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M. Sompayrac
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Table of Contents
Cover
DedicationPage
TitlePage
CopyrightPage
Acknowledgments
HowtoUseThisBook
AbouttheCompanionWebsite
LECTURE1:AnOverview
INTRODUCTION
PHYSICALBARRIERS
THEINNATEIMMUNESYSTEM
THEADAPTIVEIMMUNESYSTEM
ACOMPARISONOFTHEINNATEANDADAPTIVEIMMUNESYSTEMS
THEINNATESYSTEMRULES!
EPILOGUE
LECTURE2:TheInnateImmuneSystem
INTRODUCTION
THECOMPLEMENTSYSTEM
THEPROFESSIONALPHAGOCYTES
HOWIMMUNESYSTEMSENTINELSRECOGNIZEINVADERS
HOWTHEINNATEIMMUNESYSTEMDEALSWITHVIRUSES
THEINNATEIMMUNESYSTEM–ACOOPERATIVEEFFORT
APROPORTIONALRESPONSE
SUMMARYFIGURE
LECTURE3:BCellsandAntibodies
INTRODUCTION
THEBCELLRECEPTOR
HOWTHEBCRSIGNALS
HOWBCELLSAREACTIVATED
CLASSSWITCHING
ANTIBODYCLASSESANDTHEIRFUNCTIONS
SOMATICHYPERMUTATION
BCELLSMAKEACAREERCHOICE
SUMMARYFIGURE
LECTURE4:TheMagicofAntigenPresentation
INTRODUCTION
CLASSIMHCMOLECULES
CLASSIIMHCMOLECULES
ANTIGENPRESENTATIONBYCLASSIMHCMOLECULES
ANTIGENPRESENTATIONBYCLASSIIMHCMOLECULES
ANTIGENPRESENTINGCELLS
THELOGICOFCLASSIMHCPRESENTATION
THELOGICOFCLASSIIMHCPRESENTATION
CROSS-PRESENTATION
NON-CLASSICALMHCMOLECULESANDLIPIDPRESENTATION
MHCPROTEINSANDORGANTRANSPLANTS
SUMMARYFIGURE
LECTURE5:TCellActivation
INTRODUCTION
TCELLRECEPTORS
HOWATCELL’SRECEPTORSSIGNAL
CD4ANDCD8CO-RECEPTORS
CO-STIMULATION
ATIME-LAPSEPHOTOOFHELPERTCELLACTIVATION
HOWKILLERTCELLSAREACTIVATED
LECTURE6:TCellsatWork
INTRODUCTION
HELPERTCELLSASCYTOKINEFACTORIES
THEDENDRITICCELLAS“COACH”OFTHEIMMUNESYSTEMTEAM
Th1HELPERTCELLS
Th2HELPERTCELLS
Th17HELPERTCELLS
Th0HELPERTCELLS
LOCKINGINTHEHELPERTCELLPROFILE
DELAYED-TYPEHYPERSENSITIVITY
HOWCTLsKILL
SUMMARYFIGURE
LECTURE7:SecondaryLymphoidOrgansandLymphocyteTrafficking
INTRODUCTION
LYMPHOIDFOLLICLES
HIGHENDOTHELIALVENULES
LYMPHNODES
PEYER’SPATCHES
THESPLEEN
THELOGICOFSECONDARYLYMPHOIDORGANS
LYMPHOCYTETRAFFICKING
WHYMOTHERSKISSTHEIRBABIES
LECTURE8:RestrainingtheImmuneSystem
INTRODUCTION
ATTENUATINGTHEIMMUNERESPONSE
DEACTIVATINGTHESYSTEM
LIFEISSHORT
EXHAUSTION
LECTURE9:SelfToleranceandMHCRestriction
INTRODUCTION
THETHYMUS
MHCRESTRICTION
THELOGICOFMHCRESTRICTION
THYMICTESTINGFORTOLERANCEOFSELF
GRADUATION
THERIDDLEOFMHCRESTRICTIONANDTOLERANCEINDUCTION
TOLERANCEBYIGNORANCE
TOLERANCEINDUCTIONINSECONDARYLYMPHOIDORGANS
PERIPHERALTOLERANCEINDUCTION
TOLERANCEDUETOACTIVATION-INDUCEDCELLDEATH
BCELLTOLERANCE
MAINTENANCEOFBCELLTOLERANCEINGERMINALCENTERS
THEEDUCATIONOFNATURALKILLERCELLS
LECTURE10:ImmunologicalMemory
INTRODUCTION
INNATEMEMORY
ADAPTIVEMEMORY
PROPERTIESOFADAPTIVEMEMORYCELLS
COMPARINGBANDTCELLMEMORIES
INNATEVERSUSADAPTIVEMEMORY
LECTURE11:TheIntestinalImmuneSystem
INTRODUCTION
INTESTINALARCHITECTURE
CHALLENGESFACEDBYTHEINTESTINALIMMUNESYSTEM RESPONDINGGENTLYTOLIMITEDTHREATS
THEINTESTINALIMMUNESYSTEM’SRESPONSETOPATHOGENS HOWTORESPOND?
