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