lecture 8 hypersensitivity types ii-v type ii: cytotoxic (ith) type ii: cytotoxic (ith) type iii:...
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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