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-ff@8>?  g4hdhd z[ 0Zppp <4!d!dL 0{g49d9d z[ 0@p@ ppʚ;ʚ;<4ddddL|- 08r0___PPT10 2___PPT9/ 0? %0 'Lecture 10 Hypersensitivity Types II-IV ( XType II: Cytotoxic (ITH) Type III: Toxic Complex (ITH) Type IV: T Cell-Mediated (DTH) Y $Cytotoxic Hypersensitivity (Type II)%%( %   .Characteristics of Cytotoxic Hypersensitivity //( / yDirected against cell surface or tissue antigen Characterized by complement cascade activation and various effector cells z   Complement   Formation of membrane attack complex (lytic enzymes) Activated C3 forms opsonin recognized by phagocytes Formation of chemotactic factors Effector cells possess Fc and complement receptors macrophages/monocytes neutrophils NK cells<3+3+  $Examples of Type II Hypersensitivity%%( % Blood transfusion reactions Hemolytic disease of the newborn (Rh disease) Autoimmune hemolytic anemias Drug reactions Drug-induced loss of self-tolerance Hyperacute graft rejection Myasthenia gravis (acetylcholine receptor) Sensitivity to tissue antigens  ABO Blood Group Antigens(   ABO Blood Group Reactivities  blood group genotypes antigens antibodies to (phenotype) ABO in serum A AA, AO A anti-B B BB, BO B anti-A AB AB A and B none O OO H anti-A/B IJ    Hemolytic Disease of the Newborn!!( !   5Drug-Induced Reactions: Adherence to Blood Components66( 6   )Toxic Complex Hypersensitivity (Type III)**$ *   )Diseases associated with immune complexes**  * Persistent infection microbial antigens deposition of immune complexes in kidneys Autoimmunity self antigens deposition of immune complexes in kidneys, joints, arteries and skin Extrinsic factors environmental antigens deposition of immune complexes in lungs= S?= S?     #Inflammatory Mechanisms in Type III$_$( $ Complement activation anaphylatoxins Chemotactic factors Neutrophils attracted difficult to phagocytize tissue-trapped complexes frustrated phagocytosis leads to tissue damage\#a$# $a    Disease Models(  Serum sickness Arthus reaction$   Serum Sickness$    Arthus Reaction(   $:T-Cell Mediated Hypersensitivity (Type IV / Delayed-Type) ;;$ ;  %2Manifestations of T-Cell Mediated Hypersensitivity33$ 3 uAllergic reactions to bacteria, viruses and fungi Contact dermatitis due to chemicals Rejection of tissue transplantsvv$ v &General Characteristics of DTH$  An exaggerated interaction between antigen and normal CMI-mechanisms Requires prior priming to antigen Memory T-cells recognize antigen together with class II MHC molecules on antigen-presenting cells Blast transformation and proliferation Stimulated T-cells release soluble factors (cytokines) Cytokines attract and activate macrophages and/or eosinophils help cytotoxic T-cells become killer cells, which cause tissue damage.1z1z  '$Inducers of Type IV Hypersensitivity%%( %  (!Types of Delayed Hypersensitivity"_"( " Delayed Reaction maximal reaction time Jones-Mote 24 hours Contact 48-72 hours tuberculin 48-72 hours granulomatous at least 14 days('$^$&f    )Jones-Mote Hypersensitivity_(  Now referred to as  cutaneous basophil hypersensitivity Basophils are prominent as secondary infiltrating cells. Basophilic infiltration of area under epidermis Induced by soluble (weak) antigens Transient dermal response Prominent in reactions to viral antigens, in contact reactions, skin allograft rejections, reactions to tumor cells and in some cases of hypersensitivity pneumonitis (allergic alveolitis) May be important in rejection of blood-feeding ticks on the skin surface        8       K *Contact Hypersensitivity  nUsually maximal at 48 hours Predominantly an epidermal reaction Langerhans cells are the antigen presenting cells a dendritic antigen presenting cell carry antigen to lymph nodes draining skin Associated with hapten-induced eczema nickel salts in jewellry picryl chloride acrylates p-Phenylene diamine in hair dyes chromates chemicals in rubber