LECTURE12:TheImmuneSystemGoneWrong INTRODUCTION
DISEASESCAUSEDBYDEFECTSINIMMUNEREGULATION AUTOIMMUNEDISEASE
LECTURE13:Immunodeficiency INTRODUCTION
GENETICDEFECTSLEADINGTOIMMUNODEFICIENCY
AIDS
LECTURE14:Vaccines INTRODUCTION
GENERATINGMEMORYHELPERTANDBCELLS
GENERATINGMEMORYKILLERTCELLS STRATEGIESFORVACCINEDEVELOPMENT WILLTHEREBEANAIDSVACCINE?
VACCINATIONTOPREVENTVIRUS-ASSOCIATEDCANCER VACCINEADJUVANTS
LECTURE15:CancerandtheImmuneSystem INTRODUCTION
CANCERISACONTROLSYSTEMPROBLEM CLASSIFICATIONOFCANCERCELLS
IMMUNESURVEILLANCEAGAINSTCANCER
IMMUNESURVEILLANCEBYMACROPHAGESANDNKCELLS
LECTURE16:Immunotherapy INTRODUCTION
IMMUNOTHERAPYUSINGMONOCLONALANTIBODIES
IMMUNOTHERAPYUSINGTCELLS
LECTURE17:COVID-19andtheImmuneSystem INTRODUCTION
THERESPIRATORYSYSTEM
SARS-CoV-2
THEIMMUNERESPONSETORESPIRATORYVIRUSES
THEPATHOLOGYOFASARS-CoV-2INFECTION THEmRNAVACCINEPLATFORM
mRNAVACCINATIONVERSUSNATURALINFECTION
CORRELATESOFPROTECTION
REINFECTION
VIRALVARIANTS
Glossary
AcronymsandAbbreviations
Index
EndUserLicenseAgreement
Idedicatethisbooktomysweetheart,mybestfriend,andmywife:VickiSompayrac.
LECTURE 1
An Overview
HEADS UP!
Theimmunesystemisa“teameffort,”involvingmanydifferentplayers.Theseplayers canbedividedroughlyintotwogroups:thosethataremembersoftheinnateimmune systemteamandthosethatarepartoftheadaptiveimmunesystem.Importantly, thesetwogroupsworktogethertoprovideapowerfuldefenseagainstinvaders
INTRODUCTION
Immunologyisadifficultsubjectforseveralreasons.First,therearelotsofdetails,and sometimesthesedetailsgetinthewayofunderstandingtheconceptsTogetaroundthis problem,we’regoingtoconcentrateonthebigpicture.Itwillbeeasyforyoutofindthe detailssomewhereelse.Anotherdifficultyinlearningimmunologyisthatthereisan exceptiontoeveryrule.Immunologistslovetheseexceptions,becausetheygivecluesasto howtheimmunesystemfunctions.Butfornow,we’rejustgoingtolearntherules.Ohsure, we’llcomeuponexceptionsfromtimetotime,butwewon’tdwellonthemOurgoalisto examinetheimmunesystem,strippedtoitsessence.
Athirddifficultyinstudyingimmunologyisthatourknowledgeoftheimmunesystemis stillevolvingAsyou’llsee,therearemanyunansweredquestions,andsomeofthethings thatseemtruetodaywillbeprovenfalsetomorrow.I’lltrytogiveyouafeelingfortheway thingsstandnow,andfromtimetotimeI’lldiscusswhatimmunologistsspeculatemaybe true.ButkeepinmindthatalthoughI’lltrytobestraightwithyou,someofthethingsI’ll tellyouwillchangeinthefuture–maybeevenbythetimeyoureadthis!
Althoughthesethreefeaturesmakestudyingimmunologydifficult,Ithinkthemainreason immunologyissuchatoughsubjectisthattheimmunesystemisa“teameffort”which involvesmanydifferentplayersinteractingwitheachother.Imagineyou’rewatchinga footballgameonTV,andthecameraisisolatedononeplayer,say,thetightendYousee himrunatfullspeeddownthefield,andthenstop.Itdoesn’tseemtomakeanysense. Later,however,youseethesameplayonthebigscreen,andnowyouunderstand.That tightendtooktwodefenderswithhimdownthefield,leavingtherunningbackuncovered tocatchthepassandrunforatouchdown.Theimmunesystemisalotlikeafootballteam. It’sanetworkofplayerswhocooperatetogetthingsdone,andfocusingonasingleplayer doesn’tmakemuchsense.Youneedanoverallview.That’sthepurposeofthisfirstlecture, whichyoumightcall“turboimmunology.”Here,I’mgoingtotakeyouonaquicktourofthe immunesystem,soyoucangetafeelingforhowitallfitstogether.Theninthenext lectures,we’llgobackandtakeacloserlookattheindividualplayersandtheirinteractions.
