Table Of Content

CJASN CJASN’s Renal Immunology for the Clinician Review the fundamentals of renal immunology in this comprehensive 8-part series available now in a user-friendly compiled pdf file. Leading investigators will provide a focused update for practicing nephrologists and trainees on immunology and its relationship to kidney disease. Series Editor: Fadi G. Lakkis, MD Deputy Editor: Paul M. Palevsky, MD, FASN Editor-in-Chief: Gary C. Curhan, MD, ScD, FASN ASN LEADING THE FIGHT AGAINST KIDNEY DISEASE CJASN Clinical Journal of the American Society of Nephrology Renal Immunology for the Clinician Article1 ANewCJASNSeries:RenalImmunologyfortheClinician FadiG.LakkisandPaulM.Palevsky Article2 ABriefJourneythroughtheImmuneSystem KarimM.YatimandFadiG.Lakkis Article3 HowtheInnateImmuneSystemSensesTroubleandCausesTrouble TakashiHatoandPierreC.Dagher Article4 MoleculesGreatandSmall:TheComplementSystem DouglasR.MathernandPeterS.Heeger Article5 DendriticCellsandMacrophages:SentinelsintheKidney ChristinaK.Weisheit,DanielR.Engel,andChristianKurts Article6 TCells:SoldiersandSpies—TheSurveillanceandControlofEffectorTCellsbyRegulatoryTCells BruceM.Hall Article7 Cytokines:NamesandNumbersYouShouldCareAbout StephenR.HoldsworthandPoh-YiGan Article8 BCells,Antibodies,andMore WilliamHoffman,FadiG.Lakkis,andGeethaChalasani Article9 ImmunosuppressiveMedications AlexanderC.Wiseman CJASN Clinical Journal of the American Society of Nephrology Editors Editor-in-Chief GaryC.Curhan,MD,ScD,FASN Boston,MA DeputyEditors KirstenL.Johansen,MD SanFrancisco,CA PaulM.Palevsky,MD,FASN Pittsburgh,PA Associate Editors MichaelAllon,MD AnnM.O’Hare,MD Birmingham,AL Seattle,WA JeffreyC.Fink,MD,MS,FASN MarkA.Perazella,MD,FASN Baltimore,MD NewHaven,CT LindaF.Fried,MD,MPH,FASN VladoPerkovic,MBBS,PhD,FASN,FRACP Pittsburgh,PA Sydney,Australia DavidS.Goldfarb,MD,FASN KatherineR.Tuttle,MD,FACP,FASN NewYork,NY Spokane,WA DonaldE.Hricik,MD SushrutS.Waikar,MD Cleveland,OH Boston,MA MarkM.Mitsnefes,MD Cincinnati,OH Section Editors AttendingRoundsSeriesEditor MitchellH.Rosner,MD,FASN Charlottesville,VA EducationSeriesEditor SuzanneWatnick,MD Portland,OR EthicsSeriesEditor AlvinH.Moss,MD,FACP Morgantown,WV PublicPolicySeriesEditor AlanS.Kliger,MD NewHaven,CT RenalImmunologySeriesEditor FadiG.Lakkis,MD Pittsburgh,PA Statistical Editors RonitKatz,DPhil RobertA.Short,PhD Seattle,WA Spokane,WA Editor-in-Chief, Emeritus WilliamM.Bennett,MD,FASN Portland,OR Managing Editor ShariLeventhal Washington,DC CJASN Clinical Journal of the American Society of Nephrology Editorial Board RajivAgarwal LanceDworkin T.AlpIkizler NaderNajafian EdwardSiew Indianapolis,Indiana Providence,RhodeIsland Nashville,Tennessee Boston,Massachusetts Nashville,Tennessee ZiyadAl-Aly JeffreyFadrowski TamaraIsakova AndrewNarva TheodoreSteinman SaintLouis,Missouri Baltimore,Maryland Chicago,Illinois Bethesda,Maryland Boston,Massachusetts CSehaatrtllees,WAlapsehrsington DBaelrteimkoFrine,eMaryland MSyedgneJayr,dAinuestralia SCalenvkealraNnda,vOanheieothan PeterStenvinkel Stockholm,Sweden KevinFinkel SandraAmaral MichelleJosephson AliciaNeu Houston,Texas HaroldSzerlip Philadelphia,Pennsylvania Chicago,Illinois Baltimore,Maryland Augusta,Georgia StevenFishbane JerryAppel BryceKiberd ThomasNickolas NewYork,NewYork Mineola,NewYork Halifax,BC,Canada NewYork,NewYork EricTaylor JohnForman Boston,Massachusetts ArifAsif Boston,Massachusetts GregKnoll ToshiharuNinomiya Miami,Florida Ottawa,ON,Canada Fukuoka,Japan AshitaTolwani LuiForni Birmingham,Alabama MohamedAtta Worthing,UnitedKingdom JayKoyner RainerOberbauer Baltimore,Maryland Chicago,Illinois Vienna,Austria JamesTumlin BarryFreedman JoanneBargman WinstonSalem,NorthCarolina HollyKramer GregorioObrador Chattanooga,Tennessee Toronto,ON,Canada MasafumiFukagawa Maywood,Illinois Mexico MarkUnruh BrendanBarrett