Featured Publications
B cell phylogenetics in the single cell era
Hoehn K, Kleinstein S. B cell phylogenetics in the single cell era. Trends In Immunology 2023, 45: 62-74. PMID: 38151443, PMCID: PMC10872299, DOI: 10.1016/j.it.2023.11.004.Peer-Reviewed Original Research
2024
Inferring B Cell Phylogenies from Paired H and L Chain BCR Sequences with Dowser.
Jensen C, Sumner J, Kleinstein S, Hoehn K. Inferring B Cell Phylogenies from Paired H and L Chain BCR Sequences with Dowser. The Journal Of Immunology 2024, 212: 1579-1588. PMID: 38557795, PMCID: PMC11073909, DOI: 10.4049/jimmunol.2300851.Peer-Reviewed Original ResearchConceptsPhylogenetic treeL chainsBranch lengthsBCR sequencesTree-building methodsSingle-cell sequencing dataHistory of mutationsSingle-cell sequencingPhylogenetic methodsSequence dataSequencing technologiesL chain sequencesTree accuracyEvolutionary processSingle-cellPhylogenyImmune responseSomatic hypermutationSequenceClonesMutationsB cell clonesHuman immune responseTreesBCR
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 ResearchConceptsOlder 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
Somatic hypermutation analysis for improved identification of B cell clonal families from next-generation sequencing data
Nouri N, Kleinstein SH. Somatic hypermutation analysis for improved identification of B cell clonal families from next-generation sequencing data. PLOS Computational Biology 2020, 16: e1007977. PMID: 32574157, PMCID: PMC7347241, DOI: 10.1371/journal.pcbi.1007977.Peer-Reviewed Original ResearchMutant EZH2 Induces a Pre-malignant Lymphoma Niche by Reprogramming the Immune Response
Béguelin W, Teater M, Meydan C, Hoehn KB, Phillip JM, Soshnev AA, Venturutti L, Rivas MA, Calvo-Fernández MT, Gutierrez J, Camarillo JM, Takata K, Tarte K, Kelleher NL, Steidl C, Mason CE, Elemento O, Allis CD, Kleinstein SH, Melnick AM. Mutant EZH2 Induces a Pre-malignant Lymphoma Niche by Reprogramming the Immune Response. Cancer Cell 2020, 37: 655-673.e11. PMID: 32396861, PMCID: PMC7298875, DOI: 10.1016/j.ccell.2020.04.004.Peer-Reviewed Original ResearchConceptsFollicular lymphomaB cellsIndolent tumorsCell helpFollicular dendritic cell networksB cell requirementDendritic cell networksFollicular helper cellsGerminal center B cellsGC B cellsHelper cellsImmunological nicheImmune responseMalignant transformationHuman follicular lymphomaEZH2 mutationsPrevents inductionFunction mutationsTumorsCell requirementsCellsMutant EZH2LymphomaMutations
2019
Repertoire-wide phylogenetic models of B cell molecular evolution reveal evolutionary signatures of aging and vaccination
Hoehn KB, Vander Heiden JA, Zhou JQ, Lunter G, Pybus OG, Kleinstein SH. Repertoire-wide phylogenetic models of B cell molecular evolution reveal evolutionary signatures of aging and vaccination. Proceedings Of The National Academy Of Sciences Of The United States Of America 2019, 116: 22664-22672. PMID: 31636219, PMCID: PMC6842591, DOI: 10.1073/pnas.1906020116.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, Vander 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 roundsChange-O: a toolkit for analyzing large-scale B cell immunoglobulin repertoire sequencing data
Gupta NT, Vander Heiden JA, Uduman M, Gadala-Maria D, Yaari G, Kleinstein SH. Change-O: a toolkit for analyzing large-scale B cell immunoglobulin repertoire sequencing data. Bioinformatics 2015, 31: 3356-3358. PMID: 26069265, PMCID: PMC4793929, DOI: 10.1093/bioinformatics/btv359.Peer-Reviewed Original ResearchConceptsHigh-throughput sequencing technologyB cell immunoglobulinLarge-scale characterizationLineage treesSpecialized computational methodsSelection pressureSequencing technologiesSomatic diversityClonal populationsIg repertoireSomatic hypermutationIg sequencesDiversityNon-commercial useSuite of utilitiesRepertoire diversityGermlineComputational methodsAllelesHypermutationAutomated analysis of high-throughput B-cell sequencing data reveals a high frequency of novel immunoglobulin V gene segment alleles
Gadala-Maria D, Yaari G, Uduman M, Kleinstein SH. Automated analysis of high-throughput B-cell sequencing data reveals a high frequency of novel immunoglobulin V gene segment alleles. Proceedings Of The National Academy Of Sciences Of The United States Of America 2015, 112: e862-e870. PMID: 25675496, PMCID: PMC4345584, DOI: 10.1073/pnas.1417683112.Peer-Reviewed Original Research
2014
Influence of seasonal exposure to grass pollen on local and peripheral blood IgE repertoires in patients with allergic rhinitis
Wu YC, James LK, Vander Heiden J, Uduman M, Durham SR, Kleinstein SH, Kipling D, Gould HJ. Influence of seasonal exposure to grass pollen on local and peripheral blood IgE repertoires in patients with allergic rhinitis. Journal Of Allergy And Clinical Immunology 2014, 134: 604-612. PMID: 25171866, PMCID: PMC4151999, DOI: 10.1016/j.jaci.2014.07.010.Peer-Reviewed Original ResearchConceptsHealthy control subjectsNasal biopsy specimensAllergic rhinitisControl subjectsImmunoglobulin heavy chain geneBiopsy specimensIgE repertoireAllergic diseasesPeripheral bloodOngoing germinal center reactionsClonal relatednessNatural pollen exposureSeasonal allergic rhinitisPollen seasonRespiratory allergic diseasesIgH sequencesAntigen-driven selectionGerminal center reactionGrass pollen seasonBlood IgEAtopic statusIgG classAntibody classPatientsPollen exposureHigh-resolution antibody dynamics of vaccine-induced immune responses
Laserson U, Vigneault F, Gadala-Maria D, Yaari G, Uduman M, Vander Heiden J, Kelton W, Jung S, Liu Y, Laserson J, Chari R, Lee JH, Bachelet I, Hickey B, Lieberman-Aiden E, Hanczaruk B, Simen BB, Egholm M, Koller D, Georgiou G, Kleinstein SH, Church GM. High-resolution antibody dynamics of vaccine-induced immune responses. Proceedings Of The National Academy Of Sciences Of The United States Of America 2014, 111: 4928-4933. PMID: 24639495, PMCID: PMC3977259, DOI: 10.1073/pnas.1323862111.Peer-Reviewed Original Research
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 locusLoci
2011
Somatic 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 ResearchConceptsObserved 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
2008
Improved methods for detecting selection by mutation analysis of Ig V region sequences
Hershberg U, Uduman M, Shlomchik MJ, Kleinstein SH. Improved methods for detecting selection by mutation analysis of Ig V region sequences. International Immunology 2008, 20: 683-694. PMID: 18397909, DOI: 10.1093/intimm/dxn026.Peer-Reviewed Original Research
2003
Why are there so few key mutant clones? The influence of stochastic selection and blocking on affinity maturation in the germinal center
Kleinstein SH, Singh JP. Why are there so few key mutant clones? The influence of stochastic selection and blocking on affinity maturation in the germinal center. International Immunology 2003, 15: 871-884. PMID: 12807826, DOI: 10.1093/intimm/dxg085.sgm.Peer-Reviewed Original Research