PHYSICAL BARRIERS
Ourfirstlineofdefenseagainstinvadersconsistsofphysicalbarriers,andtocausereal trouble,viruses,bacteria,parasites,andfungimustpenetratetheseshieldsAlthoughwe tendtothinkofourskinasthemainbarrier,theareacoveredbyourskinisonlyabouttwo squaremeters.Incontrast,theareacoveredbythemucousmembranesthatlineour digestive,respiratory,andreproductivetractsmeasuresabout400squaremeters–anarea aboutasbigastwotenniscourts.Themainpointhereisthatthereisalargeperimeter whichmustbedefended
THE INNATE IMMUNE SYSTEM
Anyinvaderthatbreachesthephysicalbarrierofskinormucosaisgreetedbytheinnate immunesystem–oursecondlineofdefenseImmunologistscallthissystem“innate” becauseitisadefensethatallanimalsjustnaturallyseemtohave.Indeed,someofthe weaponsoftheinnateimmunesystemhavebeenaroundformorethan500millionyears. Letmegiveyouanexampleofhowthisamazinginnatesystemworks.
Imagineyouaregettingoutofyourhottub,andasyoustepontothedeck,yougetalarge splinterinyourbigtoe.Onthatsplinteraremanybacteria,andwithinafewhoursyou’ll notice(unlessyouhadalottodrinkinthathottub!)thattheareaaroundwherethe splinterenteredisredandswollen.Theseareindicationsthatyourinnateimmunesystem haskickedinYourtissuesarehometorovingbandsofwhitebloodcellsthatdefendyou againstattack.Tous,tissuelooksprettysolid,butthat’sbecausewe’resobig.Toacell, tissuelookssomewhatlikeaspongewithholesthroughwhichindividualcellscanmove ratherfreely.Oneofthedefendercellsthatisstationedinyourtissuesisthemostfamous innateimmunesystemplayerofthemall:themacrophage.Ifyou’reabacterium,a macrophageisthelastcellyouwanttomeetafteryourrideonthatsplinter!Hereisan electronmicrographshowingamacrophageabouttodevourabacterium.
Credit:LennartNilsson/BoehringerIngelheim/TT/SciencePhotoLibrary
Youwillnoticethatthismacrophageisn’tjustwaitinguntilitbumpsintothebacterium purelybychance.No,thismacrophagehasactuallysensedthepresenceofthebacterium andisreachingouta“foot”tograbitButhowdoesamacrophageknowthatabacteriumis outthere?Theansweristhatmacrophageshaveantennae(receptors)ontheirsurface whicharetunedtorecognize“dangermolecules”characteristicofcommonmicrobial invaders.Forexample,themembranesthatsurroundbacteriaaremadeupofcertainfats andcarbohydratesthatarenotnormallyfoundinthehumanbody.Someoftheseforeign moleculesrepresent“findmeandeatme”signalsformacrophages.Andwhen macrophagesdetectdangermolecules,theybegintocrawltowardthemicrobewhichis emittingthesemolecules
Whenitencountersabacterium,amacrophagefirstengulfsitinapouch(vesicle)calleda phagosome.Thevesiclecontainingthebacteriumisthentakeninsidethemacrophage, whereitfuseswithanothervesicletermedalysosome Lysosomescontainpowerful chemicalsandenzymeswhichcandestroybacteria.Infact,theseagentsaresodestructive
thattheywouldkillthemacrophageitselfiftheywerereleasedinsideit.That’swhythey areconfinedwithinvesiclesUsingthiscleverstrategy,themacrophagecandestroyan invaderwithoutcommittingsuicide.Thiswholeprocessiscalledphagocytosis,andthis seriesofsnapshotsshowshowithappens.
Macrophageshavebeenaroundforaverylongtime.Infact,theingestiontechnique macrophagesemployisarefinementofthestrategythatamoebasusetofeedthemselves–andamoebashaveroamedtheEarthforabout2.5billionyears.Sowhyisthiscreature calledamacrophage?“Macro,”ofcourse,meanslarge–andamacrophageisalargecell PhagecomesfromaGreekwordmeaning“toeat.”Soamacrophageisabigeater.Infact,in additiontodefendingagainstinvaders,themacrophagealsofunctionsasagarbage collector.Itwilleatalmostanything.Immunologistscantakeadvantageofthisappetiteby feedingmacrophagesironfilings.Then,usingasmallmagnet,theycanseparate macrophagesfromothercellsinacellmixtureReally!