Kanagawa,Japan ManjulaKurellaTamura RunolfurPalsson Albuquerque,NewMexico St.John’s,NL,Canada PaloAlto,California Reykjavik,Iceland SusanFurth RaymondVanholder SrinivasanBeddhu Philadelphia,PA HiddoLambersHeerspink MandipPanesar Gent,Belgium SaltLakeCity,Utah MartinGallagher Groningen,Netherlands Buffalo,NewYork AnithaVijayan JeffreyBerns Sydney,Australia CraigLangman NeeshPannu St.Louis,Missouri Philadelphia,PA MaurizioGallieni Chicago,Illinois Edmonton,Canada Milan,Italy RonWald GeoffreyBlock JamesLash RulanParekh Toronto,ON,Canada Denver,Colorado RonaldGansevoort Chicago,Illinois Baltimore,Maryland W.KlineBolton Groningen,Netherlands EleanorLederer UptalPatel MichaelWalsh Charlottesville,Virginia AmitGarg Louisville,Kentucky Durham,NorthCarolina Hamilton,ON,Canada London,ON,Canada AndrewBomback AndrewLewington AldoPeixoto MatthewWeir NewYork,NewYork MichaelGermain Leeds,UnitedKingdom WestHaven,Connecticut Baltimore,Maryland Springfield,Massachusetts UrsulaBrewster OrfeasLiangos AnthonyPortale StevenWeisbord NewHaven,Connecticut EricGibney Coburg,Germany SanFrancisco,California Pittsburgh,Pennsylvania Atlanta,Georgia PatrickBrophy JohnGill FernandoLianõ JaiRadhakrishnan JessicaWeiss IowaCity,Iowa Vancouver,BC,Canada Madrid,Spain NewYork,NewYork Portland,Oregon EmmanuelBurdmann DavidGoldsmith JohnLieske MahboobRahman AdamWhaley-Connell SaõPaulo,Brazil London,UnitedKingdom Rochester,Minnesota Cleveland,Ohio Columbia,Missouri KerriCavanaugh StuartGoldstein KathleenLiu DominicRaj Nashville,Tennessee Cincinnati,Ohio SanFrancisco,California Washington,DistrictofColumbia ColinWhite Vancouver,BC,Canada MicahChan BarbaraGreco RandyLuciano PeterReese Madison,Wisconsin Springfield,Massachusetts NewHaven,Connecticut Philadelphia,Pennsylvania MarkWilliams Boston,Massachusetts AnilChandraker OrlandoGutierrez JichengLv GiuseppeRemuzzi Boston,Massachusetts Birmingham,Alabama Beijing,China Bergamo,Italy AlexanderWiseman Aurora,Colorado DavidCharytan YoshioHall MarkMarshall MarkRosenberg Boston,Massachusetts Seattle,Washington Auckland,NewZealand Minneapolis,Minnesota JayWish MichaelChoi LeeHamm WilliamMcClellan AndrewRule Indianapolis,IN Baltimore,Maryland NewOrleans,Louisiana Atlanta,Georgia Rochester,Minnesota MylesWolf MichelChonchol ItaHeilberg AnitaMehrotra JeffreySaland Chicago,Illinois Denver,Colorado SaõPaulo,Brazil NewYork,NewYork NewYork,NewYork JerryYee StevenCoca BrendaHemmelgarn RajnishMehrotra JaneSchell Detroit,Michigan NewHaven,Connecticut Calgary,AB,Canada Seattle,Washington Pittsburgh,Pennsylvania BessieYoung AndrewDavenport JonathanHimmelfarb MichalMelamed BerndSchro¨ppel Seattle,Washington London,UnitedKingdom Seattle,Washington Bronx,NewYork Ulm,Germany IandeBoer EricHoste SharonMoe StephenSeliger EricYoung Seattle,Washington Gent,Belgium Indianapolis,Indiana Baltimore,Maryland AnnArbor,Michigan BradleyDixon Chi-yuanHsu BarbaraMurphy MichaelShlipak CarmineZoccali IowaCity,Iowa SanFrancisco,California NewYork,NewYork SanFrancisco,California ReggioCalabria,Italy CJASN ExecutiveDirector TodIbrahim TheAmericanSocietyofNephrology(ASN)marks50yearsofleadingthefight againstkidneydiseasesin2016.Throughouttheyear,ASNwillrecognizekidney DirectorofCommunications healthadvancesfromthepasthalfcenturyandlookforwardtonewinnovations RobertHenkel in kidney care. 