成果医学免疫学

HypersensitivityJianzhongChenchenjianzhong@Hypersensitivity

(hypersensitivityreaction)referstoundesirablereactionsproducedbythenormalimmunesystem.Thesereactionsmaybedamaging,uncomfortable,oroccasionallyfatal.Hypersensitivityreactionsrequireapre-sensitized(immune)stateofthehost.

IntroductionClassificationofHypersensitivityTypeI

hypersensitivity

(immediatehypersensitivity)

(anaphylaxis)TypeI

hypersensitivityImmediatehypersensitivityisarapid,IgEantibody-andmastcell-mediatedvascularandsmoothmusclereaction,oftenfollowedbyinflammation,thatoccursinsomeindividualsonencounterwithcertainforeignantigenstowhichtheyhavebeenexposedpreviously.

Immediatehypersensitivityreactionsarealsocalledallergy,oratopy

I.CharacteristicsofTypeI

hypersensitivity1.Rapid:reactanddisappearquicklyonre-exposuretoAg2.Dysfunction:dysfunctionratherthanseveretissueandcelldamageoccurs3.Stronghereditarytendency:obviousindividualdifferenceandgeneticcorrelationAllergens

areproteinsorchemicalsboundtoproteinsthatinduceIgEantibodyresponsesandelicitanimmediatehypersensitivity(allergic)reaction

inatopicindividuals.

II.ComponentsinvolvedintypeIhypersensitivityTypesofallergiesInhalant:Pollensandmolds;Animalsdander;DustmitesIngestant:Food(mostcommonlypeanuts,dairy,egg,fishandshellfish)Injectant:Stinginginsects;DrugsContactant:drug，IvyIgEisaspecificIgthatgivesriseinimmediatehypersensitivity.MostallergicIgEresponseoccuronmucousmembranesurfacesinresponsetoallergensthatenterthebodybyeitherinhalationoringestion.II.ComponentsinvolvedintypeIhypersensitivityIgEsynthesisisdependentontheactivationofCD4+helperTcellsoftheTH2subsetandtheirsecretionofIL-4.

IL-4promoteIgEswitchingIL-5activateseosinophils,acelltypethatisabundantinmanyimmediatehypersensitivityreactions.IL-13stimulatesepithelialcells(e.g.,intheairways)tosecreteincreasedamountsofmucus,andexcessivemucusproductionisalsoacommonfeatureofthesereactions.TH2cellscontributetotheinflammationofthelate-phasereaction.StructureandFunctionoftheFcRⅠFcεRI,thatisexpressedonmastcells,basophils,andeosinophils.TheaffinityofFcεRIforIgEisveryhigh(Kd=1×10-10M)

mastcells,basophilsandeosinophilsmastcellsarefoundthroughoutconnectivetissue,particularlynearbloodandlymphaticvessels.Basophilsmainlycirculateintheblood.Eosinophilsaremainlylocatedinsub-epithelialconnectivetissuesofmucousmembranesurfacesoftherespiratoryandgastrointestinaltracts.Someintheperipheralblood.MastcellMastcellMastcellactivationBiochemicaleventsinmastcellactivationIII.PathogenicmechanismsIII.PathogenicmechanismsEffectorphaseImmediatephaseTheimmediatephaseoftheinflammatoryresponseisduetopreformedmediators(especiallyhistamine)storedinthemastcellgranulesandalsotocertainrapidlysynthesizedarachidonatederivatives.Itreachesmaximalintensitywithinabout15minutesafterantigenre-exposure.Thisphaseischaracterizedgrosslybyerythema,localizededemaintheformofawheal,induration,warmth,pruritus,andaburningsensationattheaffectedsite.LatephaseManifestationofthelatephasearedueinparttopresynthesizedTNF-andinparttoothermediators(principallyPAF,LT,IL-4,etc.)whosesynthesisbeginsafterthemastcelldegranulates.Theeffectsofthesemediatorsbecomeapparentabout6hoursafterantigencontactandaremarkedbyaninfiltrationofeosinophilsandneutrophils.IV.TypeIhypersensitivity-

associateddiseasesV.Immunoprophylaxis&immunotherapy1.SkintesttoidentifyallergenandavoidtheoffendingallergenV.Immunoprophylaxis&immunotherapy2.Hyposensitizationordesensitizationwithallergens1)Forantitoxin:stimulationwithsmalldoseofAgprovokesaminimalamountofmediatorsrelease,andthelatterarerapidlyresolved.2)ForspecificallergensGraduallyincreasingquantitiesofAgareinjectedsubcutaneously.ThisisaformofimmunotherapyaimedatstimulatingtheproductionofIgGblockingantibodythatbindstheoffendingantigenandpreventsitscombiningtoIgE.TheresponsetotreatmentincludesanincreaseinIgGantibodies,adecreaseinIgEantibodiesintheserum.TherapyImmunotherapyAllergen+IL-12DNAvaccineHumanizedMoAbsIL-4RTheProtectiveRolesofIgE-andMastCell-MediatedImmuneReactionsAmajorprotectivefunctionofIgE-initiatedimmunereactionsistheeradicationofparasites.

Mastcellsplayanimportantprotectiveroleaspartoftheinnateimmuneresponsetobacterialinfections.

