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Chapter5OrganizationandExpressionofIgGenesOct26&31,2006你需要學(xué)習(xí)的課題:抗體基因是如何組成的?抗體基因重組(rearrangement)的機(jī)制抗體的多樣性(diversity)是如何產(chǎn)生的?細(xì)胞膜上的抗體如何轉(zhuǎn)變?yōu)榉置谛钥贵w?抗體的類別(class)如何變換?-classswitchingCentralFeatureofAbMolecules:VastdiversityofAbspecificitiesAvariable(V)regionattheN-terminalendandaconstant(C)regionattheC-terminalendofAbmoleculesDifferentclasses(orisotypes)ofAb(e.g.,IgGandIgM)withidenticalV-regionsequences(antigenicspecificity)TheTwo-genemodelofDryerandBennett(1965)TwoseparategenesencodeasingleIg
HorLchain,onegenefortheVregionandtheotherfortheCregion.
Thesuggestionthattwogenesencodedasinglepolypeptidecontradictedtheexisting
onegene-onepolypeptide
principleandwaswithoutprecedent(先例)inanyknownbiologicalsystem.VerificationoftheDryerandBennetHypothesis
(byTonegawaandHozumi,1976)FirstdirectevidencethatseparategenesencodetheVandCregionsofIgandthatthegenesarerearrangedinthecourseofB-celldifferentiation.-TonegawawasawardedtheNobelPrizeforthisworkin1987.DemonstrationofDNADeletionatanIgLocusNon-Bcells:spermorlivercellsB-cellsDemonstrationofDNADeletionatanIgLocusdeletedsequence比大,因此在電泳時(shí)跑得比較慢MultigeneorganizationofIggenesl-ChainMultigeneFamilyMouse:Vregion:2Vlgenesegments4Jl
genesegments(3arefunctional)Cregion:4Cl
genesegmentsHuman:30Vl,4Jland4Clsegmentsκ-ChainMultigeneFamilyMouse:Vregion:~85Vkgenesegments5Jk
genesegments(4arefunctional)Cregion:1Ck
genesegmentHuman:40Vk,5Jkand1CksegmentsH-ChainMultigeneFamilyMouse:Vregion:~134VHgenesegments13DHgenesegments4JH
genesegmentsCregion:8CH
genesegmentsHuman:51VH,27DH,6JHand9CHsegments
V-RegionGeneRearrangements-TheH-chainV-regiongenesrearrangefirst,thentheL-chainV-regiongenes.Therearrangementsoccurinanorderedsequence,buttheyarerandomevents.ThearrangementsofIgandTCRgenesarethe
onlyknownsite-specificDNArearrangementsinvertebrates.H-ChainDNAUndergoesV-D-JRearrangements(1strearrangement)(2ndrearrangement)Amature,immunocompetentBcellexpressesbothIgM&IgDwith
identicalantigenicspecificity
onitssurface.L-ChainDNAUndergoesV-JRearrangementsintronsareremovedMechanismofV-regionDNARearrangementsTwouniquerecombinationsignalsequences(RSSs)
flankingeachgerm-lineV,D,andJgenesegmentOne-turnRSS:locatedat3’toeachVk,5’toeachJl,and
bothsidesofeachDH
genesegmentTwo-turnRSS:
locatedat3’toeachVl&VHand
5’toeachJk&JH
genesegment
RecombinationSignalSequences(RSS)CACAGTG23ntACAAAAACCGTGTCAC12ntTGTTTTTGG
Vλ
Jλ
//Oneturn/two-turnjoiningruleTheruleensuresthatVH,DH,andJHsegmentsjoininproperorderandthatsegmentsofthesametypedonotjoineachother.GeneSegmentsAreJoinedbyRecombinases-Recombination-ActivatingGenes:RAG-1,RAG-2-TheproteinsencodedbyRAG-1andRAG-2actsynergisticallyandarerequiredtomediateV-(D)-Jjoining.