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CJASN A New Series: Renal Immunology for the Clinician FadiG.Lakkis*andPaulM.Palevsky† ClinJAmSocNephrol10:1273,2015.doi: 10.2215/CJN.03870415 Withthisissue,CJASNbeginsanewseriesofreview systemistheinfluenceofCKDonimmunity;paradoxically *ThomasE.Starzl articlescoveringimmunologyfortheclinicalnephrol- weakening defenses against infection while in- Transplantation ogist.Therehasbeenexplosivegrowthinourunder- creasingsystemicinflammation,whichcontributes Instituteand standingofimmunemechanismsandtherelationship to the excessive burden of cardiovascular disease Departmentsof Surgery,Immunology, between these integral defense systems within the inourpatients.Theroleofimmunologicprocesses andMedicine, bodyandthefunctionofthekidneyinhealthanddisease. in the progression of CKD is an area of growing Universityof Theroleoftheimmunesystemasabarriertotransplan- interest. PittsburghSchoolof tationhasbeenlongrecognizedandhasbeenaprimary This series, which will run over eight issues, begins Medicine,Pittsburgh, Pennsylvania;and impetusforourdrivetobetterunderstandimmunologic this month with an overview of the immune system †RenalSection, detectionofnonselfandmechanismsoftoleranceandthe fromanevolutionary/teleologicstandpoint.Insucceed- VeteransAffairs developmentofmedicationstomodulatethebody’snor- ingissues,theseries willcoverthe mechanisms ofthe PittsburghHealthcare malresponsetorejectforeignorgans.Immunologicdys- innate immune system, the normal regulation of the SystemandRenal- regulation leads to the development of autoimmune complementsystemandtheroleofitsdysregulation ElectrolyteDivision, Departmentof kidneydiseasesbothlimitedtothekidneyoraspartof indisease,therolesofdendriticcellsandmacrophages Medicine,University systemic illness. These include primary glomerular dis- asbothsensorsandeffectorsinthekidney,thebiologyof ofPittsburghSchoolof easesandinterstitialnephritisaswellassystemicvascu- Tcellsinmediatingandregulatingtheimmuneresponse, Medicine,Pittsburgh, litides, collagen vascular disorders, such as SLE, and a theroleofBcells,andtheroleoftheincreasingnumber Pennsylvania widening array of diseases understood to be mediated ofknownsolublecytokinesthatallow thecomponents bycomplementactivation,includingthromboticmicro- of the immune system to communicate and function Correspondence: Dr.PaulM.Palevsky, angiopathies and the spectrum of C nephropathy. In- harmoniously.Finally,theserieswillendwithareview 3 VeteransAffairs creasing evidence over the past decade has also of the enlarging armamentarium of pharmacologic PittsburghHealthcare shownacentralrolefortheimmunesysteminthepath- agentsatourservicetocontroltheimmuneresponse. System,MailStop: ogenesisofAKIresultingfromischemiareperfusionin- Itistheeditors’hopethatthesereviewswillserveasa 111F-U,University Drive,Pittsburgh,PA juryornephrotoxinexposure,andinsepsis,evenwhen primerforunderstandingthisimportantandrapidly the kidney is not the focus of infection. An additional advancingfieldandbehelpfultobothseasonedprac- 15240.Email: [email protected] importantconnectionbetweenthekidneyandimmune titionersandnewtraineesinnephrology. www.cjasn.orgVol10July,2015 Copyright©2015bytheAmericanSocietyofNephrology 1273 A Brief Journey through the Immune System KarimM.YatimandFadiG.Lakkis Abstract ThisreviewservesasanintroductiontoanImmunologySeriesfortheNephrologistpublishedinCJASN.Itprovidesa briefoverviewoftheimmunesystem,howitworks,andwhyitmatterstokidneys.Thisreviewdescribesinbroadterms themaindivisionsoftheimmunesystem(innateandadaptive),theircellularandtissuecomponents,andthewaysby whichtheyfunctionandareregulated.Thestoryistoldthroughtheprismofevolutioninordertorelaytothereader ThomasE.Starzl whytheimmunesystemdoeswhatitdoesandwhyimperfectionsinthesystemcanleadtorenaldisease.Detailed Transplantation descriptionsofcelltypes,molecules,andotherimmunologiccuriositiesareavoidedasmuchaspossibleinaneffortto Instituteandthe notdetractfromtheimportanceofthebroaderconceptsthatdefinetheimmunesystemanditsrelationshiptothe Departmentsof Surgery,Immunology, kidney. andMedicine, ClinJAmSocNephrol10:1274–1281,2015.doi: 10.2215/CJN.10031014 Universityof PittsburghSchoolof Medicine,Pittsburgh, Pennsylvania The Beginning of the Journey howwouldyou(withtheguidinghandofevolution,of Imagine that you are a primitive