poison ivy (urushiol)\rO&rO&@   *   z             8   +Poison Ivy contact dermatitis   ,Tuberculin Hypersensitivity_(  =Maximum at 48-72 hours Inflitration of lesion with mononuclear cells First described as a reaction to the lipoprotein antigen of tubercle bacillus Responsible for lesions associated with bacterial allergy cavitation, caseation, general toxemia seen in TB May progress to granulomatous reaction in unresolved infectionB2?2?t         -   " -Granulomatous Hypersensitivity(   Clinically, the most important form of DTH, since it causes many of the pathological effects in diseases which involve T cell-mediated immunity Maximal at 14 days Continual release of cytokines Leads to accumulation of large numbers of macrophages Granulomas can also arise from persistence of  indigestible antigen such as talc (absence of lymphocytes in lesion)nn&   k .#Epitheloid Cell Granuloma Formation$$( $ Large flattened cells with increased endoplasmic reticulum Multinucleate giant cells with little ER May see necrosis Damage due to killer T-cells recognizing antigen-coated macrophages, cytokine-activated macrophages Attempt by the body to wall-off site of persistent infection  /Granuloma Formation(   0!Examples of Microbial-Induced DTH""( " Viruses (destructive skin rashes) smallpox measles herpes simplex Fungi candidiasis dematomycosis coccidioidomycosis histoplasmosis Parasites (against enzymes from the eggs lodged in liver) leishmaniasis schistosomiasis" <:" <:  H          ;      1$Type V Stimulatory Hypersensitivity%%$ % Interaction of autoantibodies with cellular receptors Antibody binding mimics receptor-ligand interaction Examples thyroid stimulating antibody (mimics thyroid stimulating hormone [TSH] of pituitary binds to thyroid cell receptor activation of B-cell by anti-immunoglobulin*ss  2!Innate Hypersensitivity Reactions""$ " Toxic shock syndrome (S. aureus TSS toxin) hypotension, hypoxia, oliguria and microvascular abnormalities excessive release of TNF, IL-1, IL-6 intravascular activation of complement Septicemia - Septic Shock primarily due to lipopolysaccharide Adult respiratory distress syndrome overwhelming accumulation of neutrophils in lung Platelet aggregation/adherence to macrophages by gram-positive bacteria Superantigens Gram positive enterotoxins react directly with T-cell receptors and induce massive cytokine release+$$1Wd  $$1W  d  /L 3 4 5 6 789:;<=P.  ` fy`ff3` Mj*333FV*` ffNNt^X` ffNL|>rL` +T3f3f` MMMff3f` Lx[he2` {$$>?" dd@,?nAd@    @ `  n?" dZ(: ::XXuuPR    @ ` ` p>> b(    6H; "D P  X Click to edit Master title style!! 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S ~ࡩmճmճ1 ?P  H  0f޽h ? >gԟ K0 TL( \nnpvlbl   S ~tmճmճ1 ?LT     S ~Hmճmճ1 ?>N   H  0f޽h ? >gԟ K0 $( 82F rits   S ~mճmճ1 ?D ;     ZL|A 1?on    `۶{GA 1?u ZH  0f޽h ? >gԟ K0 TL ( @   S ~Ȳmճmճ1 ?PXH$     S ~mճmճ1 ?`   H  0f޽h ? >gԟ K0 TL@(    S ~©mճmճ1 ?     S ~xémճmճ1 ?D   H  0f޽h ? >gԟ K0 TL`(    S ~ɩmճmճ1 ?     S ~ʩmճmճ1 ?I   H  0f޽h ? >gԟN 0  ( X    H1 ?"     # lp%gg1 ? @   " H  0޽h ? a( 0 04(     H1 ?"   l  # l*gg1 ? @   Study Guide If all of these reactions require "prior sensitization" before the destructive phase can begin, where is the "prior sensitization"?   H  0޽h ? a( 0 IA@$(  J M  $ $  H1 ?"    $ # l1gg1 ? @   ]5Study Guide What is the hapten? What is the carrier? 6 H $ 0޽h ? a( 0 P,*(  , ,  H1 ?"   b , # l8gg1 ? @   Study Guide What immunoglobulin class(es) are the blood group antibodies? Why are they called "naturally-occurring isohemagglutinins"?  H , 0޽h ? a( 0 `4I(   4 4  H1 ?"    4 # l(@gg1 ? @   Study Guide What immunoglobulin class(es)? 