17 Specific Immune Response

ADAPTIVEIMMUNITYTheSpecificImmuneResponse

PhysiologyUnit3

InPhysiologyToday

TheAdaptiveArmoftheImmuneSystem

• SpecificImmuneResponse• Internaldefenseagainstaspecificpathogen• Acquiredasyouareexposedtodiseases

– Theimmunesystem“learns”– Memorycellsremainforeverypathogenyourareexposedto

• Myadaptiveimmunityisnotthesameasyours!

TheAdaptiveArmoftheImmuneSystem

• Controlledbythelymphaticsystem• AcoordinatedmechanisminvolvingalinkbetweenAPC’sandlymphocytes– APC’sarenon-specific– Lymphocytesarespecific

• Identifiesspecific foreignantigens

Lymphocytes• Lymphocytesmustrecognizethespecificpathogentobeattacked

• Anyantigenthatthehostimmunecelldoesnotrecognizeasself– Lymphocytesrecognizeantigens

• Proteinsorlargecarbohydrates• Proteincoatsofvirions• Antigensonforeigncells• Cancercells• Transplantedcells

• Lymphocytetraffickingincreasesthelikelihoodthattheywillcontacttheirspecificantigen• Lymphocytesarecirculatingthroughlymph,lymphorgansandtheblood

allthetime

BLymphocytes

• MatureinBonemarrow• B-cellactivationoccursinthespleenorlymphnodes

• APC tohelperT-cells• Produceplasmacellswhichsecreteantibodies

TLymphocytes

• MigrateandmatureintheThymusgland– HelperTcells

• Necessaryforamplificationoftheimmuneresponse• ActivateB-cellsandKillerT-cellsandotherHelperT-cells

– Killer(Cytotoxic)Tcells• Attackandkillyourowncellsthathavebecomecancerousorinfectedordamaged

RolesofLymphocytes

StagesofSpecificImmuneResponseEncounterandRecognition

• Encounterandrecognitionofantigenbylymphocytes– Eachlymphocyteis

specificforjustonetypeofantigen

– ≈100milliondistinctantigenreceptors

– Progenyoflymphocytesarecalledclones

StagesofSpecificImmuneResponseLymphocyteActivation

• Lymphocyteactivation– Bindingofantigentoreceptoronlymphocyte– Triggersthelymphocytetoundergomultiple

roundsofmitosistoproduceclones– clonalexpansion

– Somelymphocyteswillbeeffectorcellsandbepartoftheattackresponse

– Somelymphocyteswillbesetasideasmemorycells forquickersubsequentresponsesinthefuture

StagesofSpecificImmuneResponseTheAttack

• Theattacklaunchedagainstspecificantigenbytheactivatedlymphocytesu ActivatedBcellsdifferentiateintoplasmacellsand

secreteantibodiesintotheblood(butthemselvesremaininlymphnodesorspleen)

u ActivatedKillerTcells directlyattackandkillcellsu ActivatedHelperTcells releaseIL-2whichamplifythe

immuneresponse

• Plasmacells,helperTcells,killerTcellsthatparticipatedintheattackdiebyapoptosis– Preventstheimmuneresponsefrombecomingexcessiveandpotentiallydestroyingitsowntissues

The5classesofAntibodiesProducedByPlasmaCells

• Immunoglobulins• 5classesbasedontheaminoacidsequenceofconstantends

• Classes– IgA– IgD– IgE– IgG– IgM

IgAImmunoglobulinA

• Mucosalimmunity– Secretedbymucusmembranesliningdigestive,respiratory,UGtractandprostate

– Foundinbodysecretions• Breastmilk• Sweat• Tears

– Providesprotectionagainstmicrobesthatmultiplyinmucussecretions

IgDImmunoglobulinD

• Littleknownregardingfunction

IgEImmunoglobulinE

• Defenseagainstmulticellularparasites

• Implicatedinallergicresponses• Activatesmastcellsand/orbasophilstosecretehistamine

