2021
Sex-Biased Aging Effects on Ig Somatic Hypermutation Targeting
Cui A, Chawla DG, Kleinstein SH. Sex-Biased Aging Effects on Ig Somatic Hypermutation Targeting. The Journal Of Immunology 2021, 206: 101-108. PMID: 33288546, PMCID: PMC8582005, DOI: 10.4049/jimmunol.2000576.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAgingB-LymphocytesDNA RepairFemaleHumansImmunity, HumoralImmunoglobulinsMaleMiddle AgedMutationSex CharacteristicsSex FactorsSomatic Hypermutation, ImmunoglobulinYoung AdultConceptsOlder individualsDNA mismatch repair genesSex groupsObserved clinical differencesMismatch repair genesB cell IgDecreased expression levelDNA repair activityImmunologic responseClinical differencesAb responsesFemale human subjectsOld maleAged individualsImpaired levelDifferent agesYounger counterpartsPhase ILargest fold changeYoung individualsError-prone DNA repair activityExpression levelsHuman subjectsMutation patternsRepair activity
2020
Position-Dependent Differential Targeting of Somatic Hypermutation
Zhou JQ, Kleinstein SH. Position-Dependent Differential Targeting of Somatic Hypermutation. The Journal Of Immunology 2020, 205: 3468-3479. PMID: 33188076, PMCID: PMC7726104, DOI: 10.4049/jimmunol.2000496.Peer-Reviewed Original ResearchMeSH KeywordsAllelesComputer SimulationHumansImmunoglobulin Heavy ChainsModels, GeneticNucleotide MotifsSomatic Hypermutation, ImmunoglobulinConceptsSomatic hypermutationSHM targetingIg sequencesSame DNA motifTranscription start siteAllele-specific effectsInfluence of selectionGene familyVariable gene familiesDNA motifsSequence neighborhoodError-prone repairStart siteAb diversityDNA lesionsDifferential targetingUnique motifMotifSequenceTargetingHypermutationEffective humoral immunityIntrinsic biasesAffinity maturationLarge collection
2018
Local Clonal Diversification and Dissemination of B Lymphocytes in the Human Bronchial Mucosa
Ohm-Laursen L, Meng H, Chen J, Zhou JQ, Corrigan CJ, Gould HJ, Kleinstein SH. Local Clonal Diversification and Dissemination of B Lymphocytes in the Human Bronchial Mucosa. Frontiers In Immunology 2018, 9: 1976. PMID: 30245687, PMCID: PMC6137163, DOI: 10.3389/fimmu.2018.01976.Peer-Reviewed Original ResearchMeSH KeywordsB-Lymphocyte SubsetsB-LymphocytesCell MovementClonal EvolutionClonal Selection, Antigen-MediatedHumansImmunoglobulin IsotypesLymphocyte CountRespiratory MucosaSomatic Hypermutation, ImmunoglobulinConceptsHumoral immune responseBronchial mucosaB cell repertoireHealthy subjectsAsthmatic patientsImmune responseCell repertoireAdaptive humoral immune responseB cell antibody productionFeatures of atopyB cell clonesHuman bronchial mucosaMucosal migrationAdaptive immune receptor repertoire sequencingAtopic asthmaAsthmatic individualsBronchial biopsiesRight lungPeripheral bloodDistal biopsiesAdjacent biopsiesLarge cohortB cellsB lymphocytesAntibody productionAffinity Maturation Is Impaired by Natural Killer Cell Suppression of Germinal Centers
Rydyznski CE, Cranert SA, Zhou JQ, Xu H, Kleinstein SH, Singh H, Waggoner SN. Affinity Maturation Is Impaired by Natural Killer Cell Suppression of Germinal Centers. Cell Reports 2018, 24: 3367-3373.e4. PMID: 30257198, PMCID: PMC6192537, DOI: 10.1016/j.celrep.2018.08.075.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsB-LymphocytesGerminal CenterKiller Cells, NaturalMaleMiceMice, Inbred C57BLSomatic Hypermutation, ImmunoglobulinT-Lymphocytes, Helper-InducerVaccines, ConjugateConceptsNK cellsGC B cell frequencyNatural killer cell suppressionAntigen-reactive B cellsB cell frequenciesNatural killer cellsFollicular helper TAntigen-specific immunoglobulinsAdministration of alumGerminal center reactionVaccine elicitationHelper TKiller cellsHumoral immunityProtective antibodiesHigh-affinity antibodiesCell suppressionGerminal centersB cellsCell frequencyCenter reactionSomatic hypermutationGC developmentGC reactionAntibody affinity