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   #Inflammatory Mechanisms in Type III$_$( $Complement activation anaphylatoxins Chemotactic factors Neutrophils attracted difficult to phagocytize tissue-trapped complexes frustrated phagocytosis leads to tissue damage\#a$# $a   Disease Models( Serum sickness Arthus reaction$  Serum Sickness$   Arthus Reaction(  $:T-Cell Mediated Hypersensitivity (Type IV / Delayed-Type) ;;$ ; %2Manifestations of T-Cell Mediated Hypersensitivity33$ 3uAllergic reactions to bacteria, viruses and fungi Contact dermatitis due to chemicals Rejection of tissue transplantsvv$ v&General Characteristics of DTH$ An exaggerated interaction between antigen and normal CMI-mechanisms Requires prior priming to antigen Memory T-cells recognize antigen together with class II MHC molecules on antigen-presenting cells Blast transformation and proliferation Stimulated T-cells release soluble f#_  Legend UserLegend Useractors (cytokines) Cytokines attract and activate macrophages and/or eosinophils help cytotoxic T-cells become killer cells, which cause tissue damage.1z1z '$Inducers of Type IV Hypersensitivity%%( % (!Types of Delayed Hypersensitivity"_"( "Delayed Reaction maximal reaction time Jones-Mote 24 hours Contact 48-72 hours tuberculin 48-72 hours granulomatous at least 14 days('$^$f )Jones-Mote Hypersensitivity_( Now referred to as  cutaneous basophil hypersensitivity Basophils are prominent as secondary infiltrating cells. Basophilic infiltration of area under epidermis Induced by soluble (weak) antigens Transient dermal response Prominent in reactions to viral antigens, in contact reactions, skin allograft rejections, reactions to tumor cells and in some cases of hypersensitivity pneumonitis (allergic alveolitis) May be important in rejection of blood-feeding ticks on the skin surfacen  8   K*Contact Hypersensitivity nUsually maximal at 48 hours Predominantly an epidermal reaction Langerhans cells are the antigen presenting cells a dendritic antigen presenting cell carry antigen to lymph nodes draining skin Associated with hapten-induced eczema nickel salts in jewellry picryl chloride acrylates p-Phenylene diamine in hair dyes chromates chemicals in rubber poison ivy (urushiol)\rO&rO&@ * z   8+Poison Ivy contact dermatitis  ,Tuberculin Hypersensitivity_( =Maximum at 48-72 hours Inflitration of lesion with mononuclear cells First described as a reaction to the lipoprotein antigen of tubercle bacillus Responsible for lesions associated with bacterial allergy cavitation, caseation, general toxemia seen in TB May progress to granulomatous reaction in unresolved infectionB2?2?Z   - "-Granulomatous Hypersensitivity( Clinically, the most important form of DTH, since it causes many of the pathological effects in diseases which involve T cell-mediated immunity Maximal at 14 days Continual release of cytokines Leads to accumulation of large numbers of macrophages Granulomas can also arise from persistence of  indigestible antigen such as talc (absence of lymphocytes in lesion)nn k.#Epitheloid Cell Granuloma Formation$$( $Large flattened cells with increased endoplasmic reticulum Multinucleate giant cells with little ER May see necrosis Damage due to killer T-cells recognizing antigen-coated macrophages, cytokine-activated macrophages Attempt by the body to wall-off site of persistent infection /Granuloma Formation(  0!Examples of Microbial-Induced DTH""( "Viruses (destructive skin rashes) smallpox measles herpes simplex Fungi candidiasis dematomycosis coccidioidomycosis histoplasmosis Parasites (against enzymes from the eggs lodged in liver) leishmaniasis schistosomiasis" <:" <:  H  ; 1$Type V Stimulatory Hypersensitivity%%$ %Interaction of autoantibodies with cellular receptors Antibody binding mimics receptor-ligand interaction Examples thyroid stimulating antibody (mimics thyroid stimulating hormone [TSH] of pituitary binds to thyroid cell receptor activation of B-cell by anti-immunoglobulin*ss 2!Innate Hypersensitivity Reactions""$ "Toxic shock syndrome (S. aureus TSS toxin) hypotension, hypoxia, oliguria and microvascular abnormalities excessive release of TNF, IL-1, IL-6 intravascular activation of complement Septicemia - Septic Shock primarily due to lipopolysaccharide Adult respiratory distress syndrome overwhelming accumulation of neutrophils in lung Platelet aggregation/adherence to macrophages by gram-positive bacteria Superantigens Gram positive enterotoxins react directly with T-cell receptors and induce massive cytokine release+$$1Wd  $$1W  d /L 3 4 5 6 789:;<=PX @ 0t(  tx t c $lOq   x t c $s%l   ` t c $A ??p h< H t 0f޽h ? >gԟrL 2 (9?