Lecture 8Lecture 8Hypersensitivity Types II-VHypersensitivity Types II-V

Type II: Cytotoxic (ITH)Type II: Cytotoxic (ITH) Type III: Toxic Complex (ITH)Type III: Toxic Complex (ITH) Type IV: T Cell-Mediated Type IV: T Cell-Mediated

(DTH)(DTH) Type V: StimulatoryType V: Stimulatory

Cytotoxic Hypersensitivity (Type II)Cytotoxic Hypersensitivity (Type II)

Characteristics of Cytotoxic Characteristics of Cytotoxic Hypersensitivity Hypersensitivity

Directed against cell surface or tissue Directed against cell surface or tissue antigenantigen

Characterized by complement cascade Characterized by complement cascade activation and various effector cellsactivation and various effector cells

ComplementComplement Formation of membrane attack complex (lytic Formation of membrane attack complex (lytic

enzymes)enzymes) Activated C3 forms opsonin recognized by Activated C3 forms opsonin recognized by

phagocytesphagocytes Formation of chemotactic factorsFormation of chemotactic factors

Effector cells possess Fc and complement Effector cells possess Fc and complement receptorsreceptors

macrophages/monocytesmacrophages/monocytes neutrophilsneutrophils NK cellsNK cells

Examples of Type II HypersensitivityExamples of Type II Hypersensitivity

Blood transfusion reactionsBlood transfusion reactions Hemolytic disease of the newborn (Rh disease)Hemolytic disease of the newborn (Rh disease) Autoimmune hemolytic anemiasAutoimmune hemolytic anemias Drug reactionsDrug reactions Drug-induced loss of self-toleranceDrug-induced loss of self-tolerance Hyperacute graft rejectionHyperacute graft rejection Myasthenia gravis (acetylcholine receptor)Myasthenia gravis (acetylcholine receptor) Sensitivity to tissue antigensSensitivity to tissue antigens

ABO Blood Group ABO Blood Group AntigensAntigens

Precursor Precursor oligosaccharide oligosaccharide H antigen H antigen

B antigen B antigen

NAcGA NAcGA Gal Gal NAGNAG

Fuc Fuc

NAGNAG Gal Gal NAGNAG Gal Gal

Fuc Fuc

HH

Fuc Fuc

Gal Gal Gal Gal NAGNAG

B B

AA

A antigen A antigen

NAcGA (N-acetylgalactoseamine)NAcGA (N-acetylgalactoseamine)Gal (galactose)Gal (galactose)

ABO Blood Group ReactivityABO Blood Group Reactivity

blood groupblood groupgenotypesgenotypesantigensantigensantibodies antibodies toto

(phenotype)(phenotype) ABO in serumABO in serum

AA AA, AOAA, AO AA anti-Banti-B

BB BB, BOBB, BO BB anti-Aanti-A

ABAB ABAB A and BA and B nonenone

OO OOOO HH anti-A/Banti-A/B

Hemolytic Disease of the NewbornHemolytic Disease of the Newborn

RhD positive RhD positive red cells red cells

RhD RhD negativenegativemothermother

RhD positive RhD positive fetus fetus

LysisLysisOfOfRBC’s RBC’s

B cellB cell

anti-RhD anti-RhD

first birth first birth post partum post partum subsequentsubsequent

anti-RhD anti-RhD

RhD positive RhD positive fetus fetus

Drug-Induced Reactions:Drug-Induced Reactions:Adherence to Blood Adherence to Blood

ComponentsComponents

complementcomplement

blood cell adsorbed drug blood cell adsorbed drug or antigen drug metaboliteor antigen drug metabolite

antibody to drugantibody to drug

lysis

Toxic Complex Hypersensitivity Toxic Complex Hypersensitivity (Type III)(Type III)

Diseases associated with immune complexesDiseases associated with immune complexes

Persistent infectionPersistent infection microbial antigensmicrobial antigens deposition of immune complexes in kidneysdeposition of immune complexes in kidneys

AutoimmunityAutoimmunity self antigensself antigens deposition of immune complexes in kidneys, joints, deposition of immune complexes in kidneys, joints,

arteries and skinarteries and skin Extrinsic factorsExtrinsic factors

environmental antigensenvironmental antigens deposition of immune complexes in lungsdeposition of immune complexes in lungs