Wheredomacrophagescomefrom?Macrophagesandalltheotherbloodcellsinyourbody arethedescendantsofself-renewingbloodstemcells–thecellsfromwhichalltheblood cells“stem.”Byself-renewing,Imeanthatwhenastemcellgrowsanddividesintotwo daughtercells,itdoesa“oneforme,oneforyou”thinginwhichsomeofthedaughtercells gobacktobeingstemcells,andsomeofthedaughtersgoontobecomematurebloodcells Thisstrategyofcontinualself-renewalinsuresthattherewillalwaysbebloodstemcellsin reservetocarryontheprocessofmakingmaturebloodcells
Macrophagesaresoimportanttoourdefensethattheyactuallytakeuptheirsentinel positionsinthetissueswellbeforeweareborn.Afterbirth,bloodstemcells,whichreside inthebonemarrow,canreplenishthesupplyofmacrophagesandalltheotherbloodcells astheyareneeded.Asthedaughtersofbloodstemcellsmature,theymustmakechoices thatdeterminewhichtypeofbloodcelltheywillbecomewhentheygrowup.Asyoucan imagine,thesechoicesarenotrandom,butarecarefullycontrolledtomakesureyouhave enoughofeachkindofbloodcell.Forexample,somedaughtercellsbecomeredbloodcells, whichcaptureoxygeninthelungs,andtransportittoallpartsofthebodyOurstemcell “factories”mustturnoutmorethantwomillionnewredbloodcellseachsecondtoreplace thoselostduetonormalwearandtear.Otherdescendantsofabloodstemcellmaybecome macrophages,neutrophils,orothertypesof“white”bloodcells.Andjustaswhitewineisn’t reallywhite,thesecellsaren’twhiteeither.Theyarecolorless,butbiologistsusetheterm “white”toindicatethattheylackhemoglobin,andthereforearenotredWhitebloodcells alsoarecalledleukocytes.Hereisafigureshowingsomeofthemanydifferentkindsof bloodcellsastemcellcanbecome
Whenthecellsthatcanmatureintomacrophagesfirstexitthebonemarrowandenterthe bloodstream,theyarecalledmonocytes Allinall,youhaveabouttwobillionofthesecells circulatinginyourbloodatanyonetime.Thismayseemalittlecreepy,butyoucanbevery gladtheyarethereWithoutthem,you’dbeindeeptroubleMonocytesremainintheblood foranaverageofaboutthreedays.Duringthistimetheytraveltothecapillaries–which representthe“endoftheline”forbloodvessels–lookingforacrackbetweenthe endothelialcellsthatlinetheinsideofthecapillaries.Theseendothelialcellsareshaped likeshingles,andbystickingafootbetweenthem,amonocytecanleavetheblood,enter thetissues,andmatureintoamacrophage.Inthetissues,mostmacrophagesjusthangout,
dotheirgarbagecollectingthing,andwaitforyoutogetthatsplintersotheycandosome realwork
Whenmacrophageseatthebacteriaonthatsplinterinyourfoot,theygiveoffchemicals whichincreasetheflowofbloodtothevicinityofthewound.Thebuildupofbloodinthis areaiswhatmakesyourtoewiththesplinterred.Someofthesechemicalsalsocausethe cellsthatlinethebloodvesselstocontract,leavingspacesbetweenthemsothatfluidfrom thecapillariescanleakoutintothetissues.Itisthisfluidwhichcausestheswelling.In addition,chemicalsreleasedbymacrophagescanstimulatenervesinthetissuesthat surroundthesplinter,sendingpainsignalstoyourbraintoalertyouthatsomethingisn’t quiterightintheareaofyourbigtoe.
Duringtheirbattlewithbacteria,macrophagesproduceandgiveoff(secrete)proteins calledcytokines.Thesearehormone-likemessengerswhichfacilitatecommunication betweencellsoftheimmunesystem.Someofthesecytokinesalertmonocytesandother immunesystemcellstravelinginnearbycapillariesthatthebattleison,andencourage thesecellstoexitthebloodtohelpfighttherapidlymultiplyingbacteria.Prettysoon,you haveavigorousinflammatoryresponsegoingoninyourtoe,astheinnateimmune systembattlestoeliminatetheinvaders.
Sohere’sthestrategy:Youhavealargeperimetertodefend,soyoustationsentinels (macrophages)tocheckforinvaders.Whenthesesentinelsencountertheenemy,theysend outsignals(cytokines)thatrecruitmoredefenderstothesiteofthebattle.The macrophagesthendotheirbesttoholdofftheinvadersuntilreinforcementsarrive.
Becausetheinnateresponseinvolveswarriorssuchasmacrophages,whichare programmedtorecognizemanycommoninvaders,yourinnateimmunesystemusually respondssoquicklythatthebattleisoverinjustafewdays
ThereareotherplayersontheinnateteamForexample,inadditiontotheprofessional phagocytessuchasmacrophages,whichmakeittheirbusinesstoeatinvaders,theinnate systemalsoincludesthecomplementproteinsthatcanpunchholesinbacteria,andnatural killercellswhichareabletodestroybacteria,parasites,virus-infectedcells,andsome cancercells.Wewilltalkmoreaboutthemacrophage’sinnatesystemteammatesinthe nextlecture
THE ADAPTIVE IMMUNE SYSTEM
About99%ofallanimalsgetalongjustfinewithonlynaturalbarriersandtheinnate immunesystemtoprotectthemHowever,vertebrateslikeushaveathirdlevelofdefense: theadaptiveimmunesystem.Thisisadefensesystemwhichactuallycanadapttoprotect usagainstalmostanyinvader.Oneofthefirstcluesthattheadaptiveimmunesystem existedcamebackinthe1790swhenEdwardJennerbeganvaccinatingtheEnglishagainst smallpoxvirus.Inthosedays,smallpoxwasamajorhealthproblem.Hundredsof thousandsofpeoplediedfromthisdisease,andmanymorewerehorriblydisfiguredWhat Jennerobservedwasthatmilkmaidsfrequentlycontractedadiseasecalledcowpox,which causedlesionsontheirhandsthatlookedsimilartothesorescausedbythesmallpoxvirus Jenneralsonotedthatmilkmaidswhohadcontractedcowpoxalmostnevergotsmallpox (which,itturnsout,iscausedbyacloserelativeofthecowpoxvirus).