2017
Hierarchical Clustering Can Identify B Cell Clones with High Confidence in Ig Repertoire Sequencing Data
Gupta NT, Adams KD, Briggs AW, Timberlake SC, Vigneault F, Kleinstein SH. Hierarchical Clustering Can Identify B Cell Clones with High Confidence in Ig Repertoire Sequencing Data. The Journal Of Immunology 2017, 198: 2489-2499. PMID: 28179494, PMCID: PMC5340603, DOI: 10.4049/jimmunol.1601850.Peer-Reviewed Original Research
2016
A Model of Somatic Hypermutation Targeting in Mice Based on High-Throughput Ig Sequencing Data
Cui A, Di Niro R, Vander Heiden JA, Briggs AW, Adams K, Gilbert T, O'Connor KC, Vigneault F, Shlomchik MJ, Kleinstein SH. A Model of Somatic Hypermutation Targeting in Mice Based on High-Throughput Ig Sequencing Data. The Journal Of Immunology 2016, 197: 3566-3574. PMID: 27707999, PMCID: PMC5161250, DOI: 10.4049/jimmunol.1502263.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsB-LymphocytesCells, CulturedClonal Selection, Antigen-MediatedDNA RepairFemaleGerminal CenterHigh-Throughput Nucleotide SequencingHumansImmunoglobulin Heavy ChainsImmunoglobulin Variable RegionMiceMice, Inbred BALB CMice, TransgenicModels, GeneticMutationMutation RateSomatic Hypermutation, ImmunoglobulinConceptsSpecific DNA motifsSimilar biological processesObserved mutation patternDNA repair activityIg sequencesNonfunctional sequencesDNA motifsMutation patternsHigh mutation frequencySelection pressureUnselected mutationsSequencing dataBiological processesFunctional sequencesRepair activityTransition mutationsSomatic hypermutation patternsGerminal center B cellsSomatic hypermutationNext-generation methodsHypermutation patternsMutation frequencyMutationsSequenceMotifLong-lived antigen-induced IgM plasma cells demonstrate somatic mutations and contribute to long-term protection
Bohannon C, Powers R, Satyabhama L, Cui A, Tipton C, Michaeli M, Skountzou I, Mittler RS, Kleinstein SH, Mehr R, Lee FE, Sanz I, Jacob J. Long-lived antigen-induced IgM plasma cells demonstrate somatic mutations and contribute to long-term protection. Nature Communications 2016, 7: 11826. PMID: 27270306, PMCID: PMC4899631, DOI: 10.1038/ncomms11826.Peer-Reviewed Original ResearchMeSH KeywordsAdoptive TransferAmino Acid MotifsAnimalsAntigensComplementarity Determining RegionsCytidine DeaminaseGerminal CenterImmunityImmunoglobulin Heavy ChainsImmunoglobulin MMice, Inbred C57BLMutationNeutralization TestsOrthomyxoviridaeOrthomyxoviridae InfectionsPlasma CellsSomatic Hypermutation, ImmunoglobulinSpleenConceptsIgM plasma cellsIgG plasma cellsPlasma cellsGerminal centersBone marrowLethal virus challengeProtective host immunitySomatic mutationsActivation-induced cytidine deaminaseHumoral immunityProtective antibodiesVirus challengeLong-term protectionHost immunityB cellsAffinity maturationMarrowLifelong sourceImmunityAntibodiesCellsCytidine deaminaseMutationsReplacement mutationsSpleen
2015
The mutation patterns in B-cell immunoglobulin receptors reflect the influence of selection acting at multiple time-scales
Yaari G, Benichou JI, Heiden J, Kleinstein SH, Louzoun Y. The mutation patterns in B-cell immunoglobulin receptors reflect the influence of selection acting at multiple time-scales. Philosophical Transactions Of The Royal Society B Biological Sciences 2015, 370: 20140242. PMID: 26194756, PMCID: PMC4528419, DOI: 10.1098/rstb.2014.0242.Peer-Reviewed Original ResearchMeSH KeywordsAntibody AffinityAntibody DiversityB-LymphocytesCell LineageClonal Selection, Antigen-MediatedComplementarity Determining RegionsGenes, ImmunoglobulinHumansImmunoglobulin Heavy ChainsImmunoglobulin Variable RegionModels, GeneticModels, ImmunologicalMutationReceptors, Antigen, B-CellSomatic Hypermutation, ImmunoglobulinTime