THEPROTECTIVEROLESOFIgE-ANDMASTCELL–

MEDIATEDIMMUNEREACTIONSActivationofeosinophilstokillhelminthsTypeII

hypersensitivity

(cytotoxictype)TypeII

hypersensitivityreactionsaremediatedbyIgGandIgMantibodybindingtospecificcellsortissues.Thedamagecausedisthusrestrictedtothespecificcellsortissuesbearingtheantigen.Theantibodiesdamagecellsandtissuesbyactivatingcomplement,andbybindingandactivatingeffectorcellscarryingFcR.I.Pathogenicmechanisms

Agsonthesurfaceoftargetcells↓

body→IgG,IgM

↓

1.damagethetargetcell

1)

activationofcomplement2)

opsonizationorADCC

FcRC3bR

2.targetcelldysfunctionEffectormechanismsofAb-mediateddiseasesII.ClinicaldiseaseTransfusionreactionsBloodGroupAgs

BloodGroupAgAbAAanti-BBBanti-AABA&BNoneO----anti-A&anti-BAbsagainstbloodgroupAgsarenaturallypresentandareIgMtype.TransfusionReaction:+ComplementFcKcelllysisResult:AnaphylacticShockduetoComplementactivation.RBCRBCIgMII.Clinicaldisease2.HemolyticdiseaseofthenewbornoccurswhenanRh-mothergivesbirthtoanRh+infant.

Prophylaxis(RhoGAM)RhD-vemotherRhD+vefetusAnti-RhDAbsRhD+vefetusTheadministrationofanti-RhAbtoanRh-motherwithin72hoursofdeliveringanRh+infantwillpreventsensitizationandproblemswithsubsequentpregnancies.II.Clinicaldisease3.

AutoimmunehemolyticdiseaseSomedrugsorvirusesstimulateAbformationbychangingtheerythrocytesurfacecomponentstoformnewepitopes.4.

Drug-inducedreactiontoblood

componentsThesediseaseshavebeenassociatedwithmanydifferentchemotherapeutics,suchaspenicillin,thesulfonamidesandcytotoxicdrugs.Drug-inducedreactiontoblood

componentsRedcells:Penicillin,chloropromazine,phenacetinGranulocytes:Quinidine,amidopyridinePlatelets:sulphonamides,thiazidesHumanantibody-mediateddiseasesThepatientsproduceantibodiestothyrotropin(thyroidstimulatinghormone,TSH)receptor.Theendresultisoverproductionofthyroidhormoneandhyperthyroidism5.GravesdiseaseTypeIII

hypersensitivity

(immunecomplextype)Immunecomplexes(IC)depositinbasementmembranesofsmallbloodvesselsinvariousorgans.FeaturesThepathologicfeaturesofdiseasescausedbyimmunecomplexesreflectthesiteofimmunecomplexdepositionandarenotdeterminedbythecellularsourceoftheantigenandantigenissolubleImmunecomplex–mediateddiseasestendtoaffectmultipletissuesandorgans,althoughsomeareparticularlysusceptible,suchaskidneysandjoints.Ag+AbImmunecomplex,ICLargeICPhagocytosisbyphagocytesSmallICDischargedfromcirculationMediumICExistincirculation,anddepositMechanismoftypeIIIhypersensitivity

1.FormationofmediumimmunecomplexDepositionofICintissuesAnincreaseinvascularpermeabilityIngeneral,complement,mastcells,basophilsandplateletsmustallbeconsideredaspotentialproducersofvasoactiveamines.LocalhighbloodpressureandturbulenceThebloodpressureintheglomerularcapillariesisapproximatelyfourtimesthatofmostothercapillaries.ICarecapableoftriggeringavarietyofinflammatoryprocessesICsinteractwiththecomplementsystemtogenerateC3aandC5a.Thesecomplementfragmentsstimulatethereleaseofvasoactiveaminesandarechemotacticfactorsformastcellsandbasophils,eosinophilsandneutrophils.ICsinteractdirectlywithbasophilsandplatelets(viaFcR)toinducethereleaseofvasoactiveamines.NeutrophilsexocytosetheirlysosomalenzymesontothesiteofICdepositionanddamagetheunderlyingtissue.HumanimmunecomplexdiseaseSequenceofimmunologicresponsesinexperimentalacuteserumsickness.Becausethecomplexesaredepositedmainlyinsmallarteries,renalglomeruli,andthesynoviaofjoints,theclinicalandpathologicmanifestationsarevasculitis,nephritis,andarthritis.Hemorrhagingoftheskininthecourseofaserum-sicknessreaction.Urticarialrashasaconsequenceofaserum-sicknessreaction.Arthus’sreaction:Alocalizedformofexperimentalimmunecomplex–mediatedvasculitisiscalledtheArthusreaction.TypeIV

hypersensitivity

(T-cellmediateddiseases)DelayedtypehypersensitivityisinitiatedbysensitizedTcellsreactingwithspecificantigens.Thereactionsaremanifestasinflammationatthesiteofantigenexposure,whichusuallypeaks24-72hoursafterexposure.Thisreactionisindependentofantibodyandcomplement.I.PathogenicmechanismsII.Clinicaldiseases1.InfectiousDTH

Intheinfectiveprocess,intracellularparasiticalbacteria(Mycobacteriumtuber