Inflammatory Mechanisms in Type IIIInflammatory Mechanisms in Type III

Complement activationComplement activation anaphylatoxinsanaphylatoxins Chemotactic factorsChemotactic factors

Neutrophils attractedNeutrophils attracted difficult to phagocytize tissue-trapped complexesdifficult to phagocytize tissue-trapped complexes frustrated phagocytosis leads to tissue damagefrustrated phagocytosis leads to tissue damage

Disease ModelsDisease Models

Serum sicknessSerum sickness Arthus reactionArthus reaction

Serum SicknessSerum Sickness

Arthus ReactionArthus Reaction

T-Cell Mediated HypersensitivityT-Cell Mediated Hypersensitivity(Type IV / Delayed-Type) (Type IV / Delayed-Type)

Manifestations of T-Cell Mediated Manifestations of T-Cell Mediated HypersensitivityHypersensitivity

Allergic reactions to bacteria, viruses and fungiAllergic reactions to bacteria, viruses and fungi Contact dermatitis due to chemicalsContact dermatitis due to chemicals Rejection of tissue transplantsRejection of tissue transplants

General Characteristics of DTHGeneral Characteristics of DTH An exaggerated interaction between antigen and normal CMI-An exaggerated interaction between antigen and normal CMI-

mechanismsmechanisms Requires prior priming to antigenRequires prior priming to antigen Memory T-cells recognize antigen together with class II MHC Memory T-cells recognize antigen together with class II MHC

molecules on antigen-presenting cellsmolecules on antigen-presenting cells Blast transformation and proliferationBlast transformation and proliferation Stimulated T-cells release soluble factors (cytokines)Stimulated T-cells release soluble factors (cytokines) CytokinesCytokines

attract and activate macrophages and/or eosinophilsattract and activate macrophages and/or eosinophils help cytotoxic T-cells become killer cells, which cause tissue damagehelp cytotoxic T-cells become killer cells, which cause tissue damage

Inducers of Type Inducers of Type IV HypersensitivityIV Hypersensitivity

Types of Delayed HypersensitivityTypes of Delayed Hypersensitivity

Delayed ReactionDelayed Reaction maximal reaction timemaximal reaction time

Jones-MoteJones-Mote 24 hours24 hours

ContactContact 48-72 hours48-72 hours

tuberculintuberculin 48-72 hours48-72 hours

granulomatousgranulomatous at least 14 daysat least 14 days

Jones-Mote HypersensitivityJones-Mote HypersensitivityJones-Mote HypersensitivityJones-Mote Hypersensitivity Now referred to as “cutaneous basophil hypersensitivity”Now referred to as “cutaneous basophil hypersensitivity” Basophils are prominent as secondary infiltrating cells.Basophils are prominent as secondary infiltrating cells. Basophilic infiltration of area under epidermisBasophilic infiltration of area under epidermis Induced by soluble (weak) antigensInduced by soluble (weak) antigens Transient dermal responseTransient dermal response Prominent in reactions to viral antigens, in contact reactions, skin Prominent in reactions to viral antigens, in contact reactions, skin

allograft rejections, reactions to tumor cells and in some cases of allograft rejections, reactions to tumor cells and in some cases of hypersensitivity pneumonitis (allergic alveolitis)hypersensitivity pneumonitis (allergic alveolitis)

May be important in rejection of blood-feeding ticks on the skin surfaceMay be important in rejection of blood-feeding ticks on the skin surface

Contact HypersensitivityContact Hypersensitivity

Usually maximal at 48 hoursUsually maximal at 48 hours Predominantly an epidermal reactionPredominantly an epidermal reaction Langerhans cells are the antigen presenting cellsLangerhans cells are the antigen presenting cells

a dendritic antigen presenting cella dendritic antigen presenting cell carry antigen to lymph nodes draining skincarry antigen to lymph nodes draining skin

Associated with hapten-induced eczemaAssociated with hapten-induced eczema nickel salts in jewellrynickel salts in jewellry picryl chloridepicryl chloride acrylatesacrylates p-Phenylene diamine in hair dyesp-Phenylene diamine in hair dyes chromateschromates chemicals in rubberchemicals in rubber poison ivy (urushiol)poison ivy (urushiol)

