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Hypersensi)vityReac)onsKris)neKra2s,M.D.
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Hypersensi)vityReac)onsOutline
• Introduc)on
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• Normalimmunereac)onsdotheirjobwithouthur)ngthehost.
• Some)mes,immunereac)onscanbeexcessive,resul)ngindisease.
• Peoplewhomountnormalimmuneresponsesaresensi)zedtothatan)gen.
• Peoplewhohaveexcessiveresponsesarehypersensi)ve.
Introduc)on
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• Bugs
• Environmentalan)gens
• Selfan)gens
Whatan)gensini)atethesereac)ons?
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• Theimmuneresponseistriggeredandmaintainedinappropriately.
• Hardtoeliminates)mulus!
• Hardtostopresponseonceitstarts!
• …sohypersensi)vitydiseasesareo2enchronic,debilita)ng,hardtotreat.
Whathappensinthesereac)ons?
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Fourtypesofhypersensi)vityreac)ons
• TypeIHypersensi)vity• TypeIIHypersensi)vity
• TypeIIIHypersensi)vity• TypeIVHypersensi)vity
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Hypersensi)vityReac)onsOutline
• Introduc)on• TypeIHypersensi)vity
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• ALLERGY
• “Immediate”hypersensi)vity
• An)gen(allergen)bindstoIgEan)bodiesonsurfaceofmastcell
• Mastcellreleasesnastymediators
• Endresult:vesselsdilate,smoothmusclecontracts,inflamma)onpersists
TypeIHypersensi)vity
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• Allergenisinhaled/eaten/injected
• Allergens)mulatesTH2produc)on
• TH2cellsecretescytokines:• IL-4s)mulatesBcellstomakeIgE• IL-5recruitseosinophils• IL-13s)mulatesmucoussecre)on
• MastcellbindsIgE
• AllergenbridgesIgEonmastcell
• Mastcelldegranulates
SequenceofEvents
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Mastcells:Normal(le2)anddegranulated(right)
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• Granulecontents• histamine• somechemotac)cfactors
• Membranephospholipidmetabolites• prostaglandinD2• leukotrienes
• Cytokines• TNF• interleukins• IL-13
Whatnastystuffdomastcellsrelease?
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• Actonbloodvessels,smoothmuscle,andWBCs.
• Immediateresponse(minutes)• vasodila)on,vascularleakage,smoothmusclespasm• granulecontents,prostaglandin,leukotrienes
• Latephasereac)on(hours)• inflamma)on,)ssuedestruc)on• cytokines
Whatdothesenastysubstancesdo?
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• Localreac)ons• skin:itching,hives• GI:diarrhea• lung:bronchoconstric)on
• Anaphylaxis• itching,hives,erythema• constric)onofbronchioles,wheezing• laryngealedema,hoarseness,obstruc)on• vomi)ng,cramps,diarrhea• shock• DEATH
Whathappenstothepa)ent?
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Hypersensi)vityReac)onsOutline
• Introduc)on• TypeIHypersensi)vity• TypeIIHypersensi)vity
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• ANTIBODIES
• “An)body-mediated”hypersensi)vity
• An)bodiesbindtoan)gensoncellsurface
• Macrophageseatupcells,complementgetsac)vated,inflamma)oncomesin
• Endresult:cellsdie,inflamma)onharms)ssue
TypeIIHypersensi)vity
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Disease An)gen Symptoms
Autoimmunehemoly)canemia
RBCan)gens,drugs Hemolysis
Pemphigusvulgaris Proteinsbetweenepithelialcells Bullae
Goodpasturesyndrome
Proteinsinglomeruliandalveoli
Nephri)s,lunghemorrhage
Myastheniagravis Acetylcholinereceptor Muscleweakness
Gravesdisease TSHreceptor Hyperthyroidism
WhichdiseasesinvolvetypeIIhypersensi)vity?
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• An)bodiesbindtocell-surfacean)gens
• Oneofthreethingshappens:• Opsoniza)onandphagocytosis• Inflamma)on• Cellulardysfunc)on
SequenceofEvents
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Opsoniza)onandphagocytosis
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Inflamma)on
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Cellulardysfunc)on
Gravesdisease Myastheniagravis
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Hypersensi)vityReac)onsOutline
• Introduc)on• TypeIHypersensi)vity• TypeIIHypersensi)vity• TypeIIIHypersensi)vity
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• IMMUNECOMPLEXES
• “Immunecomplex-mediated”hypersensi)vity
• An)bodiesbindtoan)gens,formingcomplexes
• Complexescirculate,getstuckinvessels,s)mulateinflamma)on
• Endresult:badinflamma)on,necro)zingvasculi)s
TypeIIIHypersensi)vity
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Disease An)gen Symptoms
Systemiclupuserythematosus Nuclearan)gens Nephri)s,skinlesions,
arthri)s…
Post-streptococcalglomerulonephri)s Streptococcalan)gen Nephri)s
Polyarteri)snodosa Hepa))sBan)gen Systemicvasculi)s
Serumsickness Foreignproteins Arthri)s,vasculi)s,nephri)s
Arthusreac)on Foreignproteins Cutaneousvasculi)s
WhichdiseasesinvolvetypeIIIhypersensi)vity?
