第2講自然免疫系統(tǒng)

學習目的了解自然免疫系統(tǒng)的基本功能及免疫學基礎理論學習要點自然免疫系統(tǒng)對解決工程問題有用的特性，對解決工程問題有用的免疫學理論主要內(nèi)容2.1免疫系統(tǒng)基本組成2.2免疫系統(tǒng)基本功能2.3適于工程求解的免疫系統(tǒng)特性2.4免疫學理論2.1免疫系統(tǒng)基本組成Theimmunesystemishighlycomplicateddetectingandeliminatinginfectionssimilarproblem:creditcardfrauddetection6(simplifiedview)macrophage2.1免疫系統(tǒng)基本組成7固有免疫系統(tǒng)InnateImmuneSystemComposedmainlyofphagocytesandthecomplementsystem(bloodproteins)FirstlineofdefensethatworksrapidlyControlsbacterialinfectionsRegulatestheadaptiveimmunityImportantforself/non-selfdiscrimination2.1免疫系統(tǒng)基本組成ThepartoftheimmunesystemwithwhichwearebornDoesn’tchangeoradaptComplementsystemMacrophagesCytokines,naturalkillercellshttp://www.aids-info.ch/e_te/aas-e-imm.htm2.1免疫系統(tǒng)基本組成9diversity自適應免疫系統(tǒng)AdaptiveImmuneSystemComposedmainlyofB-cellsandT-cellsB-CellsaregeneratedanddevelopedintheBoneMarrowT-CellsaregeneratedintheBoneMarrowanddevelopedintheThymusGeneratespecificantigenreceptorsontheirsurface(clonalselection

B-CellsandT-Cells)Capableoffine-tuningthecellreceptors(maturation

B-Cells)Conferresistanceagainstfutureinfections(memory

B-CellsandT-Cells)memory2.1免疫系統(tǒng)基本組成TheAdaptiveImmuneSystemAdaptstorecognisespecificpathogensRetainsamemorywhichspeedsupfutureresponsesConsistsprimarilyoflymphocyteswhichcirculatearoundthebodyDistributeddetectionsystemwithoutanycentralcontrol/Bio/HAP/Lymphocyte.jpg

/pelvic2/blyphocytes.htm2.1免疫系統(tǒng)基本組成AdaptiveImmunityAdetectioneventoccurswhenthereceptorofalymphocytebindstoanepitopeonapathogenStrengthofthebondistermedtheaffinityEachlymphocytecanhavemultiple,identicalreceptorsepitopelymphocyteLowaffinityreceptorstructurallysimilar–highaffinity12固有和自適應免疫系統(tǒng)比較CharacteristicsCellsMoleculesInnateImmunityRespondsRapidlyPhagocytesNaturalkillersMastCellsCytokinesComplementAcutePhaseProteinsLowspecificityNomemoryAdaptiveImmunitySlowtostartTandB-cellsAntibodiesCytokynesHighlySpecificMemory2.1免疫系統(tǒng)基本組成13AdaptiveIS:howitworks?InvasionDetectionReactionMaturationMemorizing2.1免疫系統(tǒng)基本組成14KillerT-cells2.1免疫系統(tǒng)基本組成15Howdoestheimmunesystemkillinfectedcells?KillerT-cells: matureinthethymus toleratedviaclonaldelection donothypermutateduringcloning recognizeonlyproteinspresentedbyMHCmolecules ...andkilltherespectivecells!KillerT-cells2.1免疫系統(tǒng)基本組成JonTimmis.ComputingLaboratory,UniversityofKentatCanterbury免疫系統(tǒng)層次ExternalsurfacesSkinChemicalandtemperaturebarriersMucusInnateimmunityMacrophagesAcquired(adaptive)immunityLymphocytes2.1免疫系統(tǒng)基本組成17DetectionB-CellsReceptors(BCR)T-CellsReceptors(TCR)

VariableregionVariableregionConstantregionConstantregion2.2免疫系統(tǒng)基本功能AntigenRecognitionbyB-cell2.2免疫系統(tǒng)基本功能19ReceptorsdiversityFromGeneLibrariestoaheavychainofareceptorGenefragmentsareconcatenatedinastrictorderTranscriptionjoinsvariableandconstantregionsRNAsplicingbringseverythingtogether2.2免疫系統(tǒng)基本功能20ReactionClonalSelection