animal, perhaps a course)goaboutdevisingsuchasystem,whatwould Correspondence: distantpredecessorofallmammals.Youhavelivedalong it look like, and why will it eventually matter to our Dr.FadiG.Lakkis, life, thus far relying solely on a basic defense system. If kidneys? ThomasE.Starzl you are invaded by a microbe or parasite, you quickly Transplantation Instituteandthe expelorkillitbyreleasingchemicals,producingabarrage Departmentsof ofdefensiveproteinmoleculesorunleashingphagocytic Innate and Adaptive Immunity Surgery,Immunology, cells(1).Ifallfails,youwalltheinvaderofforregenerate Devisingasophisticatedbiologicsystem,asevolution andMedicine, thatpartofyourbodyreducedtorotbyinfection.Even teachesus,doesnotrequirethedestructionofpreexist- Universityof ifinfectionprovesfatal,yourextremefecundity,which ing,primitivetools,butinsteaddependsonpreserving PittsburghSchoolof Medicine,W1548 started at a very early age, has already ensured the andbuildingonthebestofthem(3).Heedingthisad- ThomasE.Starzl continuity of your species. This seemingly imaginary vice,youtakeyourtime,spendinghundredsofmillions BiomedicalSciences scenarioisinfacthowthemoreancientofourancestors ofyears,choosingthebestanddiscardingtheleastuse- Tower,200Lothrop attainnearimmortality(2). ful of your primitive defense mechanisms. You call Street,Pittsburgh,PA Nowimaginethatevolutionhassomethinggrander whatisleftinnateimmunity:innatebecausethedefense 15261.Email: [email protected] in store for you. You are destined to become the pro- mechanisms you have chosen are encoded in your genitor of more sophisticated beings. Your descendants germline, having been selected over evolutionary time willgrowcomplexorgans—robustkidneysthatempower and passed down from generation to generation with them to roam the earth and mighty brains that enable only minor refinements (4). In other words, they have them to rule it. To do so, they will carry their embryos stood the test of time. They include household names andnurturetheiryoungforanextendedperiodoftime. such as the complement system, Toll-like receptors Reproductionbecomesalaterandinfrequenteventinlife, (TLRs), and phagocytic cells. Modern-day genome se- and life itself becomes a much shorter journey. The ca- quencing has established that much of these defense pacitytoregenerate tissues,limbs,andorgans dwindles systems are conserved across animal phyla, a true re- astissuearchitectureandfunctiongrowincreasinglydif- flection of not only their remarkable effectiveness but ferentiatedandcomplex.Althoughlessabundant,lifefor alsotheirversatility(3).Acomplementmolecule,aTLR, your descendants becomes more valuable as failure to or a phagocyte is not only essential for detecting and surviveuntilareproductiveagespellsdoomforthespe- eliminatingharmfulnonselfbutisalsokeytomaintain- cies. Faced with these burdens, you quickly realize that ingnormaltissuehomeostasis,beitsensingandrepair- youhavetodeviseamoreintelligentdefensesystem:one ingdamagedtissuesorquietlyeliminatingsenescentor thatprotectsagainstvirtuallyallpathogensthatyoursuc- apoptoticcells.Obviously,youhavechosenprudently. cessors may encounter during their forays into known However,thatisclearlynotsufficient.Aninnateim- andunknownrealms,onethatprovideslong-lastingse- mune system provides immediate albeit incomplete curityagainstinfection,andonethatiscarefullyregulated protectionagainstintrudersand,atbest,hasonlyshort- so that it does not attack its own tissues or endanger term memory (4,5). Instead of mounting a faster and beneficialcohabitants.Youwillcallthisdefensesystem more effective response upon encountering a known immunity (Figure 1). Defense, after all, is a primitive trespasser, it starts sluggishly from scratch each time. termthatisequallyassociatedwithdefeatandvictory, Innate immunity has additional