SoJennerdecidedtoconductadaringexperiment.Hecollectedpusfromthesoresofa milkmaidwhohadcowpox,andusedittoinoculatealittleboynamedJamesPhipps.Later, whenPhippswasre-inoculatedwithpusfromthesoresofapersoninfectedwithsmallpox, hedidnotcontractthatdiseaseInLatin,thewordforcowis vacca –whichexplainswhere wegetthewordvaccine.HistorymakesouttheherointhisaffairtobeEdwardJenner,but Ithinktherealherothatdaywastheyoungboy.Imaginehavingthisbigmanapproachyou withalargeneedleandatubefullofpus!Althoughthisisn’tthesortofthingthatcouldbe donetoday,wecanbethankfulthatJenner’sexperimentwasasuccess,becauseitpaved thewayforvaccinationsthathavesavedcountlesslives.
Smallpoxviruswasnotsomethinghumansencounteredregularly.SoJenner’sexperiment showedthatifthehumanimmunesystemwasgiventimetoprepare,itcouldproduce weaponsthatcouldprovideprotectionagainstanintruderithadneverseenbefore Importantly,thesmallpoxvaccinationonlyprotectedagainstsmallpoxorcloselyrelated virusessuchascowpox.Phippswasstillabletogetmumps,measles,andtherest.Thisis oneofthehallmarksoftheadaptiveimmunesystem:Itadaptstodefendagainstspecific invaders.
Antibodies and B cells
Eventually,immunologistsdeterminedthatimmunitytosmallpoxwasconferredbyspecial proteinsthatcirculatedinthebloodofimmunizedindividuals.Theseproteinswerenamed antibodies,andtheagentthatcausedtheantibodiestobemadewascalledanantigen–in thiscase,thecowpoxvirus.Here’sasketchthatshowstheprototypeantibody, immunoglobulinG(IgG).
Asyoucansee,anIgGantibodymoleculeismadeupoftwopairsoftwodifferentproteins, theheavychain(Hc)andthelightchain(Lc).Becauseofthisstructure,eachmoleculehas twoidentical“hands”(Fabregions)thatcanbindtoantigensProteinsaretheideal moleculestouseforconstructingantibodiesthatcangraspattackers,becausedifferent proteinscanfoldupintoamyriadofcomplexshapes IgGmakesupabout75%oftheantibodiesintheblood,buttherearefourotherclassesof antibodies:IgA,IgD,IgE,andIgM.AlltheseclassesofantibodyareproducedbyBcells–whitebloodcellsthatareborninthebonemarrowandcanmaturetobecomeantibody factoriescalledplasmaBcells.
Inadditiontohavinghandsthatcanbindtoanantigen,anantibodymoleculealsohasa constantregion(Fc)“tail”whichcanbindtoreceptors(Fcreceptors)onthesurfaceof cellssuchasmacrophagesInfact,itisthespecialstructureoftheantibodyFcregionthat determinesitsclass(e.g.,IgGvs.IgA),whichimmunesystemcellsitwillbindto,andhowit willfunction
Thehandsofeachantibodybindtoaspecificantigen(eg,aproteinonthesurfaceofthe smallpoxvirus),soinordertohaveantibodiesavailablethatcanbindtomanydifferent antigens,manydifferentantibodymoleculesarerequired.Now,ifwewantantibodiesto protectusfromeverypossibleinvader(andwedo!),howmanydifferentantibodieswould weneed?Well,immunologistsestimatethatabout100millionshoulddothetrick.Since eachantigen-bindingregionofanantibodyiscomposedofaheavychainandalightchain, wecouldmixandmatchabout10,000differentheavychainswith10,000differentlight chainstogetthe100milliondifferentantibodiesweneed.However,humancellsonlyhave about25,000genesinall,soifeachheavyorlightchainproteinwereencodedbya differentgene,mostofahuman’sgeneticinformationwouldbeusedupjusttomake antibodiesYouseetheproblem
Generating antibody diversity by modular design
TheriddleofhowBcellscouldproducethe100milliondifferentantibodiesrequiredto protectuswassolvedin1977bySusumuTonegawa,whoreceivedtheNobelPrizeforhis discovery.WhenTonegawastartedworkingonthisproblem,thedogmawasthattheDNA ineverycellinthebodywasthesame.Thismadeperfectsense,becauseafteraneggis fertilized,theDNAintheeggiscopied.Thesecopiesarethenpasseddowntothedaughter cells,wheretheyarecopiedagain,andpasseddowntotheirdaughters–andsoon. Therefore,barringerrorsincopying,eachofourcellsshouldendupwiththesameDNAas theoriginal,fertilizedegg.Tonegawa,however,hypothesizedthatalthoughthisisprobably trueingeneral,theremightbeexceptionsHisideawasthatallofourBcellsmightstartout withthesameDNA,butthatasthesecellsmature,theDNAthatmakesuptheantibody genesmightchange–andthesechangesmightbeenoughtogeneratethe100million differentantibodiesweneed.
