抗体多样性是如何产生的_精品文档.ppt

抗体多样性是如何产生的_精品文档.ppt

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Howisantibodydiversitygenerated?

Twoearlytheories:

GermlinehypothesisThegenomecontainsmanylociencodingantibodymolecules.Bcellsexpressoneoftheseloci.DifferentBcellsexpressdifferentloci.,SomaticmutationhypothesisThereareasmallnumberofantibodygeneswhichundergomutationastheBcellmatures-thusgivingrisetoBcellsexpressingantibodyofdifferentspecificity.,Threegeneticlociencodeimmunoglobulinmolecules:

-twolociencodingthelightchains-kappalocus-lambdalocus-onelocusencodingtheheavychainThesethreelociarelocatedondifferentchromosomes.,Thelociencodingimmunoglobulinshaveauniquestructure.-composedofgenesegmentsTheheavychainlocushasmultipleV（variable）segments,multipleD（diversity）segments,multipleJ（joining）segmentsandmultipleC（constant）segments.Duringmaturation,oneofeachV,DandJsegmentisrandomly“chosen”andusedtoencodethefinalantibodymolecule.,Germlineconfigurationoftheheavychainlocus（mice）,Eachgenesegmentmayhaveitsownintron-exonstructure-e.g.theCmgenesegment,KubyFigure5-3,Thekappalocushasasimilarstructure-BUT-doesnothaveDsegments.AkappachainisencodedbyoneVsegment,oneJsegmentandoneCsegment.,KubyFigure5-3,ThelambdalocusalsohasonlyV,JandCsegments.,KubyFigure5-3,ReadKubypages109-110:

MultigeneOrganizationofIgGenes,KubyFigure5-3,Inheavychains,theV,DandJsegmentsencodethevariabledomainwhiletheCsegmentencodestheconstantdomain.Inlightchains,theVandJsegmentsencodethevariabledomainwhiletheCsegmentencodestheconstantdomain.,DuringBcellmaturation,immunoglobulingenesundergorearrangement.,DuringBcellmaturation,immunoglobulingenesundergorearrangement.,DuringBcellmaturation,immunoglobulingenesundergorearrangement.,DuringBcellmaturation,immunoglobulingenesundergorearrangement.,Thekappaandlambdalociundergosimilarrearrangement.SincetherearenoDsegments,thereisasingleV-Jrearrangement.Inbothheavyandlightchainrearrangement,anumberofJsegmentsmayremainbetweentheV（D）andCsegments.TheseareincludedintheRNAtranscriptbutaresplicedoutduringRNAprocessing.ThefinallightchainmRNAcontainsoneVJCunit.,KubyFigure5-4,KubyFigure5-4,InthecaseoftheheavychainInnaive,matureBcells,theprimarymRNAtranscriptcontainsVDJandBOTHCmandCd.ThisprimarytranscriptcanbedifferentiallyprocessedtogiverisetomRNAencodingeitherIgMorIgD.ThisexplainswhynaiveBcellsexpressbothIgMandIgD.ThevariableregionofbothareencodedbythesameVDJ-sotheyhavethesameantigenspecificity.,KubyFigure5-5,ReadKubypages110-112:

Variable-RegionGeneRearrangements,Whatmechanismensurescorrectjoiningofgenesegmentsduringrearrangementoftheheavyandlightchainloci?

KubyFigure5-3,Recombinationsignalsequences-conservedsequencesinregionsjustupstreamordownstreamofgenesegments.Consistofaconservedheptamerandnonamerwitha12or23bpspacer.,KubyFigure5-3,Whatmechanismensurescorrectjoiningofgenesegmentsduringrearrangementoftheheavyandlightchainloci?

Recombinationsignalsequences-conservedsequencesinregionsjustupstreamordownstreamofgenesegments.Consistofaconservedheptamerandnonamerwitha12or23bpspacer.Theone-turn/two-turnrule（12/23rule）-recombinationoccursonlybetweenasegmentwitha12bpspacerandasegmentwitha23bpspacer.,Theone-turn/two-turnrule（12/23rule）-recombinationoccursonlybetweenasegmentwitha12bpspacerandasegmentwitha23bpspacer.,ReadKubypage113:

RecombinationSignalSequencesDirectRecombination,KubyFigure5-6,RecombinationActivatingGenes（encodeRAG-1andRAG-2）RAG-1andRAG-2mediaterecognitionofsignalsequencesandrearrangementofDNAsegments.MicedeficientinRAG-1orRAG-2areunabletorearrangeheavyorlightchaingenes.ThesemicehavenomatureBcells.-BcellswillnotmatureiftheycannotexpressaBCR.,RAG-deficientmicealsolackmatureTcells.-TheTcellreceptorisalsoencodedbylocicontaininggenesegmentsthatmustberearrangedbeforetheTCRcanbeexpressed.TcellswillnotmatureiftheycannotexpressaTCR.SCIDmicealsohaveadefectthataffectsrearrangementofBCRandTCRloci.TheyalsohavenomatureTorBcells.,Flowcytometryofnormalvs.RAG-1deficientmice:

LymphnodecellsFITCanti-CD19（Bcellmarker）andPEanti-CD3（Tcellmarker）,Normalmice,RAG-1-deficientmice,5,3,3,5,5,3,AGCT,TATA,Terminaldeoxynucleotidyltransferase（Tdt）Anenzymethatrandomlyaddsinnucleotidesduringjoiningofheavychain（NOTlightchain）segments.,ReadKubypages113-115:

GeneSegmentsAreJoinedbyRecombinases,ProductiveandnonproductiverearrangementsJoiningofsegmentsisnotpreciseandmayresultinlossofthecorrectreadingframe.Thismayleadtointroductionofstopcodons-nonproductiverearrangements.ReadKubypage115:

Ig-GeneRearrangementsMayBeP