shortcomings. Recep- whereasimmunityexudesstrengthandconfidence.So torsutilizedbyinnatecells,suchastheTLR,areadept 1274 Copyright©2015bytheAmericanSocietyofNephrology www.cjasn.orgVol10July,2015 ClinJAmSocNephrol10:1274–1281,July,2015 IntroductiontotheImmuneSystem,YatimandLakkis 1275 on any given lymphocyte, this exquisite specificity ensures thatonlypertinentlymphocytesareactivated,thusminimiz- ingbystanderdamage. However,thereismoretotheplan.Uponencountering antigens,lymphocytesproliferateextensivelytomaximize theirfightingpoweranddifferentiateintospecializedsubsets to further hone it. B lymphocytes transform into antibody factories knownas plasma cells,whereas T lymphocytes differentiateintohelperandeffector(e.g.,cytotoxic)subsets, each with its distinct set of secreted molecules (cytokines). Helper T lymphocyte subsets orchestrate the mounting immune response by dictating what defense strategy is used against a particular intruder, whereas cytotoxic T lympho- cytesdirectlyeffectthedeathofcellsharboringtheintruder. Importantly, immune responses do not march on indefi- nitely or haphazardly but are tightly regulated by special- ized B and T lymphocytes known as regulatory cells (8,9). Moreover, the exponential proliferation and differentiation of lymphocytes responding to an antigen is ultimately re- strainedbythedeathofthemajorityofantigen-specificlym- phocytes involved in the response (Figure 2). The precious Figure1.|Evolutionoftheimmunesystem.Adaptiveimmunityas few that survive become long-lived memorycells. Memory weknowitinhumansdidnotevolveuntiltheemergenceofthefirst lymphocytes ensure that asecondencounter withthesame jawedvertebrates(fish)around450millionyears(my)ago.Evolution invader is dealt with swiftly and effectively because of the ofadaptiveimmunitywasheraldedbytheappearanceoflymphocytes, manyadvantagestheyhaveovertheirinexperienced(naïve) themajorhistocompatibilitycomplex(MHC),immunoglobulin(Ig)mol- predecessors (10). These include their greater number (for ecules, T-cell receptor for antigen (TCR), and recombinase activating any given antigen), extended lifespan, more rapid response genes(RAG)responsibleforthediversityintheserecognitionmol- rate,superiorproliferationcapacity,andwideraccesstotissues. ecules.Ourmoreancientancestors,suchasthesponges(2700my), Withthejobcompleted,youmarvelattheadaptivefeaturesof reliedonbasicdefensesystemswithoutthebenefitoflymphocytes, the lymphocytes you have created (clonal expansion, differ- antigen receptors with fine molecular specificity, or any noteworthy entiation, regulation, and memory) and you name this new immunologicmemory.Anapproximatetimelineforevolutionofinnate immune components (antimicrobial peptides, phagocytosis, comple- systemadaptiveimmunity. ment,andToll-likereceptors)isalsoshown. at discerning self fromnonselfbutlackthemolecular spec- Linking Innate to Adaptive Immunity ificityrequiredfordistinguishingbetweennonselves,causing What good, however, are two immune systems in one themtotriggerdefensesagainstbothfriendandfoe.Tomake bodyiftheydonotcommunicatewitheachother?Because matters worse, the imprecise defenses discharged by innate the newly devised lymphocytes of the adaptive immune cellscanwreakhavoconthesurroundingtissueandoften system and the receptors they express are destined to the entire organism itself. Imagine, by way of example, a recognize fine molecular specificities on antigens, you co- renalabscessfullofneutrophils(atypicalinnatecell)growing opt the phagocytic cells of the innate immune system to uncheckedinahaplesspatient. captureantigens,cutthemintosmallmolecularfragments Realizing these dangers, you set out to build a more (peptides), and present them to the lymphocytes waiting sophisticateddefensesystem(Figure1).Inarelativelyshort in anticipation. Immunologists refer to the subset of