Hypersensitivity

Robert Beatty
MCB150

GelandCoombsclassificationofhypersensitivities.

Type I

Type II

Type III

Type IV

IgE Mediated

IgG/IgM
Mediated

IgG Mediated

T cell

Immune
complex
Disease

Delayed
Type
Hypersensitivity

Classic Allergy
rbc lysis

TYPE I Hypersensitivity
Classic allergy
MediatedbyIgEattachedtoMastcells.
Thesymptomsresultingfromallergicresponses

areknownasanaphylaxis.
Includes:Hayfever,asthma,eczema,beestings,food
allergies.

Allergens

Allergensarenonparasiteantigensthatcan

stimulateatypeIhypersensitivityresponse.
AllergensbindtoIgEandtrigger

degranulationofchemicalmediators.

Allergens
In the US --36 million people
said to have hay fever!

Characteristics of allergens
Small1540,000MWproteins.
Specificproteincomponents
Oftenenzymes.

Lowdoseofallergen
Mucosalexposure.
MostallergenspromoteaTh2immune.

Allergens
Example: Der P1
Der P1 is an enzyme allergen
from the fecal pellets
of the dust mite.

Dermatophagoides pteronyssinus
(common dust mite)

Der P1 Allergen

Allergen is easily aerosolized and inhaled.

Der P1 breaks down components of tight junctions
which helps it to cross mucosa.

Atopy

Atopyisthetermforthegenetictraittohavea

predispositionforlocalizedanaphylaxis.

AtopicindividualshavehigherlevelsofIgE

andeosinophils.

Genetic Predisposition
TypeIhypersensitivity

Candidatepolymorphicgenesinclude:

IL4Receptor.
IL4cytokine(promoterregion).
FcRI.HighaffinityIgEreceptor.
ClassIIMHC
(presentpeptidespromotingTh2response).
Inflammationgenes.

Mechanismsofallergicresponse

Sensitization
Repeatedexposuretoallergensinitiates
immuneresponsethatgeneratesIgE
isotype.
Th2cellsrequiredtoprovidetheIL4
requiredtogetisotypeswitchingtoIgE.

Mechanismsofallergicresponse

Sensitization
Th2/Bcellinteraction
IL-4
IL-4R
CD40
Drive B cell
Activation and IgE
isotype switch.

Busse and Lemanske NEJM Feb 2001. 344:350

Mechanismsofallergicresponse

Sensitization

TheIgEcanattachtoMastcellsbyFc

receptor,whichincreasesthelifespanof
theIgE.
HalflifeofIgEinserumisdayswhereas
attachedtoFcRitisincreasedtomonths.

Mechanismsofallergicresponse

Fcreceptors(FcR)
FcR1
highaffinityIgEreceptorfoundon
mastcells/basophils/activatedeosinophils.

AllergenbindingtoIgEattachedtoFcR1

triggersreleaseofgranulesfromcell.

Mechanismsofallergicresponse

FcRI
High affinity
IgE Fc
Receptor
Has ITAM
motifs

Mechanismsofallergicresponse

EffectorStageofHypersensitivity
Secondaryexposuretoallergen
MastcellsareprimedwithIgEonsurface.
AllergenbindsIgEandcrosslinkstoactivate

signalwithtyrosinephosphorylation,Ca++
influx,degranulationandreleaseofmediators.

FcRITriggersReleaseofMediators

Early mediators
cause immediate symptoms
e.g. histamine (preformed in granules)
leukotriene C4 and prostaglandin D2
are quickly made 2' mediators

MediatorsofTypeIHypersensitivity

Immediateeffects
Histamine
Constrictionofsmoothmuscles.
Bronchiole
constriction=wheezing.Constrictionofintestine=
crampsdiarrhea.
Vasodilationwithincreasedfluidintotissues
causingincreasedswellingorfluidinmucosa.
Activatesenzymesfortissuebreakdown.

Leukotrienes
Prostaglandins

ImmediatevsLateEffects

(early mediators)

Early/Late
Effect on lung
airflow
OR
Wheezing

MediatorsofTypeIHypersensitivity

PrimaryMediators

Preformedmediatorsingranules
Histamine
CytokinesTNF,IL1,IL6.
ChemoattractantsforNeutrophilsand

Eosinophils.
Enzymes
tryptase,chymase,cathepsin.
Changesinconnectivetissuematrix,tissue
breakdown.

TypeIHypersensitivity

Secondarymediators

Mediatorsformedafteractivation

Leukotrienes
Prostaglandins
Th2cytokinesIL4,IL5,IL13,GMCSF

Continuationofsensitizationcycle
Mastcellscontroltheimmediateresponse.
Eosinophilsandneutrophilsdrivelateor

chronicresponse.
MoreIgEproductionfurtherdrivenby

activatedMastcells,basophils,eosinophils.

Continuationofsensitizationcycle

Eosinophils
Eosinophilsplaykeyroleinlatephase

reaction.
Eosinophilsmake

enzymes,
cytokines(IL3,IL5,GMCSF),
Lipidmediators(LTC4,LTD4,PAF)

EosinophilscanprovideCD40LandIL4

forBcellactivation.

Localizedanaphylaxis
Targetorganrespondstodirectcontactwithallergen.
Digestivetractcontactresultsinvomiting,

cramping,diarrhea.
Skinsensitivityusuallyreddenedinflamed
arearesultinginitching.
Airwaysensitivityresultsinsneezingand
rhinitisORwheezingandasthma.

