Gell Coombs Classification Mechanisms of Immunologically

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Author(s): Joseph Fantone, MD, 2009

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Classification of Immune Classification of Immune Mediated Tissue Injury: Mediated Tissue Injury: Gell Coombs ClassificationGell Coombs Classification

Mechanisms of Immune-Mediated Mechanisms of Immune-Mediated DisordersDisorders

(4- types)(4- types)J. Fantone: Host Defense2/17/0910:00-12:00am

Winter 2009

type l

allergen

mast cell degranulationmediator release

Fc receptor

type ll

cell surface antigenlgG

target cell

complement

cytotoxic action

antibody

complement mediated lysis

target cell

type lllimmune-complex

deposition

complement

blood vessel

tissuebasementmembrane

antigens

inflammatory mediators

lymphokines

activated macrophage

type lV

The four types of hypersensitivity reaction

Source Undetermined

Type I Anaphylactic TypeType I Anaphylactic Type

• Prototype Prototype DisordersDisorders– Allergic rhinnitisAllergic rhinnitis– Allergic asthmaAllergic asthma– Anaphylaxis Anaphylaxis

(insect venom)(insect venom)

• Immune Immune MechanismsMechanisms– IgE-Mast cellsIgE-Mast cells– Vascular Vascular

permeabilitypermeability– EosinophilsEosinophils

Type II, Cytotoxic TypeType II, Cytotoxic Type

• Prototype DisordersPrototype Disorders– Hemolytic reactionsHemolytic reactions– Goodpastures Goodpastures

SyndromeSyndrome– Myasthenia GravisMyasthenia Gravis– Grave’s Disease Grave’s Disease

(hyperthyroidism)(hyperthyroidism)

• Immune Immune MechanismsMechanisms– IgGIgG– ComplementComplement– Phagocytic cellsPhagocytic cells– ADCCADCC

Type III, Immune Complex Type III, Immune Complex DiseaseDisease

• Prototype DisordersPrototype Disorders– Post-streptococcal Post-streptococcal

glomerulonephritisglomerulonephritis– VasculitisVasculitis

• Polyarteritis nodosaPolyarteritis nodosa

• Immune MechanismsImmune Mechanisms– Ab-Ag reactionsAb-Ag reactions– ComplementComplement– NeutrophilsNeutrophils– Fibrin, hemorrhageFibrin, hemorrhage

Type IV, Cell-Mediated Type IV, Cell-Mediated (Delayed) Hypersensitivity(Delayed) Hypersensitivity

• Prototype DisordersPrototype Disorders– Poison IvyPoison Ivy– TuberculosisTuberculosis (granulomatous (granulomatous

inflammation)inflammation)– Cytotoxic T-cellCytotoxic T-cell

• Dr. King’s lecturesDr. King’s lectures

• Immune Immune MechanismsMechanisms– T-lymphocytesT-lymphocytes– Monocyte/macro-Monocyte/macro-

phagephage

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

ReactionsReactions

Objectives:

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

Objectives Objectives (cont.)(cont.)

• The role of IgE-mediated Mast cell degranulation in The role of IgE-mediated Mast cell degranulation in Type I reactionsType I reactions

• The primary effector mediators released during Mast The primary effector mediators released during Mast cell stimulationcell stimulation

• The pathologic changes observed in tissues The pathologic changes observed in tissues associated with anaphylactic hypersensitivity associated with anaphylactic hypersensitivity reactionsreactions

• The modulatory role of eosinophils in these reactionsThe modulatory role of eosinophils in these reactions• To correlate the effect of mediators on target organs To correlate the effect of mediators on target organs

with the clinical expression of anaphylactic reactionswith the clinical expression of anaphylactic reactions

ClinicalClinical

• Type I reactions are usually the result of Type I reactions are usually the result of exposure to environmental allergens in exposure to environmental allergens in genetically susceptible individualsgenetically susceptible individuals

• 1/10 persons in USA affected to varying degrees1/10 persons in USA affected to varying degrees• Genetics not clearly defined, although there is a Genetics not clearly defined, although there is a

familial associationfamilial association• Atopy: a genetic predisposition for developing Atopy: a genetic predisposition for developing

IgE responses to many antigensIgE responses to many antigens• Local or systemic symptomsLocal or systemic symptoms

Clinical Clinical (cont.)(cont.)