FactorsConceptsLineage treesPositive selectionStrong selection pressureLong-term selectionInfluence of selectionGene familyVariable gene familiesComplementarity determining regionsClone membersMutation patternsSelection pressureB cell populationsImmunoglobulin genesB cellsFramework regionsSomatic hypermutationSomatic mutationsAffinity maturationMutationsClone sizeMaturation processLong trunkAffinity maturation processSignificant diversityMultiple roundsSalmonella Infection Drives Promiscuous B Cell Activation Followed by Extrafollicular Affinity Maturation
Di Niro R, Lee SJ, Vander Heiden J, Elsner RA, Trivedi N, Bannock JM, Gupta NT, Kleinstein SH, Vigneault F, Gilbert TJ, Meffre E, McSorley SJ, Shlomchik MJ. Salmonella Infection Drives Promiscuous B Cell Activation Followed by Extrafollicular Affinity Maturation. Immunity 2015, 43: 120-131. PMID: 26187411, PMCID: PMC4523395, DOI: 10.1016/j.immuni.2015.06.013.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, MonoclonalB-LymphocytesClonal Selection, Antigen-MediatedGerminal CenterImmunoglobulin GLymphocyte ActivationMiceMice, Inbred BALB CMice, Inbred C57BLMice, KnockoutReceptors, Antigen, B-CellSalmonella InfectionsSalmonella typhimuriumSomatic Hypermutation, ImmunoglobulinSpleenConceptsB cell receptorExtrafollicular sitesGerminal centersAffinity maturationInfection of miceB cell responsesB cell activationDetectable antibodiesSomatic hypermutationExtrafollicular responseAntigen microarraysSalmonella infectionAntigen targetsCell activationSalmonella typhimuriumCell responsesBCR specificityFlow cytometryCell receptorMonoclonal antibodiesUndetectable affinityClonal selectionInfectionAntibodiesLaser microdissection
2014
Integrating B Cell Lineage Information into Statistical Tests for Detecting Selection in Ig Sequences
Uduman M, Shlomchik MJ, Vigneault F, Church GM, Kleinstein SH. Integrating B Cell Lineage Information into Statistical Tests for Detecting Selection in Ig Sequences. The Journal Of Immunology 2014, 192: 867-874. PMID: 24376267, PMCID: PMC4363135, DOI: 10.4049/jimmunol.1301551.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibody AffinityAntibody DiversityB-Lymphocyte SubsetsCell LineageClonal Selection, Antigen-MediatedComputer SimulationConfounding Factors, EpidemiologicGene Rearrangement, B-LymphocyteGenes, ImmunoglobulinHumansMiceModels, ImmunologicalModels, StatisticalROC CurveSequence Analysis, DNASomatic Hypermutation, ImmunoglobulinVDJ ExonsConceptsLineage treesHigh-throughput sequencing technologyLineage tree shapesCell lineage informationIg sequencesRatio of replacementTree-shape analysisStatistical frameworkSequence-based methodsBinomial statistical analysisExperimental data setsIndicators of selectionSequencing technologiesLineage informationSequencing depthNumber of generationsData setsHybrid methodVivo selectionSilent mutationsTree shapeStatistical testsSequenceShape analysisMutations
2013
Multiple Transcription Factor Binding Sites Predict AID Targeting in Non-Ig Genes
Duke JL, Liu M, Yaari G, Khalil AM, Tomayko MM, Shlomchik MJ, Schatz DG, Kleinstein SH. Multiple Transcription Factor Binding Sites Predict AID Targeting in Non-Ig Genes. The Journal Of Immunology 2013, 190: 3878-3888. PMID: 23514741, PMCID: PMC3689293, DOI: 10.4049/jimmunol.1202547.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsB-Lymphocyte SubsetsBinding SitesCytidine DeaminaseE-Box ElementsGenes, ImmunoglobulinMiceMice, Inbred BALB CMice, KnockoutMice, TransgenicPredictive Value of TestsSomatic Hypermutation, ImmunoglobulinTranscription FactorsConceptsTranscription Factor Binding SitesAID-induced lesionsNon-Ig genesGenome instabilityTranscription factorsAberrant targetingSequence dataCertain genesGenesAID targetingGerminal center B cellsSomatic mutationsLikely targetBinding sitesAID targetsTargetingClassification tree modelMistargetingB cellsLociMechanismTargetMutationsSites
