Hypersensi)vityReac)onsKris)neKra2s,M.D.

Hypersensi)vityReac)onsOutline

•  Introduc)on

•  Normalimmunereac)onsdotheirjobwithouthur)ngthehost.

•  Some)mes,immunereac)onscanbeexcessive,resul)ngindisease.

•  Peoplewhomountnormalimmuneresponsesaresensi)zedtothatan)gen.

•  Peoplewhohaveexcessiveresponsesarehypersensi)ve.

Introduc)on

•  Bugs

•  Environmentalan)gens

•  Selfan)gens

Whatan)gensini)atethesereac)ons?

•  Theimmuneresponseistriggeredandmaintainedinappropriately.

•  Hardtoeliminates)mulus!

•  Hardtostopresponseonceitstarts!

•  …sohypersensi)vitydiseasesareo2enchronic,debilita)ng,hardtotreat.

Whathappensinthesereac)ons?

Fourtypesofhypersensi)vityreac)ons

•  TypeIHypersensi)vity•  TypeIIHypersensi)vity

•  TypeIIIHypersensi)vity•  TypeIVHypersensi)vity

Hypersensi)vityReac)onsOutline

•  Introduc)on•  TypeIHypersensi)vity

•  ALLERGY

•  “Immediate”hypersensi)vity

•  An)gen(allergen)bindstoIgEan)bodiesonsurfaceofmastcell

•  Mastcellreleasesnastymediators

•  Endresult:vesselsdilate,smoothmusclecontracts,inflamma)onpersists

TypeIHypersensi)vity

•  Allergenisinhaled/eaten/injected

•  Allergens)mulatesTH2produc)on

•  TH2cellsecretescytokines:•  IL-4s)mulatesBcellstomakeIgE•  IL-5recruitseosinophils•  IL-13s)mulatesmucoussecre)on

•  MastcellbindsIgE

•  AllergenbridgesIgEonmastcell

•  Mastcelldegranulates

SequenceofEvents

Mastcells:Normal(le2)anddegranulated(right)

•  Granulecontents•  histamine•  somechemotac)cfactors

•  Membranephospholipidmetabolites•  prostaglandinD2•  leukotrienes

•  Cytokines•  TNF•  interleukins•  IL-13

Whatnastystuffdomastcellsrelease?

•  Actonbloodvessels,smoothmuscle,andWBCs.

•  Immediateresponse(minutes)•  vasodila)on,vascularleakage,smoothmusclespasm•  granulecontents,prostaglandin,leukotrienes

•  Latephasereac)on(hours)•  inflamma)on,)ssuedestruc)on•  cytokines

Whatdothesenastysubstancesdo?

•  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?

Hypersensi)vityReac)onsOutline

•  Introduc)on•  TypeIHypersensi)vity•  TypeIIHypersensi)vity

•  ANTIBODIES

•  “An)body-mediated”hypersensi)vity

•  An)bodiesbindtoan)gensoncellsurface

•  Macrophageseatupcells,complementgetsac)vated,inflamma)oncomesin

•  Endresult:cellsdie,inflamma)onharms)ssue

TypeIIHypersensi)vity

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?

•  An)bodiesbindtocell-surfacean)gens

•  Oneofthreethingshappens:•  Opsoniza)onandphagocytosis•  Inflamma)on•  Cellulardysfunc)on

SequenceofEvents

Opsoniza)onandphagocytosis

Inflamma)on

Cellulardysfunc)on

Gravesdisease Myastheniagravis

Hypersensi)vityReac)onsOutline

•  Introduc)on•  TypeIHypersensi)vity•  TypeIIHypersensi)vity•  TypeIIIHypersensi)vity

•  IMMUNECOMPLEXES

•  “Immunecomplex-mediated”hypersensi)vity

•  An)bodiesbindtoan)gens,formingcomplexes

•  Complexescirculate,getstuckinvessels,s)mulateinflamma)on

•  Endresult:badinflamma)on,necro)zingvasculi)s

TypeIIIHypersensi)vity

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?

•  Systemicimmunecomplexdisease•  complexesformedincircula)on•  depositedinseveralorgans•  example:serumsickness

•  Localimmunecomplexdisease•  complexesformedatsiteofan)geninjec)on

•  precipitatedatinjec)onsite•  example:Arthusreac)on

TwoKindsofTypeIIIHypersensi)vityReac)ons

•  Inoldendays:usedhorseserumforimmuniza)on

•  Injectforeignprotein(an)gen)

•  An)bodiesaremade;theyformcomplexeswithan)gens

•  Complexeslodgeinkidney,joints,smallvessels

•  Inflamma)oncausesfever,jointpain,proteinuria

SerumSickness

•  “Arthusreac)on”=localizedareaofskinnecrosisresul)ngfromimmunecomplexvasculi)s

•  Injectan)genintoskinofpreviously-immunizedperson

•  Pre-exis)ngan)bodiesformcomplexeswithan)gen

•  Complexesprecipitateatsiteofinfec)on

•  Inflamma)oncausesedema,hemorrhage,ulcera)on

ArthusReac)on

•  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?

Immune-complex-mediatedvasculi)s

•  C3b:promotesphagocytosisofcomplexes(andbugs!)

•  C3a,C5a(anaphylatoxins):increasepermeability

•  C5a:chemotac)cforneutrophils,monocytes

•  C5-9:membranedamageorcytolysis

Whatcomplementfrac)onsareimportanttoknow?

C5aischemotac)c

Hypersensi)vityReac)onsOutline

•  Introduc)on•  TypeIHypersensi)vity•  TypeIIHypersensi)vity•  TypeIIIHypersensi)vity•  TypeIVHypersensi)vity

•  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

•  Delayed-typehypersensi)vity(DTH)•  CD4+Tcellssecretecytokines•  macrophagescomeandkillcells

•  Directcellcytotoxicity•  CD8+Tcellskilltargetedcells

TwoKindsofTypeIVHypersensi)vity

•  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

Delayed-TypeHypersensi)vity(DTH)

PerivascularcuffingbyCD4+cells

•  GoodexampleofDTH:posi)veMantouxtest

•  Pa)entpreviouslyexposedtoTB

•  Inject(inac)ve)TBan)genintoskin

•  Seereddening,indura)on.Peaksin1-3days

Delayed-TypeHypersensi)vity

•  CD8+Tcellsrecognizean)gensonthesurfaceofcells

•  Tcellsdifferen)ateintocytotoxicTlymphocytes(CTLs)whichkillan)gen-bearingcells

•  CTLsnormallykillvirusesandtumorcells

•  InT-cellmediatedcytotoxicity,CTLskillotherthings:•  Transplantedorgancells•  Pancrea)cisletcells(TypeIdiabetes)

T-CellMediatedCytotoxicity

T-Cell-MediatedCytotoxicity

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