• Most common form - allergic rhinnitisMost common form - allergic rhinnitis– AlsoAlso

• Certain types of asthmaCertain types of asthma• Atopic dermatitis (eczema)Atopic dermatitis (eczema)• Certain gastrointestinal food allergiesCertain gastrointestinal food allergies

• AllergensAllergens– Pollens, molds, house dust mite, animal Pollens, molds, house dust mite, animal

danderdander

Source Undetermined

pharmacological effectsblood vesselsairways etc.cell infiltration (see Fig. 19.22)

Pathophysiology

processing and presentation

antigen

TH BeIL-4

lL-4, lL-5, lL-6

cytokines

mediator release

clinical effectsasthmaeczemahay fever(see Fig. 19.23)

feedback effectson the immunesystem (see FSig. 19.23)

preformed and newly

formed mediators

lL-3, lL-4

antigen presentation lgE production mast cell activation clinical effects

Ca2+ l

GM-CSF, TNFalL-8/9, inflammatory

cell activation

Induction and effector mechanisms in Type l Hypersensitivity

Source Undetermined

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 synthesisof mediators

Degranulation and release of preformed mediators

De novo synthesisof mediators

HistamineChemotactic factors

Proteases

Leukotrienes (C4, D4, E4)Prostaglandins

Platelet activating factorCytokines

Smooth muscle: bronchial, GI,vascularVascular endothelium

Secretory glands (e.g. mucous)Eosinophils

Resting mast cell Activated mast cell

Multivalent antigen crosslinksbound lgE antibody causing release

of granule contents

Fce receptor lgE antibody

Resting mast cell shows granules containing serotonin

and histamine

J. Fantone

Effects of Mediators in Effects of Mediators in Anaphylaxis: Reversible Anaphylaxis: Reversible

ResponseResponse• Histamine - vascular permeability, Histamine - vascular permeability,

vasodilation (post-capillary venule),vasodilation (post-capillary venule), smooth muscle contractionsmooth muscle contraction• Chemotactic FactorsChemotactic Factors• CytokinesCytokines• Lipid mediatorsLipid mediators

Response Response (cont.)(cont.)

• Lipid Mediators: Arachidonic acid Lipid Mediators: Arachidonic acid metabolitesmetabolites– Leukotriene C4, D4, E4 - smooth muscle Leukotriene C4, D4, E4 - smooth muscle

contractioncontraction– Prostaglandins - vasodilationProstaglandins - vasodilation

Response Response (cont.)(cont.)

• Lipid Mediators: PAF - platelet Lipid Mediators: PAF - platelet activating factor - low molecular weight activating factor - low molecular weight lipidlipid– Acetylated glycerol ether phosphocholine Acetylated glycerol ether phosphocholine

(AGEPC)(AGEPC)– Activates phagocytic cellsActivates phagocytic cells– Smooth muscle contractionSmooth muscle contraction

Role of Eosinophils in Role of Eosinophils in Anaphylaxis:Anaphylaxis:

• Normal levels 2 to 3% circulating leukocytesNormal levels 2 to 3% circulating leukocytes• Type 1 response: up to 10%+ circulating Type 1 response: up to 10%+ circulating

leukocytesleukocytes• Secretory products include:Secretory products include:

– NADPH oxidase-derived oxidantsNADPH oxidase-derived oxidants– Prostaglandins and Leukotrienes (LTC4)Prostaglandins and Leukotrienes (LTC4)– Major basic protein (MBP): cytotoxicMajor basic protein (MBP): cytotoxic– CytokinesCytokines– othersothers

J. Fantone

Pathologic Changes Associated Pathologic Changes Associated with Anaphylactic Reactions: with Anaphylactic Reactions:

ReversibleReversible

• Symptoms depend on target organ: skinSymptoms depend on target organ: skin– Gross: swelling, wheal and flare responseGross: swelling, wheal and flare response

• early response: preformed mediatorsearly response: preformed mediators• late response: synthesized mediatorslate response: synthesized mediators

– Light microscopic: edema, eosinophilsLight microscopic: edema, eosinophils– Electron microscopic: edema, endothelial Electron microscopic: edema, endothelial

cell gapscell gaps

Source Undetermined

Pathologic Changes Associated Pathologic Changes Associated with Anaphylactic Reactions: with Anaphylactic Reactions:

ReversibleReversible

• Mucous and serous glandsMucous and serous glands– Increased secretionIncreased secretion

• Bronchial and GI smooth muscle Bronchial and GI smooth muscle – ContractionContraction

Therapeutic ApproachesTherapeutic Approaches• Avoid antigenAvoid antigen• Mediator antagonistsMediator antagonists

– anti-histamines: receptor antagonistanti-histamines: receptor antagonist– leukotriene inhibitors: lipase inhibitors, receptor leukotriene inhibitors: lipase inhibitors, receptor

antagonistsantagonists– functional: sympathetic stimulantsfunctional: sympathetic stimulants

• Inhibit mast cell degranulationInhibit mast cell degranulation– cromolyncromolyn

• Non-specific anti-inflammatory agentsNon-specific anti-inflammatory agents– corticosteroidscorticosteroids

• Immunotherapy Immunotherapy (“allergy shots”)(“allergy shots”)

Comparison of Skin Tests

Hypersensitivity Type Time Features

Type 1 Minutes Wheal: edemaFlare: vasodilation

Eosinophils

DiagnosisDiagnosis• Skin test - most frequently usedSkin test - most frequently used

Source Undetermined

Serologic Tests: RASTSerologic Tests: RAST - - Radioallergosorbent Test - Radioallergosorbent Test -

SpecificSpecific IgE IgE

+ Patient’s serum(Ab)

Anti-human IgEBead with Ag

J. Fantone

RISTRIST - Radioimmunosorbent - Radioimmunosorbent TestTest - Total IgE - Total IgE

+ Patient’s serum(Ab)

Bead + Anti humanIgE

Anti-human IgE

J. Fantone

Summary: Type I ReactionSummary: Type I Reaction

• Antibody: IgEAntibody: IgE• Effector Cells: Mast Cell & Effector Cells: Mast Cell &

EosinophilEosinophil• Complement: NoComplement: No• Reaction: MinutesReaction: Minutes

Antibody-Mediated Cell and Antibody-Mediated Cell and Tissue InjuryTissue Injury

(Type II and Type III Reactions)(Type II and Type III Reactions)

type l

allergen

Fc receptor

type ll

target cell

complement

cytotoxic action

antibody

target cell

deposition

complement

blood vessel

antigens

lymphokines

type lV

Source Undetermined

PathophysiologyPathophysiology

• Cytotoxic or Type II Reactions: Binding of Antibody Cytotoxic or Type II Reactions: Binding of Antibody (IgG or IgM) with cell membrane or tissue antigens(IgG or IgM) with cell membrane or tissue antigens– Red blood cell membrane antigens - hemolytic anemiasRed blood cell membrane antigens - hemolytic anemias– Platelet antigens - thrombocytopenia cell membrane - Platelet antigens - thrombocytopenia cell membrane -

petechial hemorrhagepetechial hemorrhage– Basement Membrane - Goodpasture’s syndromeBasement Membrane - Goodpasture’s syndrome

• Kidney - proteinuriaKidney - proteinuria• Lung - hemorrhageLung - hemorrhage

MechanismsMechanisms

• Opsonin dependent phagocytosisOpsonin dependent phagocytosis• Complement-dependent Ab lysisComplement-dependent Ab lysis• Antibody-dependent cell cytotoxicityAntibody-dependent cell cytotoxicity

J. Fantone

Rh Incompatibility in Newborn: Hemolytic Anemia

Sensitized during birth of Rh+ First child

Pregnant womanRh-

forms circulating lgG antibody (Anti-D)

IgG crosses placenta

Block sensitization by giving mother anti-D (Rho) Immunoglobulin within 72 hours after first birth or abortion

hemolysis

2nd pregnancyRh+ child

Preventative Therapy:

J. Fantone

Mechanisms Mechanisms (cont.)(cont.)