Foreignantigens

Proliferation

Differentiation

PlasmaCells

MemoryCells

Selection

M

M

Antibody

Self-antigen

Self-antigen

Clonaldeletion

(negativeselection)

Clonaldeletion

(negativeselection)

(I)

(II)

(III)

(IV)

2.2免疫系統(tǒng)基本功能21Maturation親和力成熟ThoseB-cellsthatfitthebestwillbehavemoreaffinityandsotheywillbindtomorepathogens,beactivatedandclone.B-cellsbindingtopathogensbyusingreceptors(antibodies) inactivatethemor markthemfortheinnateIS

cloningsubjecttoSomatic

Hypermutation2.2免疫系統(tǒng)基本功能plasmacellantibodyHighaffinityselectedmemorycellLowaffinitynoselectioncelldeath1.activation2.proliferation3.differentiation2.2免疫系統(tǒng)基本功能親和力成熟23MemorizingSeveralResponses2.2免疫系統(tǒng)基本功能24Memory(secondaryresponse)AfterreactingagainstapathogenmostoftheB-cellsdie,butothersadaptedB-cellsarekeptaliveandwillbeusedinthenexttimethesamepathogeninvadestheorganismThememoryisassociative:theadaptedB-cellsarealsoactivatedbyasimilarpathogen(cross-reactiveresponse)

Memory2.2免疫系統(tǒng)基本功能25Ifthediversity

ofreceptorspresentisseveralordersofmagnitudelessthanthediversityofpathogenpatterns,howdoestheimmunesystemdetectmostpathogens?Byusingapproximatebinding:eachmonoclonallymphocytecanbindtoseveralvariantsofapathogen,i.e.itcanrecognizeasimilaritysubsetofpatterns.Bybeingverydynamic:lymphocytesareveryshort-lived(2to3days)andareconstantlyreplaced(100millionnewlymphocytesaregeneratedeveryday).Diversity2.2免疫系統(tǒng)基本功能GeneratingReceptorDiversity2.2免疫系統(tǒng)基本功能27AutoimmuneResponsesandToleranceoftheSelfHowdoestheISensuretolerancetoself?

HelperT-cells:T-cellsmatureintheThymuswheretheyareexposedtoproteinsoftheself.Iftheybindtoaselfproteintheyarecensored(deleted)ClonalDeletionIfnot,theymatureandcanleavethethymus.

2.2免疫系統(tǒng)基本功能28T-cellsthatleavetheThymuswillhelptheB-cells

TobestimulatedtheB-cellsneedtoreceivetwosignals:1-exceedaffinitythreshold;2-fromhelperT-cellsCostimulation2.2免疫系統(tǒng)基本功能SomaticHypermutationMutationrateinproportiontoaffinityVerycontrolledmutationinthenaturalimmunesystemTrade-offbetweenthenormalizedantibodyaffinityD*anditsmutationrate

,2.2免疫系統(tǒng)基本功能ImmunePatternRecognitionTheimmunerecognitionisbasedonthecomplementaritybetweenthebindingregionofthereceptorandaportionoftheantigencalledepitope.Antibodiespresentasingletypeofreceptor,antigensmightpresentseveralepitopes.Thismeansthatdifferentantibodiescanrecognizeasingleantigen

2.2免疫系統(tǒng)基本功能ImmuneResponses2.2免疫系統(tǒng)基本功能ClonalSelectionForeignantigenProliferation(Cloning)DifferentiationPlasmacells

MemorycellsSelectionMMAntibody

Self-antigenClonaldeletion(negativeselection)2.2免疫系統(tǒng)基本功能Self/Non-SelfRecognitionImmunesystemneedstobeabletodifferentiatebetweenselfandnon-selfcellsAntigenicencountersmayresultincelldeath,therefore2.2免疫系統(tǒng)基本功能34

uniqueness distributeddetection imperfectdetection(noisetolerance) anomalydetection(non-self) learningandmemoryDistiguishingbetweenselfandnonselfisahardproblem: 1016patternsofthenon-self 106patternsoftheself thebodymustcontinuetoworkproperlyShortSummaryAbouttheISdiversity:WhatistheImmuneSystem?

