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