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ADAPTIVEIMMUNITYTheSpecificImmuneResponsePhysiologyUnit3
TheAdaptiveImmuneSystem
• Exposuretoantigentriggersthespecificimmuneresponse• Theresponse“adapts”todifferentantigenasyouareexposedtothem• Youacquireimmunityasyouareexposedtodifferentantigensthroughoutyourlife
• Theimmunesystem“learns”• Memorycellsareproducedandremainforantigensyouhavebeenexposedto
• Youarethen“immune”tothatantigen• Lymphocytesareinvolvedinyourspecificimmuneresponsetoantigen
• BLymphocytes• TLymphocytes
• Myadaptiveimmunityisnotthesameasyours!
Antigen
• Antigenisamoleculethatbindstoanantibody
• Anymolecule(orfragment)thatkindbindtoaT-cellreceptor(TCR)
• AnymoleculethatcanbindtoaB-cellreceptor(BCR)
• Antigensareusually• Peptides• Proteins• Carbohydrates
SpecificImmuneResponse
• Amplifiedimmuneresponsetoanantigen• Lymphocytesmust beactivated
• Mediatedbylymphokines releasedfromactivatedlymphocytes• Activatedlymphocytesundergoproliferation• Progenyofactivatedlymphocytesarecalledclones
• Somewillbe effectorcells• Somewillbememorycells
SpecificImmuneResponse
• ThespecificimmuneresponsebeginswiththeactivationofHelperTcellsby AntigenPresentingCells(APC’s)
• ActivatedHelperTcellsreleaseInterleukin2(IL-2)thatactivatesotherlymphocytes(amplification)
Lymphocytes
• Lymphocytesmustrecognize/verifyantigen• Virus,bacteria,cancercells,transplantedcells,otherinfectiousagents
• Lymphocyteshaveareceptorforantigen• Bcellreceptors(BCR’s)• Tcellreceptors(TCR’s)
• ≈100milliondistinctantigenreceptorsonlymphocytes• Createdbygeneticrecombination• Theantigenreceptorsonlymphocytesareverifiedduringthematuration
processtoensurethelymphocytesareNOTselfreactive
BLymphocytes
• Naïve(mature)B-cellsarefoundprimarilyinlymphnodesandthespleenwheretheywillencounterantigen
• Uponactivation,produceplasmacellswhichsecreteantibodies againstanantigen
• Some plasmacellswillremainasMemoryBcells
• AlsoactasanAPC toHelperT-cellsThe “B” stands for Bursa of Fabricius
(a lymph organ) – that is where B Cells mature in birds
BCellReceptors/Antibodies• TheBcellreceptor(BCR)istheantibodyitsecretes
• Antibodiesareproducedbygeneticrecombination,producinganearinfinitevarietyofantibodiesforantigen
The5classesofAntibodiesProducedByPlasmaCells• 5antibodyclasses• Constantends
• Bindtomacrophage,C1proteins
• Variableends• Bindantigen
• Classificationofantibodiesisdeterminedbythesequenceofaminoacidsformingtheconstantends
IgGImmunoglobulinG
• Generatedafterclassswitching• Involvedinsecondaryimmuneresponse
• Mostabundantantibodyinthebody• Bindstomanykindsofpathogens(bacteria,virus,fungi)
• Causesagglutination• Neutralizestoxins• Activatesthecomplementpathway• Opsonization forphagocytosis• Directsboundvirustoproteosomes fordestruction
• Crossestheplacentaforfetalimmunity• 4subclasses
IgMImmunoglobulinM
• Firstantibodyproduceduponinitialexposuretoantigen
• Naturalantibody
• Foundinplasmaandlymph• ToolargetomoveintoIF
• BindstocomplimentproteinC1andactivatesthecomplimentpathway(classicalpathway).