Terminaldeoxynucleotidyl
transferase(TdT),anotherlymphoid-specificgeneproduct,isalsoinvolvedinV-(D)-Jrearrangement.ProcessofRecombinationofIgGeneSegmentsDoubleStrandBreakRepairTerminaldeoxy-nucleotidyl
Transferase
DefectsinIg-GeneRearrangementsRAG-1-/-orRAG-2-/-mice:-lackRAG-1orRAG-2-cannotstarttherecombinationprocessSCID(severecombinedimmunodeficiency)mice:-lackdoublestrandbreakrepair(DSBR)enzymes-cancarryoutsynapsis,introduced.s.breaks-cannotproperlyjointhecodingsequencesImpreciseJoining
-productiveandnonproductiverearrangementsproductiverearrangementin
onealleleisenoughIfrearrangementisnotproduced,theBcelldiesbyapoptosis.Ig-geneRearrangementsMayBeNonproductive!!!!
Only1/3attemptsatVL–JLjoining,and1/3subsequentattemptsatVH–DHJHjoining,areproductive.Asaresult,<1/9(11%)oftheearly-stagepre-BcellsinthebonemarrowprogresstomaturityandleavethebonemarrowasmatureimmunocompetentBcells.AllelicExclusionEnsuresaSingleAntigenicSpecificityAsingleBcellisonlyspecificforasingleepitope!!!
Onceaproductiverearrangementisattained,itsencodedproteinisexpressedandthepresenceofthisproteinactsasasignaltopreventfurthergenerearrangement.(1)(2)*activeallelesGenerationofAbDiversityAntibodyDiversity
SevenmeansofgenerationofAbdiversity:1.Multiplegerm-lineV,D,andJgenesegments2.CombinatorialV-(D)-Jjoining3.Junctionalflexibility4.P-regionnucleotideaddition(P-addition)5.N-regionnucleotideaddition(N-addition)6.Somatichypermutation7.CombinatorialassociationoflightandheavychainsJunctionalFlexibilityAddsDiversity-4differentjoiningsofVk21-Jk1inpre-Bcelllines
(Flexible)(Precise)Since
CDR3
makesamajorcontributiontoAgbindingbytheAb
molecule,aminoacidchangesgeneratedbyjunctionalflexibilitycanmakeamajorcontributiontoAbdiversity.P-AdditionAddsDiversityatPalindromicSequences{Palindromicsequences}N-AdditionAddsConsiderableDiversitybyAdditionofNucleotidesaddnew(N)-nucleotides-Upto15N-nucleotidescanbeaddedtoboththeDH-JHandVH-DHJHjoints.Thus,acompleteH-chainVregionisencodedbyaVHNDHNJHunit.NregionsappearstoconsistofwhollyrandomsequencesP-nucleotide及
N-nucleotideaddition有些什麼優(yōu)缺點(diǎn)?SomaticHypermutationAddsDiversityinAlready-rearrangedGeneSegment
-Somatichypermutationoccursonlywithingerminalcenters,structuresthatforminsecondarylymphoidorganswithinaweekorsoofimmunizationwithanAgthatactivatesaT-cell-dependentB-cellresponse.-Somatichypermutationoccursatafrequencyapproaching
10-3/bp/generation.Thisrateisatleast100,000-foldhigherthanthespontaneousmutationrate,about10-8/bp/generation,inothergenes.-Bcellswithhigher-affinityIgreceptorswillbepreferentiallyselectedforsurvivalbecauseoftheirgreaterabilitytobindtotheAg.-----AffinityMaturation
ExperimentalEvidenceforSomaticMutationinVregionofIgGenesMostofthemutationsareclusteredinthe
CDR1
and
CDR2
hypervariableregion.
AntibodyDiversity
SevenmeansofgenerationofAbdiversity:1.Multiplegerm-lineV,D,andJgenesegments2.CombinatorialV-(D)-Jjoining3.Junctionalflexibility4.P-regionnucleotideaddition(P-addition)5.N-regionnucleotideaddition(N-addition)6.Somatichypermutation–afterAgstimulation7.CombinatorialassociationoflightandheavychainsClassSwitchingAmongC-RegionGenesOrganizationofHchain
VregionCregionAfterantigenicstimulationofaBcell,theH-chainDNAcanundergoafurtherrearrangementinwhichtheVHDHJHunitcancombinewithanyCHgenesegment.Thisprocessiscalledclassswitching.
Class(isotype)switchingClass-specificswitchrecombinasesmaybindtoswitchregionsandfacilitateDNArecombination.-CytokinessecretedbyactivatedTHcellshavebeenshowntoinduceBcellstoclassswitchtoaparticularisotype.-IL-4,forexample,inducesclasss
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