TonegawadecidedtotestthishypothesisbycomparingtheDNAsequenceofthelightchain fromamatureBcellwiththeDNAsequenceofthelightchainfromanimmatureBcell. Sureenough,hefoundthattheyweredifferent,andthattheyweredifferentinavery interestingway.WhatTonegawaandothersdiscoveredwasthatmatureantibodygenes aremadebymodulardesign.
IneveryBcell,onthechromosomesthatencodetheantibodyheavychain,thereare multiplecopiesoffourtypesofDNAmodules(genesegments)calledV,D,J,andC.Each copyofagivenmoduleisslightlydifferentfromtheothercopiesofthatmodule.For example,inhumansthereareaboutfortydifferentVsegments,abouttwenty-fivedifferent Dsegments,sixdifferentJsegments,andsoon.Toassembleamatureheavychaingene, eachBcellchooses(moreorlessatrandom)oneofeachkindofgenesegment,andpastes themtogetherlikethis.
Youhaveseenthiskindofmix-and-matchstrategyusedbeforetocreatediversity.For example,twentydifferentaminoacidsaremixedandmatchedtocreatethehugenumber ofdifferentproteinsthatourcellsproduce.Andtocreategeneticdiversity,the chromosomesyouinheritedfromyourmotherandfatheraremixedandmatchedtomake thesetofchromosomesthatgoesintoyoureggorspermcells.OnceMotherNaturegetsa goodidea,sheusesitoverandover–andmodulardesignisoneofherverybestideas. TheDNAthatencodesthelightchainoftheantibodymoleculeisalsoassembledbypicking genesegmentsandpastingthemtogetherBecausetherearesomanydifferentgene segmentsthatcanbemixedandmatched,thisschemecanbeusedtocreateabout10 milliondifferentantibodies–notquiteenough.So,tomakethingsevenmorediverse,when thegenesegmentsarejoinedtogether,additionalDNAbasesareaddedordeleted.When thisjunctionaldiversityisincluded,thereisnoproblemcreating100millionBcells,each withtheabilitytomakeadifferentantibody.Themagicofthisschemeisthatbyusing modulardesignandjunctionaldiversity,onlyasmallamountofgeneticinformationis requiredtocreateincredibleantibodydiversity
Clonal selection
Inthehumanbloodstream,thereareaboutthreebillionBcells.Thisseemslikealot,butif thereare100milliondifferentkindsofBcells(toproducethe100milliondifferentkindsof antibodiesweneedforprotection),thismeansthat,onaverage,therewillonlybeabout thirtyBcellsinthebloodthatcanproduceanantibodywhichwillbindtoagivenantigen (eg,aproteinonthesurfaceofavirus)Thepointhereisthat,althoughwehaveBcellsin ourarsenalthatcandealwithessentiallyanyinvader,wedon’thavealotofanyonekindof BcellAsaresult,whenweareattacked,moreoftheappropriateBcellsmustbemade
Indeed,Bcellsaremade“ondemand.”ButhowdoestheimmunesystemknowwhichB cellstomakemoreof?Thesolutiontothisproblemisoneofthemostelegantinallof immunology:theprincipleofclonalselection.
AfterBcellsdotheirmix-and-matchthingandpastetogetherthemodulesrequiredtoform the“recipes”fortheirheavyandlightchainantibodyproteins,arelativelysmallnumberof theseproteinsismade–a“testbatch”ofantibodymolecules,ifyouwill.Thesetester antibodies,calledBcellreceptors(BCRs),aretransportedtothesurfaceoftheBcelland aretetheredtherewiththeirantigen-bindingregionsfacingoutEachBcellhasroughly 100,000BCRsanchoredonitssurface,andalltheBCRsonagivenBcellrecognizethesame antigen.
TheBcellreceptorsonthesurfaceofaBcellactlike“bait.”Whattheyare“fishingfor”is themoleculewhichtheirFabregionshavetherightshapetograsp–theircognate antigen.Sadly,thevastmajorityofBcellsfishinvain.Forexample,mostofuswillnever beinfectedwithpoliovirusorHIV-1Consequently,thoseBcellsinourbodywhichcould makeantibodiesthatrecognizethesevirusesneverwillfindtheirmatch.Itmustbevery frustratingformostBcellsTheyfishalltheirlives,andnevercatchanything!