@(P  l x2                                      A=>CCEHHGBKOB?D@3GMEHJH??CCIIEILGRJ=>A?>FGIH?;@??@EGBCCADI@C>CCEQNE?CATHDFOEFFHHJIMKF=DIIDGGBGIEC?@BCCA?FBLED@DD?AADHFCC?GIIKGGBEG??@EGD@@BPF>?ADHJCGIHC@?JJBGIDBDD@CHOGGJH?AAFJGDIIDGA@AACCHHLH==@B?CFFBIKFEFDE>ADRUL@B@?EDG?EBFBBECFENKC>FHJHFCCHG@?A?FEDAGCDIBAFEAAcCDDEC@C>GHIIE@>DD?CHFEBADJODDEGKJFCGJJH?AFC?A@FHIGICEFLPIDJH@CBFN                                      FEEIKGEEFGB>>FHABFKLGGJH?DCGJGBAABA?JBFLHGGEA<@FE@BHEELKBBECB?DHSMC@EA?GAB=DFGDBGEHKECBIDLB>@BB>@A@I/ECFJCCL@BEB;CDBBDBDB?FHIBB>>DB>BEB?EAGHECHHKMHHIJA?EDCCEFKKEHAIINLC>IF>>AGJ02            F              I           FCHKDFE@DACBBEF?EFLJHDMAHG??@DAEECJIHB==DDFDG KFGFCGDGADHB@A@BHHGIEFIIDHG?BF@=@CCGI@@D>>A?A?AB@>>FNGEECACA?BDEHJEIIGDEBFEEFGLHLLE@@FBBHFLIBBKLHGC>GI?=<>AF k         k                  IEBDABDBHFHDCA>ABBECA>@? 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-ff@8>?V g4FdFdR 0dPxٺRppp <4!d!dS V ʚR g49d9dR 0V S @Rp@ ppʚ;ʚ;<4ddddS ʚ;ʚ;0___PPT10 h___PPT2001D<4X0? %50 &Lecture 21 Hypersensitivity Types II-VmType II: Cytotoxic (ITH) Type III: Toxic Complex (ITH) Type IV: T Cell-Mediated (DTH) Type V: StimulatorynZna $Cytotoxic Hypersensitivity (Type II)%%( %  .Characteristics of Cytotoxic Hypersensitivity //( /yDirected against cell surface or tissue antigen Characterized by complement cascade activation and various effector cells z  Complement  Formation of membrane attack complex (lytic enzymes) Activated C3 forms opsonin recognized by phagocytes Formation of chemotactic factors Effector cells possess Fc and complement receptors macrophages/monocytes neutrophils NK cells@3+3+6B& g$Examples of Type II Hypersensitivity%%(Blood transfusion reactions Hemolytic disease of the newborn (Rh disease) Autoimmune hemolytic anemias Drug reactions Drug-induced loss of self-tolerance Hyperacute graft rejection Myasthenia gravis (acetylcholine receptor) Sensitivity to tissue antigens>>b *ABO Blood Group Antigens( ABO Blood Group Reactivity$ blood group genotypes antigens antibodies to (phenotype) ABO in serum A AA, AO A anti-B B BB, BO B anti-A AB AB A and B none O OO H anti-A/B IJ  Hemolytic Disease of the Newborn!!( !  5Drug-Induced Reactions: Adherence to Blood Components66( 6  )Toxic Complex Hypersensitivity (Type III)**$ *  )Diseases associated with immune complexes**  *Persistent infection microbial antigens deposition of immune complexes in kidneys Autoimmunity self antigens deposition of immune complexes in kidneys, joints, arteries and skin Extrinsic factors environmental antigens deposition of immune complexes in lungs= S?= S?    #Inflammatory Mechanisms in Type III$_$( $Complement activation anaphylatoxins Chemotactic factors Neutrophils attracted difficult to phagocytize tissue-trapped complexes frustrated phagocytosis leads to tissue damage\#a$# $a   Disease Models( Serum sickness Arthus reaction$  Serum Sickness$   Arthus Reaction(  $:T-Cell Mediated Hypersensitivity (Type IV / Delayed-Type) ;;$ ; %2Manifestations of T-Cell Mediated Hypersensitivity33$ 3uAllergic reactions to bacteria, viruses and fungi Contact dermatitis due to chemicals Rejection of tissue transplantsvv$ v&General Characteristics of DTH$ An exaggerated interaction between antigen and normal CMI-mechanisms Requires prior priming to antigen Memory T-cells recognize antigen together with class II MHC molecules on antigen-presenting cells Blast transformation and proliferation Stimulated