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• Systemicimmunecomplexdisease• complexesformedincircula)on• depositedinseveralorgans• example:serumsickness
• Localimmunecomplexdisease• complexesformedatsiteofan)geninjec)on
• precipitatedatinjec)onsite• example:Arthusreac)on
TwoKindsofTypeIIIHypersensi)vityReac)ons
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• Inoldendays:usedhorseserumforimmuniza)on
• Injectforeignprotein(an)gen)
• An)bodiesaremade;theyformcomplexeswithan)gens
• Complexeslodgeinkidney,joints,smallvessels
• Inflamma)oncausesfever,jointpain,proteinuria
SerumSickness
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• “Arthusreac)on”=localizedareaofskinnecrosisresul)ngfromimmunecomplexvasculi)s
• Injectan)genintoskinofpreviously-immunizedperson
• Pre-exis)ngan)bodiesformcomplexeswithan)gen
• Complexesprecipitateatsiteofinfec)on
• Inflamma)oncausesedema,hemorrhage,ulcera)on
ArthusReac)on
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• Immunecomplexesac)vatecomplement,which:• airactsandac)vatesneutrophilsandmonocytes• makesvesselsleaky
• Neutrophilsandmonocytesreleasebadstuff(PG,)ssue-dissolvingenzymes,etc.)
• Immunecomplexesalsoac)vateclojng,causingmicrothrombi
• Outcomes:vasculi)s,glomerulonephri)s,arthri)s,other-i)ses
Howdothecomplexescauseinflamma)on?
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Immune-complex-mediatedvasculi)s
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• C3b:promotesphagocytosisofcomplexes(andbugs!)
• C3a,C5a(anaphylatoxins):increasepermeability
• C5a:chemotac)cforneutrophils,monocytes
• C5-9:membranedamageorcytolysis
Whatcomplementfrac)onsareimportanttoknow?
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C5aischemotac)c
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Hypersensi)vityReac)onsOutline
• Introduc)on• TypeIHypersensi)vity• TypeIIHypersensi)vity• TypeIIIHypersensi)vity• TypeIVHypersensi)vity
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• TCELLS
• “T-cell-mediated”hypersensi)vity
• Ac)vatedTcellsdooneoftwothings:• releasecytokinesthatac)vatemacrophages,or• killcellsdirectly
• Thisprocessisnormallyusefulagainstintracellularorganisms(viruses,fungi,parasites)
• Here,itcausesbadstuff:inflamma)on,celldestruc)on,granulomaforma)on
TypeIVHypersensi)vity
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• Delayed-typehypersensi)vity(DTH)• CD4+Tcellssecretecytokines• macrophagescomeandkillcells
• Directcellcytotoxicity• CD8+Tcellskilltargetedcells
TwoKindsofTypeIVHypersensi)vity
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• Pa)entexposedtoan)gen• APCpresentsan)gentoCD4+Tcell• Tcellsdifferen)ateintoeffectorandmemoryTH1cells
• Pa)entexposedtoan)genagain• TH1cellscometositeofan)genexposure• Releasecytokinesthatac)vatemacrophages,increaseinflamma)on
• Results• Macrophageseatan)gen(good)• Lotsofinflamma)onand)ssuedamage(bad)
Delayed-TypeHypersensi)vity
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Delayed-TypeHypersensi)vity(DTH)
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PerivascularcuffingbyCD4+cells
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• GoodexampleofDTH:posi)veMantouxtest
• Pa)entpreviouslyexposedtoTB
• Inject(inac)ve)TBan)genintoskin
• Seereddening,indura)on.Peaksin1-3days
Delayed-TypeHypersensi)vity
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• CD8+Tcellsrecognizean)gensonthesurfaceofcells
• Tcellsdifferen)ateintocytotoxicTlymphocytes(CTLs)whichkillan)gen-bearingcells
• CTLsnormallykillvirusesandtumorcells
• InT-cellmediatedcytotoxicity,CTLskillotherthings:• Transplantedorgancells• Pancrea)cisletcells(TypeIdiabetes)
T-CellMediatedCytotoxicity
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T-Cell-MediatedCytotoxicity
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TypeI• Allergy• TH2cells,IgEonmastcells,nastymediators
TypeII• An)bodies• Opsoniza)on,complementac)va)on,orcelldysfunc)on
TypeIII• Immunecomplexes• Lodge,causeinflamma)on,)ssueinjury
TypeIV• CD4+orCD8+Tcells• DTHorT-cell-mediatedcytotoxicity
Summary