Onoccasion,however,aBcelldoesmakeacatchAndwhenaBcell’sreceptorsbindtoits cognateantigen,thatBcellistriggeredtodoubleinsizeanddivideintotwodaughtercells –aprocessimmunologistscallproliferation.Bothdaughtercellsthendoubleinsizeand dividetoproduceatotaloffourcells,andsoforth.Eachcycleofcellgrowthanddivision takesabouttwelvehourstocomplete,andthisperiodofproliferationusuallylastsabouta weekAttheendofthistime,a“clone”ofroughly20,000identicalBcellswillhavebeen produced,allofwhichhavereceptorsontheirsurfacethatcanrecognizethesameantigen. NowthereareenoughBcellstomountarealdefense!
AftertheselectedBcellsproliferatetoformthislargeclone,mostofthembegintomake antibodiesinearnest.TheantibodiesproducedbytheseselectedBcellsareslightly differentfromtheantibodymoleculesdisplayedontheirsurfaceinthatthereisno “anchor”toattachthemtotheBcell’ssurface.Asaresult,theseantibodiesaretransported outoftheBcellandintothebloodstream.OneBcell,workingatfullcapacity,canpump outabout2,000antibodymoleculespersecond!Aftermakingthisheroiceffort,mostof theseBcellsdie,havingworkedforonlyaboutaweekasantibodyfactories.
Whenyouthinkaboutit,thisisamarvelousstrategy.First,becausetheyemploymodular design,Bcellsuserelativelyfewgenestocreateenoughdifferentantibodymoleculesto recognizeanypossibleinvader.Second,Bcellsaremadeondemand.Soinsteadoffillingup ourbodieswithahugenumberofBcellswhichmayneverbeused,webeginwitha relativelysmallnumberofBcellsofeachkind,andthenselecttheparticularBcellsthat willbeusefulagainsttheinvader du jour.Onceselected,theBcellsproliferaterapidlyto producealargecloneofBcellswhoseantibodiesareguaranteedtobeusefulagainstthe invader.Third,afterthecloneofBcellshasgrownsufficientlylarge,mostofthesecells becomeantibodyfactorieswhichmanufacturehugequantitiesoftheveryantibodiesthat arerighttodefendagainsttheinvader.Finally,whentheintruderhasbeenconquered, mostoftheBcellsdie.Asaresult,wedon’tfillupwithBcellsthatareappropriateto defendagainstyesterday’sinvader,butwhichwouldbeuselessagainsttheenemythat attacksustomorrow.Ilovethissystem!
What antibodies do
Interestingly,althoughantibodiesareveryimportantinthedefenseagainstinvaders,they don’treallykillanythingTheirjobistoplantthe“kissofdeath”onaninvader–totagitfor destruction.Ifyougotoafancywedding,you’llusuallypassthroughareceivinglinebefore youareallowedtoenjoythechampagneandcake.Ofcourse,oneofthefunctionsofthis receivinglineistointroduceeveryonetothebrideandgroom.Buttheotherfunctionisto besurenooutsidersareadmittedtothecelebration.Asyoupassthroughtheline,youwill bescreenedbysomeonewhoisfamiliarwithalltheinvitedguestsIfshefindsthatyou don’tbelongthere,shewillcallthebouncerandhaveyouremoved.Shedoesn’tdoit herself–certainlynotHerroleistoidentifyundesirables,nottoshowthemtothedoor Andit’sthesamewithantibodies:Theyidentifyinvaders,andletotherplayersdothedirty work.
Indevelopedcountries,theinvadersweencountermostfrequentlyarebacteriaand viruses.Antibodiescanbindtobothtypesofinvadersandtagthemfordestruction. Immunologistsliketosaythatantibodiescanopsonizetheseinvaders.Thistermcomes fromaGermanwordthatmeans“toprepareforeating”Iliketoequateopsonizewith “decorate,”becauseIpicturethesebacteriaandviruseswithantibodieshangingallover them,decoratingtheirsurfaces.Anyway,whenantibodiesopsonizebacteriaorviruses, theydosobybindingtotheinvaderwiththeirFabregions,leavingtheirFctailsavailable tobindtoFcreceptorsonthesurfaceofcellssuchasmacrophages.Usingthisstrategy, antibodiescanformabridgebetweentheinvaderandthephagocyte,bringingtheinvader inclose,andpreparingitforphagocytosis.
Infact,it’sevenbetterthanthisWhenaphagocyte’sFcreceptorsbindtoantibodiesthat areopsonizinganinvader,theappetiteofthephagocyteincreases,makingitevenmore phagocyticMacrophageshaveproteinsontheirsurfacethatcanbinddirectlytomany commoninvaders.However,theabilityofantibodiestoformabridgebetweena macrophageandaninvaderallowsamacrophagetoincreaseitscatalogofenemiesto includeanyinvadertowhichanantibodycanbind,commonoruncommon.Ineffect,
antibodiesfocusamacrophage’sattentiononinvaders,someofwhich(theuncommon ones)amacrophagewouldotherwiseignore.