• Antibody directed to tissue antigens: examplesAntibody directed to tissue antigens: examples– Goodpasture’s syndrome: antigen = basement Goodpasture’s syndrome: antigen = basement

membrane of kidney and lungmembrane of kidney and lung– Dermatitis Herpetiformis: antigen = epidermis Dermatitis Herpetiformis: antigen = epidermis

basement membrane reticulinbasement membrane reticulin– Bullous Pemphigoid: antigen = epidermis Bullous Pemphigoid: antigen = epidermis

basement membranebasement membrane– Pemphigus vulgaris: antigen = epidermis Pemphigus vulgaris: antigen = epidermis

keratinocyte membraneskeratinocyte membranes

Goodpasture’s SyndromeGoodpasture’s Syndrome

• HemoptysisHemoptysis• Pulmonary infiltratesPulmonary infiltrates• Renal failureRenal failure• AnemiaAnemia

PathologyPathology

• Circulating anit-GBM antibodiesCirculating anit-GBM antibodies• Lightmicroscopy: frequently neutrophils, Lightmicroscopy: frequently neutrophils,

hemorrhagehemorrhage• Immunofluorescence: immunoglobulin Immunofluorescence: immunoglobulin

and complement deposition; linear and complement deposition; linear immunoflourescenceimmunoflourescence

• Electron microsocpy: no electron dense Electron microsocpy: no electron dense depositsdeposits

Goodpastures Syndrome: Goodpastures Syndrome: Anti-GBM DiseaseAnti-GBM Disease

+ ComplementC3b deposition C3a + C5a Proteases + PMN recruitment reactive oxygen metabolites tissue injury lung: hemorrhage, hemoptysis, alveolar infiltrates kidney: proteinuria, hematuria, renal failure

J. Fantone

Goodpastures Syndrome: Goodpastures Syndrome: Anti-GBM DiseaseAnti-GBM Disease

+ complement C3a,C5a

proteases oxygen metabolites

tissue injury

Lung: hemorrhage, hemoptysis, alveolar infiltrates

Kidney: proteinuria, hematuria, renal failure

J. Fantone

glomerulusJ. Fantone

Source Undetermined

Goodpastures SyndromeGoodpastures Syndrome

• Linear antigen distributionLinear antigen distribution• Linear antibody + complement distributionLinear antibody + complement distribution• Linear secondary anti-human antibody to IgG Linear secondary anti-human antibody to IgG

or complement containing a fluorescent markeror complement containing a fluorescent marker

J. Fantone

Source Undetermined

Mechanisms Mechanisms (cont.)(cont.)

• Antibody Binds to Cell Receptor (Type V Antibody Binds to Cell Receptor (Type V Reactions)Reactions)– Hyperthyroidism (Grave’s Disease): Thyroid Hyperthyroidism (Grave’s Disease): Thyroid

follicle cell - IgG antibody binds to thyroid follicle cell - IgG antibody binds to thyroid stimulating hormone (TSH) receptor and stimulating hormone (TSH) receptor and stimulates stimulates cellcell

– Myasthenia Gravis: antibody to acetylcholine Myasthenia Gravis: antibody to acetylcholine receptor at neuromuscular synapse antibody receptor at neuromuscular synapse antibody blocks neuromuscular transmission (decreased blocks neuromuscular transmission (decreased receptors) causing muscle weaknessreceptors) causing muscle weakness

Antibody to Cell Receptors

J. Fantone

type l

allergen

Fc receptor

type ll

target cell

complement

cytotoxic action

antibody

target cell

deposition

complement

blood vessel

antigens

lymphokines

type lV

Source Undetermined

Type III: Immune Complex Mediated Tissue Injury

antibody antigen

Ag-Ab complex

Monocyte/macrophageactivation

Complement activation

Cytokines(e.g. TNF, chemokines)

Neutrophil influx

J. Fantone

Summary: Immune Complex Mediated Tissue Injury

Neutrophil influx

Phagocytosis of immune complexes

Oxygen metabolitesO2-, H2O2 etc.