Poison Ivy Poison Ivy contact contact

dermatitisdermatitis

Tuberculin HypersensitivityTuberculin Hypersensitivity

Maximum at 48-72 hoursMaximum at 48-72 hours Inflitration of lesion with mononuclear cellsInflitration of lesion with mononuclear cells First described as a reaction to the lipoprotein antigen of tubercle First described as a reaction to the lipoprotein antigen of tubercle

bacillusbacillus Responsible for lesions associated with bacterial allergyResponsible for lesions associated with bacterial allergy

cavitation, caseation, general toxemia seen in TBcavitation, caseation, general toxemia seen in TB May progress to granulomatous reaction in unresolved infectionMay progress to granulomatous reaction in unresolved infection

Granulomatous HypersensitivityGranulomatous Hypersensitivity

Clinically, the most important form of DTH, since it Clinically, the most important form of DTH, since it causes many of the pathological effects in diseases which causes many of the pathological effects in diseases which involve T cell-mediated immunityinvolve T cell-mediated immunity

Maximal at 14 daysMaximal at 14 days Continual release of cytokinesContinual release of cytokines Leads to accumulation of large numbers of macrophagesLeads to accumulation of large numbers of macrophages Granulomas can also arise from persistence of Granulomas can also arise from persistence of

“indigestible” antigen such as talc (absence of “indigestible” antigen such as talc (absence of lymphocytes in lesion)lymphocytes in lesion)

Epitheloid Cell Granuloma FormationEpitheloid Cell Granuloma Formation

Large flattened cells with increased endoplasmic reticulumLarge flattened cells with increased endoplasmic reticulum Multinucleate giant cells with little ERMultinucleate giant cells with little ER May see necrosisMay see necrosis Damage due to killer T-cells recognizing antigen-coated Damage due to killer T-cells recognizing antigen-coated

macrophages, cytokine-activated macrophagesmacrophages, cytokine-activated macrophages Attempt by the body to wall-off site of persistent infectionAttempt by the body to wall-off site of persistent infection

Granuloma FormationGranuloma Formation

Examples of Microbial-Induced DTHExamples of Microbial-Induced DTH Viruses (destructive skin rashes)Viruses (destructive skin rashes)

smallpoxsmallpox measlesmeasles herpes simplexherpes simplex

FungiFungi candidiasiscandidiasis dematomycosisdematomycosis coccidioidomycosiscoccidioidomycosis histoplasmosishistoplasmosis

Parasites (against enzymes from the eggs lodged in liver)Parasites (against enzymes from the eggs lodged in liver) leishmaniasisleishmaniasis schistosomiasisschistosomiasis

Type V Stimulatory HypersensitivityType V Stimulatory Hypersensitivity

Interaction of autoantibodies with cellular receptorsInteraction of autoantibodies with cellular receptors Antibody binding mimics receptor-ligand interactionAntibody binding mimics receptor-ligand interaction ExamplesExamples

thyroid stimulating antibody (mimics thyroid stimulating thyroid stimulating antibody (mimics thyroid stimulating hormone [TSH] of pituitary binds to thyroid cell receptorhormone [TSH] of pituitary binds to thyroid cell receptor

activation of B-cell by anti-immunoglobulinactivation of B-cell by anti-immunoglobulin

Innate Hypersensitivity ReactionsInnate Hypersensitivity Reactions

Toxic shock syndrome (Toxic shock syndrome (S. aureus S. aureus TSS toxin)TSS toxin) hypotension, hypoxia, oliguria and microvascular abnormalitieshypotension, hypoxia, oliguria and microvascular abnormalities excessive release of TNF, IL-1, IL-6excessive release of TNF, IL-1, IL-6 intravascular activation of complementintravascular activation of complement

Septicemia - Septic ShockSepticemia - Septic Shock primarily due to lipopolysaccharideprimarily due to lipopolysaccharide

Adult respiratory distress syndromeAdult respiratory distress syndrome overwhelming accumulation of neutrophils in lungoverwhelming accumulation of neutrophils in lung

Platelet aggregation/adherence to macrophages by gram-positive bacteria Platelet aggregation/adherence to macrophages by gram-positive bacteria SuperantigensSuperantigens

Gram positive enterotoxinsGram positive enterotoxins react directly with T-cell receptors and induce massive cytokine releasereact directly with T-cell receptors and induce massive cytokine release