Gell Coombs Classification Mechanisms of Immunologically

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    Author(s): Joseph Fantone, MD, 2009

    License: Unless otherwise noted, this material is made available under the terms of the Creative Commons AttributionNon-commercialShare Alike 3.0 License: http://creativecommons.org/licenses/by-nc-sa/3.0/

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  • Classification of Immune Mediated Tissue Injury: Gell Coombs Classification

    Mechanisms of Immune-Mediated Disorders

    (4- types)

    J. Fantone: Host Defense

    2/17/09

    10:00-12:00am

    Winter 2009

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  • type l

    allergen

    lgE

    mast cell degranulation

    mediator release

    Fc receptor

    type ll

    cell surface antigen

    lgG

    target

    cell

    complement

    cytotoxic action

    antibody

    complement mediated lysis

    target

    cell

    K

    type lll

    immune-complex

    deposition

    complement

    blood vessel

    tissue

    basement

    membrane

    antigens

    inflammatory mediators

    lymphokines

    activated macrophage

    type lV

    The four types of hypersensitivity reaction

    T

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  • Type I Anaphylactic Type

    Prototype DisordersAllergic rhinnitisAllergic asthmaAnaphylaxis (insect venom)

    Immune MechanismsIgE-Mast cellsVascular permeabilityEosinophils

    *

  • Type II, Cytotoxic Type

    Prototype DisordersHemolytic reactionsGoodpastures SyndromeMyasthenia GravisGraves Disease (hyperthyroidism)

    Immune MechanismsIgGComplementPhagocytic cellsADCC

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  • Type III, Immune Complex Disease

    Prototype DisordersPost-streptococcal glomerulonephritisVasculitisPolyarteritis nodosa

    Immune MechanismsAb-Ag reactionsComplementNeutrophilsFibrin, hemorrhage

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  • Type IV, Cell-Mediated (Delayed) Hypersensitivity

    Prototype DisordersPoison IvyTuberculosis

    (granulomatous inflammation)

    Cytotoxic T-cellDr. Kings lectures

    Immune MechanismsT-lymphocytesMonocyte/macro-phage

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  • Antibody-Mediated Cell and Tissue Injury: IgE Mediated Hypersensitivity Reactions

    Objectives:

    To understand the pathophysiologic mechanisms associated with Type I anaphylactic hypersensitivity reactions

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  • Objectives (cont.)

    The role of IgE-mediated Mast cell degranulation in Type I reactionsThe primary effector mediators released during Mast cell stimulationThe pathologic changes observed in tissues associated with anaphylactic hypersensitivity reactionsThe modulatory role of eosinophils in these reactionsTo correlate the effect of mediators on target organs with the clinical expression of anaphylactic reactions

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  • Clinical

    Type I reactions are usually the result of exposure to environmental allergens in genetically susceptible individuals1/10 persons in USA affected to varying degreesGenetics not clearly defined, although there is a familial associationAtopy: a genetic predisposition for developing IgE responses to many antigensLocal or systemic symptoms

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  • Clinical (cont.)

    Most common form - allergic rhinnitisAlsoCertain types of asthmaAtopic dermatitis (eczema)Certain gastrointestinal food allergiesAllergensPollens, molds, house dust mite, animal dander

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  • *

  • pharmacological effects

    blood vessels

    airways etc.

    cell infiltration (see Fig. 19.22)

    Pathophysiology

    processing

    and presentation

    antigen

    lgE

    IFNy

    TH

    Be

    IL-4

    lL-4, lL-5, lL-6

    cytokines

    mediator release

    clinical effects

    asthma

    eczema

    hay fever

    (see Fig. 19.23)

    feedback effects

    on the immune

    system (see FSig. 19.23)

    preformed and newly formed mediators

    APC

    lL-3, lL-4

    antigen presentation

    lgE production

    mast cell

    activation

    clinical effects

    Ca2+ l

    Induction and effector mechanisms in Type l Hypersensitivity

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  • Sensitization to Ag

    B-cell proliferation with production of IgE

    (IL-4 driven process)

    IgE binds to surface of mast cell or basophil

    Second Ag challenge

    Multivalent Ag binds IgE on mast cells: crosslinking IgE

    Degranulation and release

    of preformed mediators

    De novo synthesis

    of mediators

  • Degranulation and release

    of preformed mediators

    De novo synthesis

    of mediators

    Histamine

    Chemotactic factors

    Proteases

    Leukotrienes (C4, D4, E4)