Lysosomal enzymesProteases etc.

Tissue injury

J. Fantone

Pathology of Immune Pathology of Immune Complex InjuryComplex Injury

• Fibrinoid necrosisFibrinoid necrosis• HemorrhageHemorrhage• NeutrophilsNeutrophils• Antibody + Complement depositionAntibody + Complement deposition• EM: Electron dense depositisEM: Electron dense depositis• Granular immunofluorescenceGranular immunofluorescence

Type III Hypersensitivity: Local I.C. DiseaseType III Hypersensitivity: Local I.C. Disease

antigen

complement

antibody

endothelial cell retraction

immune complex

lysosomalenzymes

vasoactive amines

mast cell degranulation

neutrophil neutrophil chemotaxis

platelet aggregation

antibody

The Arthus reaction

Source Undetermined

Immune Complex-Mediated Immune Complex-Mediated Hypersensitivity (Type III) Hypersensitivity (Type III) (cont.)(cont.)

• Systemic immune complex diseaseSystemic immune complex diseaseForeign Ag injected I.V.

Immune response w/Ab production (IgM, IgG)

Circulating immune complexes formed

Tissue deposition w/complement fixation

Arteritis

Glomerulonephritis (w/proteinuria)

Source Undetermined

• PathologyPathology– Light microscopy: neutrophils, Light microscopy: neutrophils,

hemorrhage, edemahemorrhage, edema– Electron microscopy: electron dense Electron microscopy: electron dense

deposits deposits – Immunofluorescence: immunoglobulin and Immunofluorescence: immunoglobulin and

complement deposition, granular complement deposition, granular immunoflouresence patternimmunoflouresence pattern

• Clinical - depends on target organ and/or site Clinical - depends on target organ and/or site of immune complex depositionof immune complex deposition– Synovium - rheumatoid arthritisSynovium - rheumatoid arthritis– Kidney - glomerulusKidney - glomerulus

• Post-streptococcal glomerulonephritisPost-streptococcal glomerulonephritis• Systemic lupus erythematosusSystemic lupus erythematosus

– Blood vessel walls - vasculitisBlood vessel walls - vasculitis• Polyarteritis nodosaPolyarteritis nodosa• Early transplant rejectionEarly transplant rejection

– Lung - hypersensitivity pneumonitisLung - hypersensitivity pneumonitis

J. Fantone

Source Undetermined

Immune Complex Disease Immune Complex Disease (post-streptococcal (post-streptococcal glomerulonephritis)glomerulonephritis)

• Irregular antigen distributionIrregular antigen distribution• Irregular antibody + complement distributionIrregular antibody + complement distribution• Irregular secondary anti-human antibody to IgG Irregular secondary anti-human antibody to IgG

or complement containing a fluorescent markeror complement containing a fluorescent marker

J. Fantone

• DiagnosisDiagnosis– Skin tests for Type III reactionsSkin tests for Type III reactions

• TherapyTherapy– Elimination of antigen - as in transfusion Elimination of antigen - as in transfusion

reactions, hypersensitivity lung reactions to reactions, hypersensitivity lung reactions to foreign antigens, and certain drug reactionsforeign antigens, and certain drug reactions

– Corticosteroid and immunosuppressive therapy Corticosteroid and immunosuppressive therapy (cytoxan, cylosporin)(cytoxan, cylosporin)