• Foundinlungs,skin,mucusmembranes

IgGImmunoglobulinG

• MostabundantantibodyinbloodandECF– Bindstomanykindsof

pathogens(bacteria,virions,fungi)

– Causesagglutination– Neutralizestoxins– Activatesthecomplement

pathway– Opsonizationforphagocytosis– Directsmarkedvirionstothe

proteosomes

• Crossestheplacentaforfetalimmunity

IgMImmunoglobulinM

• ProducedprimarilybyB-cellsinthespleen

• Foundinplasmaandlymph• ToolargetomoveintoECF

• Mostabundantuponfirstexposuretoaninfection• Naturalantibody

• Causesagglutination• Activatesthecomplement

pathway

FunctionofHelperTCells

• HelperTCells– ExpressCD4 proteinsintheirplasmamembranes– AmplifytheresponseofB-cellsandotherhelperT-cells

– Activatedbybindingtoantigen• Onceactivated,theHelperT-cellsecretesIL-2

• IL-2 isacytokine thatthatactsonB-cellsandotherT-cells

• B-cellscannotfunctionadequatelyunlesstheyarestimulatedbyIL-2

FunctionofKillerTCells

• CytotoxicTcells– ExpressCD8 proteinsintheirplasmamembranes– Musttravelthroughthebloodandlymphtoseekouttheirtargets

– Attackanddirectlykillcellsbysecretingchemicals– Attackhostcells(yourowncells):

• Cancercells– Anydamagedordysfunctionalcell

• Infectedcells– Cellsinfectedwithanypathogen

CDClassificationofTCells

• CDproteinsareintheplasmamembraneofTcells

• CD4:– HelperTcells– Macrophages

• CD8:– CytotoxicTcells

• CD4populationsdecimatedbyHIV

BCellReceptors

• ThereceptoronBcellsforitsspecificantigenistheantibodyitsecretes

• Constantends• Determineantibodyclass

• IgA,IgD,IgE,IgG,IgM

• Bindtomacrophage

• Variableends• Bindantigens• A nearinfinitevariety!

TCellReceptors

• Tcellreceptorsforantigensareintegralmembraneproteins– StayboundtothemembraneofTcells

• TcellreceptorscannotbindantigenunlesstheantigenisfirstcomplexedwithMHCproteins– 2classesof“self” plasmamembraneproteins

• TcellreceptorthencombineswiththeentirecomplexofantigenandMHCprotein

MHCProteins

• Differentfrompersontoperson

• ActascellularIDtags–markersofbiologicalself

• BindingtoMHCproteins– ClassIMHCproteins

– BindtotheCD8proteinonkillerTcells

– ClassIIMHCproteins– BindtotheCD4proteinonhelperTcells

•A group of proteins: the major histocompatibility complex are called MHC proteins

•Also called human leukocyte-associated antigens or HLA antigens

AntigenPresentingCells(APC)

• Tcellscanbindantigenonly whentheantigenappearsontheplasmamembraneofahostcellcomplexedwiththeMHCproteins

• Hostcellsbearingthesecomplexesarecalledantigenpresentingcells(APC’s)– Macrophage– Dendriticcells– B-Cells

• ProducetheMHCClass2proteins

PresentationtoHelperTcells

1. AfteranantigenhasbeenphagocytizedbyanAPC(non-specificresponse) itisbrokendownintosmallerpeptides

2. Thedigestedepitopes (fragments)bindtotheMHCClass2proteinswithinanendosomeoftheAPC

3. Theepitope-MHCcomplexistransportedtothecellssurfaceanddisplayedintheplasmamembrane

DendriticCells• Mostlikelyderivedfrom

monocytes• Madeinbonemarrow• Foundintissuesincontact

withtheoutsideworld– Skin– Liningsof:

• Nose• Lungs• Stomach• Intestines

• MigratetolymphnodesandthespleentopresenttoT-Cells

AntigenPresentationtoHelperTCells

Lymphokines• APCbindingtothehelperTcelltriggerstheAPC tosecretelargeamountsoflymphokines1. IL-1 andtumornecrosis

factor(TNF)secretedbyAPCs

2. StimulatehelperTcellstosecreteIL-2

3. IL-2 activatesmoreT-cellsandB-cells

PresentationtoCytotoxicTcells• Anyhostcellcanactasan

APCtoacytotoxicTcell1. Anyhostcellthatis

cancerous2. Anyhostcellthathas

becomeinfected3. Anyhostcellthathasbeen

damaged• APCsforCytotoxicTcells

expresstheMHCClass1protein

• HostcellssynthesizetheantigenthatcomplexeswiththeMHCClass1protein

Perforin

• ActivatedKillerTcellssecreteperforin

• Perforincausesholes(perforations)toorm inthecellmembrane

• Celldestructionresultsinthereleaseofvirions intotheECFwheretheycanbedirectlyneutralizedbyantibodies

Antibody-MediatedResponseHumoralResponse

• Humoralresponsesarethemajordefensesagainst– Bacteriaintheextracellularfluid– Virionsintheextracellularfluid– Othermicroorganismsintheextracellularfluid– Toxinsintheextracellularfluid

• Onceboundtoanantibody,antigencannot infectotherbodycellsorreproduce– Becomesimmobilizedandistaggedfordestruction

Antibody-MediatedResponseHumoralResponse

• Communicationbyantibodiesinthebloodandlymphwithotherimmunecells

• Antibodiesinactivateantigensinplasma• Antibodiesbindtobacteriaforcomplement

activation• Antibodiesrecruitandguideothercellsto

performtheattack– Phagocyticcells

AntibodiesAllowPhagocytestoBindtoPathogens

ActiveImmunity• Immunitydevelopsovertime

asaresultofthebody’scontactwithantigens

• CausesBcellstosecretetheantibodiesfortheantigen

• MemoryCells providelonglastingimmunity

• NaturalActiveImmunity– Occurswhenyouarenaturally

exposedtoantigen

• AcquiredActiveImmunity– Occurswhenyouareinjected

withtheantigenHepA, TDAP vaccines

PassiveImmunity• Youreceivepreformedantibodies• Providesinstant,temporaryimmunity• Natural PassiveImmunity

– Maternaltransferofantibodiestobaby– Breastfeeding(IgA)– Transplacentaltransfer(IgG)

• Acquired PassiveImmunity– Occurswhenyoureceivepreformedantibodies(IgG)inaninjection• HepB,Rabies,Tetanus,Varicella-Zoster(chickenpox,shingles)vaccines

AcutePhaseResponse

• Manysystemicresponsestoinfection• Initiatedbylymphokines releasedbymonocytesandmacrophage• IL-1,IL-6,TNF

• Stimulatesactionsofthe• Brain,hypothalamus• Liver• Bonemarrow• Adipocytes• Muscle

AcutePhaseResponse

DisordersoftheImmuneSystemImmunodeficiency

• Immunodeficiency• Maybecausedbyaging,stress,orviralinfection

• Mayleadto“opportunistic” diseasesorcancer(pneumonia,bronchitis)

• Manifestedbyafailureoftheimmunesystemtoprotectfromthesediseases

DisordersoftheImmuneSystemAutoimmunedisorder

• Autoimmunity– animmuneresponseismountedagainst“self”antigens

• Hostantigensthataretransformedorpreviouslyhidden

• Include– DiabetesmellitusTypeI– SystemicLupus– RheumatoidArthritis

Hypersensitivities

• Immuneresponsestoenvironmentalagentscauseinflammation

• Immediatehypersensitivities(allergies)– Antibody(IgE)productionandmastcellsecretionofhistamine

– Hayfever,allergies,penicillin,beesting• Delayedhypersensitivities

– Overstimulationoflymphocytesandmacrophages– Take2-3daystodevelop– Chronicinflammationandcytokinerelease– Againsttuberculin,transplantrejection