Systemicanaphylaxis

Systemicvasodilationandsmoothmuscle

contractionleadingtoseverebronchiole
constriction,edema,andshock.
Similartosystemicinflammation.

TreatmentforTypeI
Pharmacotherapy
Drugs.
Nonsteroidalantiinflammatories
Antihistaminesblockhistaminereceptors.
Steroids
TheophyllineORepinephrineprolongsor
increasescAMPlevelsinmastcellswhich
inhibitsdegranulation.

TreatmentforTypeI

Immunotherapy
Desensitization(hyposensitization)
alsoknownasallergyshots.
Repeatedinjectionsofallergentoreducethe
IgEonMastcellsandproduceIgG.

TreatmentforTypeI

Effectofallergyshots
AllergenSpecificAntibodies

Changeinamountof
eachisotypefrommore
IgEtomoreIgG.

TYPEIIHypersensitivity
Antibodymediatedcytotoxicity
BloodTransfusionreactions
Innocuousantigensonredbloodcells.
EXAMPLE:ABObloodgroupantigens

A and B
carbohydrate
antigens

ABOBloodGroups

Antibodyagainstrbcantigenbindsand
mediateskillingofrbcsviaCorADCC
causessystemicinflammation.
Quex:Whydowehaveantibodiestothese
innocuousantigensevenbeforewegetbloodtransfusion?

TYPEII
Antibodymediatedcytotoxicity

Drugreactions
Drugbindstorbcsurfaceandantibody
againstdrugbindsandcauseslysisofrbcs.
Immunesystemseesantibodyboundto
"foreignantigen"oncell.ADCC

TYPEII

Hemolyticdiseaseofnewborn
Rhfactorincompatibility
IgGabstoRhaninnocuousrbcantigen
Rh+babyborntoRhmotherfirsttimefine.
2ndtimecanhaveabstoRhfrom1stpregnancy.
Abcrossesplacentaandbabykillsitsownrbcs.
TreatmotherwithabtoRhantigenrightafter
birthandmothernevermakesitsownimmune
response.

TYPEII

Rhfactorincompatibility

TYPEIII
Antigenantibodyimmunecomplexes.
IgGmediated
Immune Complex Disease
Largeamountofantigenandantibodies
formcomplexesinblood.
Ifnoteliminatedcandepositincapillaries

orjointsandtriggerinflammation.

TYPEIII

Immune Complexes
PMNsandmacrophagesbindtoimmunecomplexesvia

FcRandphagocytizethecomplexes.
BUT
Ifunabletophagocytizetheimmunecomplexescan
causeinflammationviaCactivation>C3aC4a,C5a
and"frustratedphagocytes".

TYPEIII

Immune Complex Disease

"Frustrated Phagocytes"
Ifneutrophilsandmacrophagesareunableto

phagocytizetheimmunecomplexesthesecells
willdegranulateintheareaofimmunecomplex
depositionandtriggerinflammation.
Unabletoeattrytodigestoutsidecell.

TYPEIII
Immune Complex Disease
Localizeddisease
Depositedinjointscausinglocalinflammation=

arthritis.
Depositedinkidneys=glomerulonephritis.

TYPEIII
Immune Complex Disease

Serumsicknessfromlargeamountsofantigen

suchasinjectionofforeignserum.
Serumsicknessisusuallytransientimmunecomplexdisease

withremovalofantigensource.

Serum Sickness
Systemicimmunecomplexdisease

Largeamountsofantigen
suchasinjectionof
foreignserum.

Days after Antigen Injection

Delayedtypehypersensitivity
Th1cellsandmacrophages
DTHresponseisfrom:
Th1cellsreleasecytokinestoactivatemacrophages
causinginflammationandtissuedamage.
Continuedmacrophageactivationcancausechronic
inflammationresultingintissuelesions,scarring,and
granulomaformation.
DelayedisrelativebecauseDTHresponsearise2472
hoursafterexposureratherthanwithinminutes.

StagesofTypeIVDTH
Sensitizationstage
MemoryTh1cellsagainstDTHantigens
aregeneratedbydendriticcellsduringthe
sensitizationstage.
TheseTh1cellscanactivatemacrophages
andtriggerinflammatoryresponse.

StagesofTypeIVDTH
Effectorstage

SecondarycontactyieldswhatwecallDTH.
Th1memorycellsareactivatedandproduce

cytokines.

IFN,TNFandTNFwhichcausetissue
destruction,inflammation.
IL2thatactivatesTcellsandCTLs.
Chemokinesformacrophagerecruitment.
IL3,GMCSFforincreasedmonocyte/macrophage

StagesofTypeIVDTH
Effectorstage

Secondaryexposuretoantigen
Inflamedareabecomesredandfluidfilledcan
formlesion.
Fromtissuedamagethereisactivationofclotting
cascadesandtissuerepair.

Continuedexposuretoantigencancausechronic

inflammationandresultingranulomaformation.

TypeIVDTH
Contactdermatitis
TheresponsetopoisonoakisaclassicTypeIV.
Smallmoleculesactashaptensandcomplexwithskin
proteinstobetakenupbyAPCsandpresentedtoTh1
cellstogetsensitization.
DuringsecondaryexposureTh1memorycellsbecome
activatedtocauseDTH.

Contactdermatitis

Delayedtypehypersensitivity
(DTH)
DTH is a type of immune
response classified by
Th1 and macrophage
activation that results in
tissue damage.
DTH can be the result of
Chronic infection or
Exposure to some antigens.

Granuloma Formation from DTH

Mediated by Chronic Inflammation

DrugreactionscanbeanyType
ofHypersensitivity