in- period(shortontheevolutionarytimescale,ofcourse),you nateimmunecellsproficientatprocessingantigensinthis acquirethetoolstocreatenewtypesofimmunecells,known manner as antigen-presenting cells (APCs) and the most as B and T lymphocytes (6). Lymphocytes possess surface skilledamongthemasdendriticcells(DCs),becauseofthe receptors,Igs(orantibodies)onBlymphocytes,andthe conspicuous dendrites they extend into every nook and T-cell receptors (TCRs) for antigen on T lymphocytes that, crannyofourtissues(11).Toactivatetheadaptiveimmune unlike receptors on innate immune cells, recognize nonself system, DCs package antigenic peptides into major histo- molecules(referredtoasantigensinthiscase)withexquisite compatibility complex (MHC) proteins (human leukocyte specificity.Thegenesthatencodethesereceptorsarenotem- antigensinhumans),which ensures that virtuallyanynon- bedded in the germline but are the product of gene recom- self peptide is presented to the T lymphocyte with the op- binationduringlymphocytedevelopment,a niftymolecular timal TCR specificity and affinity (12). At the same time, trick that generates a very large number of unique antigen DCs provide additional signals, known as costimulatory receptorsbysplicing,rearranging,andlinkingafinitesetof signals, which guarantee full proliferation and differentia- adjacent genes (7). Antigen receptors on either B or T lym- tion of the T lymphocyte (13). Parsimoniously, you choose phocytes pinpoint the slightest distinction between self and the same molecules utilized by the innate immune system virtuallyanynonselforbetweenonenonselfandanotherand to sense nonself and trigger inflammation to be the ones setoffanimmuneresponsethatonlytargetstheantigenthat thatstimulatetheantigen-presentingandcostimulatoryca- happens to carry that distinction. Because only one type of pabilities of DCs—that is, induce the maturation of DCs antigenreceptor,orperhapsafewtypesatmost,isexpressed into potent APCs (14). A nonself microbial motif such as 1276 ClinicalJournaloftheAmericanSocietyofNephrology Helpers and secondary lymphoid organs are the lymph nodes, spleen, effectors andPeyer’spatchesinthesmallintestine.Allareorganized structures divided into T- and B-cell zones through which Regulation naïve T and B lymphocytes circulate constantly or reside for extended periods of time. DCs and other APCs, on the # yte otherhand,remainfreetoliveineithersecondarylymphoid oc tissuesorvirtuallyanynonlymphoidorganofthebody.The h mp kidney,infact,hasanextensivenetworkofsuchcells.Upon Ly sensinganonselfintruderandcapturingitsantigens(e.g.,an Escherichiacoliinfectingtheurinarytract),DCsmigratealong lymphatic channels to the nearest lymph node and, by fol- lowingchemokineandadhesionmoleculecues,strategically Naive Memory positionthemselveswithinthelymphnodetoactivateantigen- Antigen Time specific T lymphocytes and subsequently, antigen-specific B lymphocytes. This organized rendezvous between innate and Apoptotic cell Memory precursor adaptive immune cells generates ample effector and mem- orylymphocytesthatthenexitthelymphnodeandmigrate throughthebloodstreamtothesiteofantigenentry(e.g.,the Figure 2.|A two-dimensional view of the adaptive (lymphocyte) infectedkidney).Effectorandmemorycellmigrationtothe immune response. Foreign antigen triggers the exponential pro- targettissueisonceagainguidedbychemokinesandadhe- liferation of lymphocytes, whichthendifferentiateintohelperand effectorcells.Regulatorymechanismskickinatthepeakofthere- sionmoleculesand,importantly,byantigen-presentingDCs sponse,themostconspicuousofwhichisthedeathofthemajorityof within the tissue. Some memory T lymphocytes remain in thelymphocytesbyapoptosis.Thefewthatsurvivebecomememory thenonlymphoidtissuesasresidentmemorycellsthatguard precursorsandlatermemorycells.Lymphocytedeathisnecessaryto against