T-cells release soluble factors (cytokines) Cytokines attract and activate macrophages and/or eosinophils help cytotoxic T-cells become killer cells, which cause tissue damage.1z1z '$Inducers of Type IV Hypersensitivity%%( % (!Types of Delayed Hypersensitivity"_"( "Delayed Reaction maximal reaction time Jones-Mote 24 hours Contact 48-72 hours tuberculin 48-72 hours granulomatous at least 14 days('$^$f )Jones-Mote Hypersensitivity_( Now referred to as  cutaneous basophil hypersensitivity Basophils are prominent as secondary infiltrating cells. Basophilic infiltration of area under epidermis Induced by soluble (weak) antigens Transient dermal response Prominent in reactions to viral antigens, in contact reactions, skin allograft rejections, reactions to tumor cells and in some cases of hypersensitivity pneumonitis (allergic alveolitis) May be important in rejection of blood-feeding ticks on the skin surfacen  8   K*Contact Hypersensitivity nUsually maximal at 48 hours Predominantly an epidermal reaction Langerhans cells are the antigen presenting cells a dendritic antigen presenting cell carry antigen to lymph nodes draining skin Associated with hapten-induced eczema nickel salts in jewellry picryl chloride acrylates p-Phenylene diamine in hair dyes chromates chemicals in rubber poison ivy (urushiol)\rO&rO&@ * z   8+Poison Ivy contact dermatitis  ,Tuberculin Hypersensitivity_( =Maximum at 48-72 hours Inflitration of lesion with mononuclear cells First described as a reaction to the lipoprotein antigen of tubercle bacillus Responsible for lesions associated with bacterial allergy cavitation, caseation, general toxemia seen in TB May progress to granulomatous reaction in unresolved infectionB2?2?Z   - "-Granulomatous Hypersensitivity( Clinically, the most important form of DTH, since it causes many of the pathological effects in diseases which involve T cell-mediated immunity Maximal at 14 days Continual release of cytokines Leads to accumulation of large numbers of macrophages Granulomas can also arise from persistence of  indigestible antigen such as talc (absence of lymphocytes in lesion)nn k.#Epitheloid Cell Granuloma Formation$$( $Large flattened cells with increased endoplasmic reticulum Multinucleate giant cells with little ER May see necrosis Damage due to killer T-cells recognizing antigen-coated macrophages, cytokine-activated macrophages Attempt by the body to wall-off site of persistent infection /Granuloma Formation(  0!Examples of Microbial-Induced DTH""( "Viruses (destructive skin rashes) smallpox measles herpes simplex Fungi candidiasis dematomycosis coccidioidomycosis histoplasmosis Parasites (against enzymes from the eggs lodged in liver) leishmaniasis schistosomiasis" <:" <:  H  ; 1$Type V Stimulatory Hypersensitivity%%$ %Interaction of autoantibodies with cellular receptors Antibody binding mimics receptor-ligand interaction Examples thyroid stimulating antibody (mimics thyroid stimulating hormone [TSH] of pituitary binds to thyroid cell receptor activation of B-cell by anti-immunoglobulin*ss 2!Innate Hypersensitivity Reactions""$ "Toxic shock syndrome (S. aureus TSS toxin) hypotension, hypoxia, oliguria and microvascular abnormalities excessive release of TNF, IL-1, IL-6 intravascular activation of complement Septicemia - Septic Shock primarily due to lipopolysaccharide Adult respiratory distress syndrome overwhelming accumulation of neutrophils in lung Platelet aggregation/adherence to macrophages by gram-positive bacteria Superantigens Gram positive enterotoxins react directly with T-cell receptors and induce massive cytokine release+$$1Wd  $$1W  d /L 3 4 5 6 789:;<=P j h`P(( \> l>  ( ( C xymճmճ1 ?D P    ( C xXzmճmճ1 ?t4  , @` $H ( 0f޽h ? >gԟru2 Q?Root EntrydO)C@PicturesBCurrent User2SummaryInformation( a     g!"#$%&'()*+,-./0123456789:;<=>?@ABCDEFHIJKLMNTUV_`bcdefhijklmnopqrstuvxyz{|}~_fatherfathernd User