2012
Identification of Core DNA Elements That Target Somatic Hypermutation
Kohler KM, McDonald JJ, Duke JL, Arakawa H, Tan S, Kleinstein SH, Buerstedde JM, Schatz DG. Identification of Core DNA Elements That Target Somatic Hypermutation. The Journal Of Immunology 2012, 189: 5314-5326. PMID: 23087403, PMCID: PMC3664039, DOI: 10.4049/jimmunol.1202082.Peer-Reviewed Original ResearchMeSH Keywords3' Flanking RegionAnimalsB-LymphocytesCells, CulturedChickensChromatin ImmunoprecipitationCytidine DeaminaseDNAEnhancer Elements, GeneticGenes, ImmunoglobulinGenetic LociImmunoassayImmunoglobulin Variable RegionMutationPhosphorylationRNA Polymerase IISerineSomatic Hypermutation, ImmunoglobulinTranscription, GeneticConceptsActivation-induced deaminaseDNA elementsSomatic hypermutationChicken DT40 B cellsIg lociChromatin immunoprecipitation experimentsDT40 B cellsRNA polymerase IISystematic deletion analysisL chain lociNon-Ig genesCore DNA elementSerine 5Epigenetic marksPolymerase IITranscriptional elongationMutational machineryDeletion analysisReporter cassetteImmunoprecipitation experimentsDeoxycytosine residuesIg genesDNA damageChain locusLociQuantifying selection in high-throughput Immunoglobulin sequencing data sets
Yaari G, Uduman M, Kleinstein SH. Quantifying selection in high-throughput Immunoglobulin sequencing data sets. Nucleic Acids Research 2012, 40: e134-e134. PMID: 22641856, PMCID: PMC3458526, DOI: 10.1093/nar/gks457.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBayes TheoremComputer SimulationDNA Mutational AnalysisGenes, ImmunoglobulinHigh-Throughput Nucleotide SequencingHumansImmunoglobulin Heavy ChainsImmunoglobulinsMiceSomatic Hypermutation, ImmunoglobulinConceptsQuantifying selectionDifferent selection pressuresHigh-throughput immunoglobulinSomatic hypermutationNext-generation sequencing dataDNA mutation patternsSomatic mutation patternsGroups of sequencesAntigen-driven selection processMutation patternsSequence dataSelection pressureSequencing dataB cell affinity maturationB-cell cancersNegative selection
2011
Detecting selection in immunoglobulin sequences
Uduman M, Yaari G, Hershberg U, Stern JA, Shlomchik MJ, Kleinstein SH. Detecting selection in immunoglobulin sequences. Nucleic Acids Research 2011, 39: w499-w504. PMID: 21665923, PMCID: PMC3125793, DOI: 10.1093/nar/gkr413.Peer-Reviewed Original ResearchAntibody AffinityDNA Mutational AnalysisGenes, ImmunoglobulinInternetSoftwareSomatic Hypermutation, ImmunoglobulinSomatic hypermutation targeting is influenced by location within the immunoglobulin V region
Cohen RM, Kleinstein SH, Louzoun Y. Somatic hypermutation targeting is influenced by location within the immunoglobulin V region. Molecular Immunology 2011, 48: 1477-1483. PMID: 21592579, PMCID: PMC3109224, DOI: 10.1016/j.molimm.2011.04.002.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsB-LymphocytesBase SequenceGenes, ImmunoglobulinHumansImmunoglobulin Variable RegionMiceModels, GeneticModels, StatisticalMutationSequence Analysis, DNASomatic Hypermutation, ImmunoglobulinConceptsObserved mutation patternSpecific DNA motifsBiased codon usageImmunoglobulin V genesMutation accumulationGene positionCodon usageMutation patternsDNA motifsPositive selectionPosition-specific effectsImmunoglobulin V regionsNegative selectionB cellsMutationsMutation frequencyV geneGenesPeripheral B cellsSubstitution typeV regionsTargetingSpecific targetingCellsSequence
2003
Estimating Hypermutation Rates from Clonal Tree Data
Kleinstein SH, Louzoun Y, Shlomchik MJ. Estimating Hypermutation Rates from Clonal Tree Data. The Journal Of Immunology 2003, 171: 4639-4649. PMID: 14568938, DOI: 10.4049/jimmunol.171.9.4639.Peer-Reviewed Original Research