    Prostaglandins

    Platelet activating factor

    Cytokines

    Smooth muscle: bronchial, GI,vascular

    Vascular endothelium

    Secretory glands (e.g. mucous)

    Eosinophils

  • Resting mast cell

    Activated mast cell

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  • Effects of Mediators in Anaphylaxis: Reversible Response

    Histamine - vascular permeability, vasodilation (post-capillary venule),

    smooth muscle contraction

    Chemotactic FactorsCytokinesLipid mediators

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  • Effects of Mediators in Anaphylaxis: Reversible Response (cont.)

    Lipid Mediators: Arachidonic acid metabolitesLeukotriene C4, D4, E4 - smooth muscle contractionProstaglandins - vasodilation

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  • Effects of Mediators in Anaphylaxis: Reversible Response (cont.)

    Lipid Mediators: PAF - platelet activating factor - low molecular weight lipidAcetylated glycerol ether phosphocholine (AGEPC)Activates phagocytic cellsSmooth muscle contraction

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  • Role of Eosinophils in Anaphylaxis:

    Normal levels 2 to 3% circulating leukocytesType 1 response: up to 10%+ circulating leukocytesSecretory products include:NADPH oxidase-derived oxidantsProstaglandins and Leukotrienes (LTC4)Major basic protein (MBP): cytotoxicCytokinesothers

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  • Pathologic Changes Associated with Anaphylactic Reactions: Reversible

    Symptoms depend on target organ: skinGross: swelling, wheal and flare responseearly response: preformed mediatorslate response: synthesized mediatorsLight microscopic: edema, eosinophilsElectron microscopic: edema, endothelial cell gaps

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  • Pathologic Changes Associated with Anaphylactic Reactions: Reversible

    Mucous and serous glandsIncreased secretionBronchial and GI smooth muscle Contraction

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  • Therapeutic Approaches

    Avoid antigenMediator antagonistsanti-histamines: receptor antagonistleukotriene inhibitors: lipase inhibitors, receptor antagonistsfunctional: sympathetic stimulantsInhibit mast cell degranulationcromolynNon-specific anti-inflammatory agentscorticosteroidsImmunotherapy (allergy shots)

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  • Comparison of Skin Tests

    Hypersensitivity Type

    Time

    Features

    Type 1

    Minutes

    Wheal: edema

    Flare: vasodilation

    Eosinophils

  • Diagnosis

    Skin test - most frequently used

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  • Serologic Tests: RAST - Radioallergosorbent Test - Specific IgE

    + Patients serum

    (Ab)

    Anti-human IgE

    Bead with Ag

  • RIST - Radioimmunosorbent Test - Total IgE

    + Patients serum

    (Ab)

    Bead + Anti human

    IgE

    Anti-human

    IgE

  • Summary: Type I Reaction

    Antibody: IgEEffector Cells: Mast Cell & EosinophilComplement: NoReaction: Minutes

  • Antibody-Mediated Cell and Tissue Injury

    (Type II and Type III Reactions)

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  • type l

    allergen

    lgE

    mast cell degranulation

    mediator release

    Fc receptor

    type ll

    cell surface antigen

    lgG

    target

    cell

    complement

    cytotoxic action

    antibody

    complement mediated lysis

    target

    cell

    K

    type lll

    immune-complex

    deposition

    complement

    blood vessel

    tissue

    basement

    membrane

    antigens

    inflammatory mediators

    lymphokines

    activated macrophage

    type lV

    The four types of hypersensitivity reaction

    T

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  • Pathophysiology

    Cytotoxic or Type II Reactions: Binding of Antibody (IgG or IgM) with cell membrane or tissue antigensRed blood cell membrane antigens - hemolytic anemiasPlatelet antigens - thrombocytopenia cell membrane - petechial hemorrhageBasement Membrane - Goodpastures syndromeKidney - proteinuriaLung - hemorrhage

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  • Mechanisms

    Opsonin dependent phagocytosisComplement-dependent Ab lysisAntibody-dependent cell cytotoxicity

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  • Rh Incompatibility in Newborn: Hemolytic Anemia

    Sensitized during birth of Rh+ First child

    Pregnant woman

    Rh-

    forms circulating

    lgG antibody (Anti-D)

    IgG crosses placenta

    Block sensitization b