– PlasmapheresisPlasmapheresis

Summary: Type II/III ReactionSummary: Type II/III Reaction

• Antibody: IgM & IgGAntibody: IgM & IgG• Effector Cells: PhagocyticEffector Cells: Phagocytic• Complement: YesComplement: Yes• Reaction: 6-24 hoursReaction: 6-24 hours

type l

allergen

Fc receptor

type ll

target cell

complement

cytotoxic action

antibody

target cell

deposition

complement

blood vessel

antigens

lymphokines

type lV

Source Undetermined

Type IV: Cell-Mediated Immune Type IV: Cell-Mediated Immune ReactionsReactions

• ObjectiveObjective– To define the primary mechanisms involved To define the primary mechanisms involved

in contact hypersensitivity and delayed type in contact hypersensitivity and delayed type hypersensitivity reactionshypersensitivity reactions

– To review mechanisms of T-Cell mediated To review mechanisms of T-Cell mediated cytotoxicity cytotoxicity (see Dr. King)(see Dr. King)

• Cell ComponentsCell Components– Mononuclear inflammatory cells: Mononuclear inflammatory cells:

lymphocytes, monocytes/macrophages and lymphocytes, monocytes/macrophages and antigen presenting cellsantigen presenting cells

Source Undetermined

J. Fantone

Granulomatous Inflammatory Granulomatous Inflammatory ReactionsReactions

J. Fantone

Summary: Type IV ReactionSummary: Type IV Reaction

• Antibody: NoAntibody: No• Effector Cells: T-lymphocytes, Effector Cells: T-lymphocytes,

Monocyte/MacrophageMonocyte/Macrophage• Complement: NoComplement: No• Reaction: 48-72 hours Reaction: 48-72 hours (skin test)(skin test)

Type IV: T-Cell Mediated Type IV: T-Cell Mediated CytotoxicityCytotoxicity

(see Dr. King’s presentation)(see Dr. King’s presentation)

• MechanismsMechanisms– CD8+ lymphocyteCD8+ lymphocyte– Antigen expressed with Class I MHCAntigen expressed with Class I MHC– Interleukin-2 clonal expansionInterleukin-2 clonal expansion– Cytotoxic effector cellCytotoxic effector cell

• Recognizes Ag+ class I MHCRecognizes Ag+ class I MHC

T-Cell Mediated Cytotoxicity T-Cell Mediated Cytotoxicity (cont.)(cont.)

• Initiates programmed cell death Initiates programmed cell death (apoptosis)(apoptosis)

• Perforins/cytolysinsPerforins/cytolysins• Proteolytic enzymes: granzymesProteolytic enzymes: granzymes• FAS-induced apoptosis: CD8+ T cell: FAS FAS-induced apoptosis: CD8+ T cell: FAS

ligand target cell:FAS receptorligand target cell:FAS receptor• CytokinesCytokines

– Interferon Interferon – Tumor Necrosis Factor Tumor Necrosis Factor and and

type l

allergen

Fc receptor

type ll

target cell

complement

cytotoxic action

antibody

target cell

deposition

complement

blood vessel

antigens

lymphokines

type lV

Source Undetermined

Source UndeterminedSlide 13: Source UndeterminedSlide 14: Source UndeterminedSlide 17: J. FantoneSlide 22: J. FantoneSlide 24: Source UndeterminedSlide 28: Source undeterminedSlide 29: J. FantoneSlide 30: J. FantoneSlide 33: Source UndeterminedSlide 36: J. FantoneSlide 37: J. FantoneSlide 41: J. FantoneSlide 42: J. FantoneSlide 43: J. FantoneSlide 44: J: FantoneSlide 45: Source UndeterminedSlide 46: Source UndeterminedSlide 47: J. FantoneSlide 48: Source UndeterminedSlide 50: J. FantoneSlide 51: J. FantoneSlide 52: Source UndeterminedSlide 53: J. FantoneSlide 54: J. FantoneSlide 56: Source UndeterminedSlide 58: Source UndeterminedSlide 61: J. Fantone

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