• Causesagglutination
IgAImmunoglobulinA
• Mucosalimmunity• Secretedbymucusmembranesliningdigestive,respiratory,UGtractandprostate
• Foundinbodysecretions• Breastmilk• Sweat• Tears
• Providesprotectionagainstmicrobesthatmultiplyinmucussecretions
IgEImmunoglobulinE
• Defenseagainstmulticellularparasites
• Helminths,protozoans
• IgE activationofmastcellsinallergicresponses
• Asthma,sinusitis,foodallergies• Activatesmastcellsand/orbasophilstosecretehistamine
• Foundinlungs,skin,mucusmembranes
TLymphocytes
• Naïve(mature)Tcells• Somewillbeincirculationinplasmaandlymph
• Mostwillbeseededinlymphnodesandthespleen
• DifferenttypesofTcells• HelperTcells• CytotoxicTcells• RegulatoryTcells
Mature in the Thymus Gland
TCellReceptorsTCR
• Tcellreceptors(TCR)forantigenareintegralmembraneproteins
• HelperTcells• TCR bindtoantigenonlywhenitispresentedbyAPC’s
• KillerTcells• TCR bindtoantigenonlywhenitispresentedbyhostcellsthatneedtobedestroyed
HelperTCells
• HelperTcellactivationisrequiredforamaximalimmuneresponse• HelperTcellsareactivatedbyAntigenPresentingCells(APC’s)• ActivatedHelperTcellssignalforanamplified immuneresponseagainstaspecificantigen
• ActivatedHelperTcellsreleaseIL-2 thatactivate:• Bcells• CytotoxicTcells• Itself(HelperTcell) Remember……activated
lymphocytes undergo clonal expansion (proliferation)
AntigenPresentingCells
• Thereare3typesofcellsthatcanpresentantigentoHelperTcells1. Macrophage2. DendriticCells3. Bcells
ActivationofHelperTcells
1. AfteranantigenhasbeenphagocytizedbyanAPC(non-specificresponse) itisbrokendownintosmallerpeptidescalledepitopes
2. Theepitopes (fragments)complexwithMHCClass2proteinswithinanendosomeoftheAPC
3. Theepitope-MHCcomplexistransportedtothecellssurfaceanddisplayedintheplasmamembrane
4. TheepitopethatispresentedbyAPC’sthenbindstotheTCR• TheHelperTcellgoesthrougha2stepverificationprocess
5. Oncethe2stepverificationiscomplete,theHelperTcellisnowactivated
StagesofSpecificImmuneResponseEncounterandVerification
Encounter• APC’swillpresentantigentoaHelperTcellinalymphnode
Verification• MemoryTcells
• Memorycellsonlyhavetogothroughstep1toactivate
• Havealreadygonethroughtheconfirmationstep
• Fasterresponseuponreinfection
StagesofSpecificImmuneResponseLymphocyteActivation
• ActivatedHelperTcellsreleaseagrowthfactorcalledIL-2• IL-2 actsasanautocrineagentwhichtriggersproliferationoftheHelperTcell.
• Thisresultsinclonalexpansion
• IL-2 alsosignalstheactivationofBcellsandCytotoxicTcells(moreclonalexpansion)
LymphocyteActivation
StagesofSpecificImmuneResponseTheAttack
• Theattacklaunchedagainstantigenbytheactivatedlymphocytesu ActivatedBcellsdifferentiateintoPlasmacells andsecrete
antibodiesfortheantigenu ActivatedCytotoxicTcells destroyhostcellsu ActivatedHelperTcells secreteIL-2whichamplifiesthe
immuneresponse
• Effectorlymphocytesdiebyapoptosis• Preventstheimmuneresponsefrombecomingexcessiveandpotentiallydestroyinghosttissues
KillerTcells
• ActivatedKillerTcellskillhostcellsthathavebecome:• Cancerous• Infected• Damaged
• Travelthroughthebloodandlymphtoseekouttargetcells• Bindtoandkillhostcellsbysecretingchemicals
CDClassificationofTCells
• CDproteinsareintheplasmamembraneofTcells
• CD4:• HelperTcells• Macrophages
• CD8:• CytotoxicTcells
• CD4populationsdecimatedbyHIV
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
AntigenPresentationtoHelperTCells
Lymphokines
• APCbindingtothehelperTcelltriggerstheAPC tosecretelargeamountsoflymphokines1. IL-1 andtumornecrosisfactor
(TNF)secretedbyAPCs2. StimulatehelperTcellsto
secreteIL-23. IL-2 activatesmoreT-cellsand
B-cells
PresentationtoCytotoxicTcells
• AnyhostcellcanactasanAPCtoacytotoxicTcell1. Anyhostcellthatiscancerous2. Anyhostcellthathasbecome
infected3. Anyhostcellthathasbeen
damaged• APCsforCytotoxicTcellsexpresstheMHCClass1protein
• HostcellssynthesizetheantigenthatcomplexeswiththeMHCClass1protein
Perforin
• ActivatedKillerTcellssecreteperforin
• Perforincausesholes(perforations)toforminthecellmembrane
• Celldestructionresultsinthereleaseofvirions intotheECFwheretheycanbedirectlyneutralizedbyantibodies
Antibody-MediatedResponseHumoralResponse
• Humoralresponsesarethemajordefensesagainst• Bacteriaintheextracellularfluid• Virionsintheextracellularfluid• Othermicroorganismsintheextracellularfluid• Toxinsintheextracellularfluid
• Onceboundtoanantibody,antigencannot infectotherbodycellsorreproduce
• Becomesimmobilizedandistaggedfordestruction
Antibody-MediatedResponseHumoralResponse
• Communicationbyantibodiesinthebloodandlymphwithotherimmunecells
• Antibodiesinactivateantigensinplasma• Antibodiesbindtobacteriaforcomplementactivation• Antibodiesrecruitandguideothercellstoperformtheattack
• Phagocyticcells
AntibodiesAllowPhagocytestoBindtoPathogens
ActiveImmunity• Immunitydevelopsovertimeasaresultofthebody’scontactwithantigens
• CausesBcellstosecretetheantibodiesfortheantigen
• MemoryCells providelonglastingimmunity
• NaturalActiveImmunity• Occurswhenyouarenaturallyexposedtoantigen
• AcquiredActiveImmunity• Occurswhenyouareinjectedwiththeantigen
HepA, 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