reinfection with the same pathogen. With the circle preventunwantedimmunopathology. completed, you are confident that the noose will tighten aroundtheintruder’sneck. Inadditiontosecondarylymphoidtissues,evolutionhas lipopolysaccharide (LPS), which unleashes innate immune set aside primary lymphoid organs dedicated to the pro- defenses by binding to its receptor TLR4, also primes DCs duction and education of nascent immune cells. These through the same receptor to present the myriad foreign arethebonemarrowandthethymus.Thebonemarrowis antigensthat themicrobecarries andto activate theappro- wherebothinnateandadaptiveimmunecellsarebornand priate T lymphocytes (15). The innate immune system you isthesitewhereBlymphocytesare educated.NewbornT havethusfarmoldedhasthereforebeentransformedfroma primitive, first-line defense system into an ingenious door- lymphocytes,ontheotherhand,receivetheireducationin thethymus.Sowhatislymphocyteeducationallaboutand bellthatawakenstheadaptiveimmuneresponse(Figure3). why is it essential? The primary goal of education is to Adaptive immune cells, in turn, cooperate with innate im- munecells—driving,fine-tuning,andsometimesregulating weed out those lymphocytes that recognize self antigens them—tomaximizethechancethatintrudersareeliminated (andthereforecouldcauseharmtotheorganismitself)by either killing them off or inducing in them a permanent at minimal cost to the host. You congratulate yourself on state of unresponsiveness called anergy. This education successfully linking the innate and adaptive immune sys- process, referred to as negative selection (17), is necessary temsandponderwhattodonext. because the specificity of antigen receptors on B and T lymphocytes arose in the first place through random, so- Lymphoid Organs: A Brief Lesson in Geography maticgenearrangementandnotthroughapredetermined, Optimal and timely activation of the adaptive immune germline embedded route selected over evolutionary time response, however, cannot possibly rely on chance en- (such as the case is with innate receptors). Therefore, un- countersbetweenTlymphocytesandthematureDCsthat lesstheyarecarefullyselected,emergingBandTlympho- carry the antigenic peptides they recognize. Nor can cyte populations would harbor an unacceptable level of random wanderings guarantee that B lymphocytes will self-reactivity, unleashing the “horror autotoxicus” de- find their target antigens or the help they need from T scribed byPaul Ehrlich more than100 years ago(18).Be- lymphocytes to differentiate into antibody-producing fore negative selection, T lymphocytes also undergo a plasma cells. After all, your descendants are destined to positive selection step in the thymus, which ensures that have large bodies with extensive mucosal surfaces and onlythosethatrecognizeself-MHCmoleculessurvive(19). complex three-dimensional organs, making the surveil- This step is essential because TCR do not engage free- lance of every tissue fold by lymphocytes an impossible swimming peptides but ones bound to MHC molecules, task. So how could one guarantee that rare immune cells implying that only those newborn T lymphocytes that ex- find antigen and each other quickly and efficiently? The pressTCRwithintrinsicaffinitytoMHCareuseful.Inany solutionthatevolutionmakesavailabletoyouturnsoutto given individual, T lymphocytes that recognize self-MHC be a simple one. Your descendants will harbor anatomic withareasonableaffinityarepositivelyselectedandthose structures, known as secondary lymphoid organs or tis- thatengageself-MHCwitheithertoolowortoohighofan sues, and will synthesize molecular messages, known as affinity die—the former by neglect and the latter in the chemokinesandadhesionmolecules,thatbringimmunecells negative selection step that ensues. What emerges at the togetherattherightplaceandtime(16).Primeexamplesof endisamaturelymphocyterepertoirethatdetectsmillions ClinJAmSocNephrol10:1274–1281,July,2015 IntroductiontotheImmuneSystem,YatimandLakkis 1277 Figure3.