytotoxins
Prevalence of Allergy:
More prevalent in poorer countries due to increased early exposure to infectious agents
Results in prolonged TH1 bias on subsequent exposure to foreign substances, including potential allergens
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TYPE II HYPERSENSITIVITY REACTIONS
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Antibody to cell-bound antigen
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Isotypes Involved: IgG (or IgM)
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Mechanism: activates complement or assists with ADCC (antibody dependent cell-mediated cytotoxicity; only IgG)
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Examples: ABO or Rh incompatability; various drugs binding to platelets and RBCs
TYPE III HYPERSENSITIVITY REACTIONS
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Antibody to soluble antigen
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Isotypes Involved: usually IgG as part of an immune complex
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Mechanism: fixes complement, and complexes accumulate in joints, kidneys and elsewhere; size of immune
complexes and clearance by phagocytes determines pathology
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Examples: SLE antibodies to DNA; Ags can also be foreign serum or purified monoclonal Abs (serum sickness)
TYPE IV HYPERSENSITIVITY REACTIONS
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Examples:
Delayed-Type Hypersensitivity:
o Ag: proteins (insect venom, mycobacterial proteins like tuberculin and lepromin)
o Consequence: local skin swelling (erythema, induration, cellular infiltrate, dermatitis)
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Contact Hypersensitivity:
o Ag: haptens (poison ivy, DNFB), small metal ions (nickel, chromate)
o Consequence: local epidermal reaction (erythema, cellular infiltrate, vesicles, intraepidermal abscess)
Gluten-Sensitive Enteropathy (Celiac Disease):
o Ag: gliadin
o Consequence: villous atrophy in small bowel, malabsorption
T cell mediated hypersensitivity takes many hours: need to recruit cells to the site