Duringaviralattack,antibodiescandosomethingelsethatisveryimportantVirusesenter ourcellsbybindingtocertainreceptormoleculesonacell’ssurface.Ofcoursethese receptorsarenotplacedtherefortheconvenienceofthevirus.Theyarenormalreceptors, suchastheFcreceptor,thathavequitelegitimatefunctions,butwhichthevirushas learnedtousetoitsownadvantage.Onceithasboundtothesereceptorsandentereda cell,avirusthenusesthecell’smachinerytomakemanycopiesofitselfThesenewlymade virusesburstoutofthecell,sometimeskillingit,andgoontoinfectneighboringcells.Now fortheneatpart:Antibodiescanactuallybindtoaviruswhileitisstilloutsideofacell,and cankeeptheviruseitherfromenteringthecellorfromreproducingonceithasentered. Forexample,someantibodiescanattachtothepartofthevirusthatnormallywouldplug intoitscellularreceptorandpreventthevirusfrom“docking”onthesurfaceofacell Antibodieswiththesespecialpropertiesarecalledneutralizingantibodies.
T cells
Althoughantibodiescantagvirusesforphagocyticingestionandcanhelpkeepviruses frominfectingcells,thereisaweaknessintheantibodydefenseagainstviruses:Oncea virusgetsintoacell,antibodiescan’tgettoit,sothevirusissafetomakethousandsof copiesofitself.Todealwiththispotentialproblem,theimmunesystemevolvedtoinclude anotherweapon:theTcell–anadditionalmemberoftheadaptiveimmunesystemteam.
TheimportanceofTcellsissuggestedbythefactthatanadulthumanhasabout300billion ofthem.TcellsareverysimilartoBcellsinappearance.Infact,underanordinary microscope,animmunologistcan’ttellthemapart.LikeBcells,Tcellsareproducedinthe bonemarrow,andontheirsurfacetheydisplayantibody-likemoleculescalledTcell receptors(TCRs).LiketheBcell’sreceptors(theantibodymoleculesattachedtoits surface),TCRsaremadebyamix-and-match,modulardesignstrategyAsaresult,TCRsare aboutasdiverseasBCRs.Tcellsalsoemploytheprincipleofclonalselection:WhenaT cell’sreceptorsbindtotheircognateantigen,theTcellproliferatestobuildupacloneofT cellswiththesamespecificity.Thisproliferationstagetakesaboutaweek,solikethe antibodyresponse,theTcellresponseisslowandspecific.
Althoughtheyaresimilarinmanyways,therearealsoimportantdifferencesbetweenB cellsandTcellsBcellsmatureinthebonemarrow,whereasTcellsmatureinthethymus (that’swhythey’recalled“T”cells).Bcellsmakeantibodiesthatcanrecognizeanyorganic molecule,butTcellsspecializeinrecognizingproteinantigensAlthoughaBcellcan secreteitsreceptorsintheformofantibodies,aTcell’sreceptorsremaintightlygluedtoits surface.Perhapsmostimportantly,aBcellcanrecognizeanantigen“byitself,”whereasaT cellwillonlyrecognizeanantigenifitis“properlypresented”byanothercell.I’llexplain whatthatmeansinabit.
ThereareactuallythreemaintypesofTcells:killerTcells(frequentlycalledcytotoxic lymphocytesorCTLs),helperTcells,andregulatoryTcells ThekillerTcellisapotent weaponthatcandestroyvirus-infectedcells.Indeed,byrecognizingandkillingthesecells, theCTLsolvesthe“hidingvirus”problem–theweaknessImentionedintheantibody defenseagainstviruses.ThewayakillerTcelldestroysvirus-infectedcellsisbymaking
contactwithitstargetandthentriggeringthecelltocommitsuicide!This“assistedsuicide” isagreatwaytodealwithvirusesthathaveinfectedcells–becausewhenavirus-infected celldies,theviruseswithinthecelldiealso.
ThesecondtypeofTcellisthehelperTcell(Thcell).Asyouwillsee,thiscellservesasthe quarterbackoftheimmunesystemteam.Itdirectstheactionbysecretingchemical messengers(cytokines)thathavedramaticeffectsonotherimmunesystemcells.These cytokineshavenameslikeinterleukin2(IL-2)andinterferongamma(IFN-γ),andwewill discusswhattheydoinlaterlecturesFornow,itisonlyimportanttorealizethathelperT cellsarebasicallycytokinefactories.
ThethirdtypeofTcellistheregulatoryTcellTheroleofthistypeofTcellistokeepthe immunesystemfromoverreactingorfromreactinginappropriately.Immunologistsare stillworkingtounderstandhowTcellsbecomeregulatoryTcellsandexactlyhowthey performtheseimportantfunctions.I’lltellyoumoreaboutregulatoryTcellsinlater lectures.
Antigen presentation
OnethingIneedtoclearupisexactlyhowantigenispresentedtoTcells.Itturnsoutthat