|Theroleoftheinnateimmunesysteminactivatingadaptiveimmunity.Theinnateimmunesystemcanbeenvisionedasadoor- bellthatawakenstheadaptiveimmunesystem(lymphocytes)uponsensingmicrobes(bacteria,viruses,fungi,andparasites).Thedendriticcell (DC)actsasthelinkbetweentheinnateandadaptivesystemsbyphagocytosing,processing,andpresentingmicrobialantigenstolymphocytes andprovidingthemwiththenecessarycostimulatorysignals.Endogenousmoleculesreleasedbystressedordyingcellsparticipateinacute kidneyinjury,transplantrejection,orautoimmunitybytriggeringthesameinnateimmunereceptorsthatsensemicrobesleadingtostimulation oftheadaptiveimmuneresponse. of nonself antigens but has a limited ability to mount an infection, and they enlist the immune system in the tissue immune response against self antigens. Your heirs will be repairprocess.Wenowknowthatbothlymphoid(e.g.,reg- beneficiaries of this well orchestrated educational system ulatory T cells) and innate myeloid cells (e.g., macrophages) but, as we shall see later, will also pay the price for its actively participate in and are essential for tissue repair in inherent imperfections. thekidneyandelsewhere(22).Inotherwords,components ofboththeinnateandadaptivesystemsarereadytoreactto selfwhenitsignalsharmorbecomesharmfulitself. Blurring the Lines Yourimmunesystemalsoquicklygraspstherealitythat Youhavethusfarconductedyourworkcarefully,dividing not all microbial nonself is harmful. The billions of com- theimmunesystemintoinnateandadaptiveandseparating mensal bacteria and other microbes that will accompany antigensalongsimple,cleanlinesintoharmlessselfantigens yourdescendantsthroughouttheirlifejourneyswillinfact ononesideandharmfulnonselfmicrobesontheother.Butis beessentialfortheirwell-being.Theimmunesystemthere- allselfharmless,andisallnonselfharmful?Areallharmful fore promptly takes advantage of the regulatory mecha- nonselvesmicrobes?Anddoallimmunecellsfitneatlyinto nismsithastoensurethatDCsandlymphocytesatbarrier separateinnateandadaptivebins? surfacessuchasthegut,skin,andlungsarecarefullycon- Theimmunesystemthatyouhaveassembledisinfacta trolled to avoid needless attacks on helpful commensals modelofversatilityratherthanrigiddivisions.Notonlydo (23).Italsorecognizesthatnonselfthatisneithermicrobial innate cells detect traditional harmful intruders (bacteria, norpathogeniccanalsobeharmfulandmustberejectedat viruses,fungi,andotherpathogens),buttheyalsorespond times. Take for example a stem cell or fetus in the wrong toasubsetofself-molecules(someproteinandnucleicacid, place or potentially transmissible tumor cells (24,25). This others simple chemicals such as uric acid) that alarm the form of nonself, known as allogeneic nonself, triggers immune system to the presence of tissue damage (20,21). powerfuladaptiveimmuneresponsesthataremostappar- Damage-associated molecules or alarmins are released by entinthesettingoftransplantrejection.Howlymphocytes dyingorstressedcellsininfected,ischemic,orinjuredtis- recognize allogeneic nonself will be discussed later. How sues and serve two purposes: they amplify the immune commensalsinteractwithandshapetheinnateandadap- response to nonself,ifnonselfispresentas isthecasewith tiveimmunesystemsandhowtheinnate immunesystem

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Saint Louis, Missouri. Charles Alpers .. factories known as plasma cells, whereas T lymphocytes differentiate ized B and T lymphocytes known as regulatory cells (8,9). Ritchlin C, Brodmerkel C, Li S, Wang Y, Mendelsohn AM, Doyle Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G,.

Renal Immunology for the Clinician PDF

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