-Alotofthings!ClassicalCohenVarelaMatzingerTherearemanydifferentviewpointsTheyarenotmutuallyexclusive!AIScanpickandchoose!AIS2.3適于工程求解的免疫系統(tǒng)特性In-vivoIStoIn-silicoISHowdowemakethejump?Historically,AISwasrootedinrealimmunologyNow,thereisatendencytoobserve-implement(butlotsofsimpleandeffectivealgorithmsdeveloped)2.3適于工程求解的免疫系統(tǒng)特性AnInterdisciplinaryApproachMathematicsComputerScienceEngineeringBiologyAnalysable,validatedsystemsthatfullyexploittheunderlyingbiology2.3適于工程求解的免疫系統(tǒng)特性Fromacomputationalperspective:UniquetoindividualsDistributedImperfectDetectionAnomalyDetectionLearning/AdaptionMemoryFeatureExtractionDiverse..andmoreRobustScalableFlexibleExhibitgracefuldegradationHomeostaticSystemsthatare:ComputationalProperties2.3適于工程求解的免疫系統(tǒng)特性04/12/01DeptofElectricalEngineeringcolloquiumseries39ClonalselectionPrincipleReinforcementlearning

ImmunememoryJerne’sidiotropicnetworktheory

Negativeselection

Affinitymaturation2.3適于工程求解的免疫系統(tǒng)特性04/12/01DeptofElectricalEngineeringcolloquiumseries40免疫系統(tǒng)特性與工程問題對應Geneticmechanisms,clonalselectionprinciple,affinitymaturation,contentaddressablememory,matchingmechanisms,andnetworkselforganizingproperties.ImmunenetworksPatternrecognition-classification,prediction,diagnosisanddataminingSensorbaseddiagnosis2.3適于工程求解的免疫系統(tǒng)特性04/12/01DeptofElectricalEngineeringcolloquiumseries41Negativeselection,self/nonselflearningImmunenetworkdynamics/negativeselectionprincipleNegativeselectionprincipleDistribution,selforganizationAnomalydetection-computersecurityintermsofviruses,unauthorizeduserdetectionandeliminationImageinspection&imagesegmentationNoveltydetectionalgorithmfortimeseriesdatatoexhibitthenormalbehaviorofthesystemAgentbasedapproach,Networkintrusiondetection免疫系統(tǒng)特性與工程問題對應2.3適于工程求解的免疫系統(tǒng)特性04/12/01DeptofElectricalEngineeringcolloquiumseries42ImmuneSystemPropertyDynamicdecentralizedconsensusmakingmechanism,Jernesnetwork,clonalselectionalgorithmandnetworkdynamicsPetrinetconceptsImmunediversity,networktheoryandclonalselectionprincipleCrossreactivememory,recruitmentmechanismApplicationtoartificialimmunesystemRobots,Mutualinteractionbetweenmodules,interactionbetweenrobotenvironments, autonomousagentsAdaptivecontrol,identificationandsynthesis,sequentialcontrolOptimizationNeuralnetworkapproaches免疫系統(tǒng)特性與工程問題對應2.3適于工程求解的免疫系統(tǒng)特性43BibliographyAnabelaSim?esandErnestoCosta,Animmunesystem-basedgeneticalgorithmtodealwithdynamicenvironments:diversityandmemory,Proc.ICANNGA’2003.LeandroN.CastroandJonathanThimmis,ArtificialImmuneSystems:anewcomputationalintelligenceapproach,Springer-Verlag,2002http://www.dca.fee.unicamp.br/~lnunes/immune.htmlStevenA.Hofmeyr,AnOverviewoftheImmuneSystem,1977/~steveah/inm-html/immune-system.html/~dasgupta/P.M.Lydyard,A.WhelanandM.W.Fanger,Immunology,Bios,2000.ToknowmoreImmuneNetworkTheoryIdiotypicnetwork(Jerne,1974)Bcellsco-stimulateeachotherTreateachotherabitlikeantigensCreatesanimmunologicalmemory2.4免疫系統(tǒng)基本理論Varela’sView“Fromtheimmunesystem'sperspective,itonly“knows”itself“(Varelaetal1988).SustainingautonomousactivityofthenetworkgraduallydefinesthesystemImpacts(withoutpre-labelling)eitherSmoothlyintegratethesystemselfArerejectedfromthesystemnon-selfThisisknownasself-assertionStewart’sViewThenetworkprovidesacellularcommunicationpathwaywhichallowsthesystemtopreserveaperfectintegrityandmaintainhomeostasisDefensiveroleoftheimm