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 ResearchMeSH KeywordsB-LymphocytesHumansImmunoglobulin Heavy ChainsImmunoglobulin Light ChainsMutationPhylogenyReceptors, Antigen, B-CellSingle-Cell AnalysisConceptsPhylogenetic 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
2023
IGHV allele similarity clustering improves genotype inference from adaptive immune receptor repertoire sequencing data
Peres A, Lees W, Rodriguez O, Lee N, Polak P, Hope R, Kedmi M, Collins A, Ohlin M, Kleinstein S, Watson C, Yaari G. IGHV allele similarity clustering improves genotype inference from adaptive immune receptor repertoire sequencing data. Nucleic Acids Research 2023, 51: e86-e86. PMID: 37548401, PMCID: PMC10484671, DOI: 10.1093/nar/gkad603.Peer-Reviewed Original ResearchThe Plasma Cell Infiltrate Populating the Muscle Tissue of Patients with Inclusion Body Myositis Features Distinct B Cell Receptor Repertoire Properties
Jiang R, Roy B, Wu Q, Mohanty S, Nowak R, Shaw A, Kleinstein S, O’Connor K. The Plasma Cell Infiltrate Populating the Muscle Tissue of Patients with Inclusion Body Myositis Features Distinct B Cell Receptor Repertoire Properties. ImmunoHorizons 2023, 7: 310-322. PMID: 37171806, PMCID: PMC10579972, DOI: 10.4049/immunohorizons.2200078.Peer-Reviewed Original ResearchMeSH KeywordsDermatomyositisHumansImmunoglobulin MMuscle, SkeletalMyositis, Inclusion BodyPlasma CellsPolymyositisReceptors, Antigen, B-CellConceptsInclusion body myositisMemory B cellsCell infiltrateBody myositisB cellsIBM muscle biopsiesB-cell infiltratesPlasma cell infiltrateClass-switched IgGMuscle tissueAdaptive immune receptor repertoire sequencingHumoral responseHealthy controlsIgA isotypePlasma cellsCell repertoireMuscle biopsyInfiltratesDegenerative disordersDisease pathologyRepertoire sequencingSkeletal muscleDermatomyositisPolymyositisMyositis
2022
Reemergence of pathogenic, autoantibody-producing B cell clones in myasthenia gravis following B cell depletion therapy
Fichtner ML, Hoehn KB, Ford EE, Mane-Damas M, Oh S, Waters P, Payne AS, Smith ML, Watson CT, Losen M, Martinez-Martinez P, Nowak RJ, Kleinstein SH, O’Connor K. Reemergence of pathogenic, autoantibody-producing B cell clones in myasthenia gravis following B cell depletion therapy. Acta Neuropathologica Communications 2022, 10: 154. PMID: 36307868, PMCID: PMC9617453, DOI: 10.1186/s40478-022-01454-0.Peer-Reviewed Original ResearchMeSH KeywordsAntibodies, MonoclonalAutoantibodiesClone CellsHumansMyasthenia GravisNeoplasm Recurrence, LocalReceptor Protein-Tyrosine KinasesReceptors, Antigen, B-CellConceptsB cell depletion therapyB cell clonesMuSK-MG patientsMyasthenia gravisB cellsMG patientsDepletion therapyCell clonesAutoantibody-producing B cellsMuscle-specific tyrosine kinaseComplete stable remissionB cell receptor repertoireCell receptor repertoireValuable candidate biomarkersB cell receptorMG relapseClinical relapseStable remissionDisease relapseAutoimmune disordersRelapsePatientsAcetylcholine receptorsCandidate biomarkersReceptor repertoirePhylogenetic analysis of migration, differentiation, and class switching in B cells
Hoehn KB, Pybus OG, Kleinstein SH. Phylogenetic analysis of migration, differentiation, and class switching in B cells. PLOS Computational Biology 2022, 18: e1009885. PMID: 35468128, PMCID: PMC9037912, DOI: 10.1371/journal.pcbi.1009885.Peer-Reviewed Original ResearchMeSH KeywordsB-LymphocytesCell DifferentiationHIV InfectionsHumansImmunoglobulin Class SwitchingPhylogenyReceptors, Antigen, B-CellSingle-cell multi-omics reveals dyssynchrony of the innate and adaptive immune system in progressive COVID-19
Unterman A, Sumida TS, Nouri N, Yan X, Zhao AY, Gasque V, Schupp JC, Asashima H, Liu Y, Cosme C, Deng W, Chen M, Raredon MSB, Hoehn KB, Wang G, Wang Z, DeIuliis G, Ravindra NG, Li N, Castaldi C, Wong P, Fournier J, Bermejo S, Sharma L, Casanovas-Massana A, Vogels CBF, Wyllie AL, Grubaugh ND, Melillo A, Meng H, Stein Y, Minasyan M, Mohanty S, Ruff WE, Cohen I, Raddassi K, Niklason L, Ko A, Montgomery R, Farhadian S, Iwasaki A, Shaw A, van Dijk D, Zhao H, Kleinstein S, Hafler D, Kaminski N, Dela Cruz C. Single-cell multi-omics reveals dyssynchrony of the innate and adaptive immune system in progressive COVID-19. Nature Communications 2022, 13: 440. PMID: 35064122, PMCID: PMC8782894, DOI: 10.1038/s41467-021-27716-4.Peer-Reviewed Original ResearchMeSH KeywordsAdaptive ImmunityAgedAntibodies, Monoclonal, HumanizedCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCells, CulturedCOVID-19COVID-19 Drug TreatmentFemaleGene Expression ProfilingGene Expression RegulationHumansImmunity, InnateMaleReceptors, Antigen, B-CellReceptors, Antigen, T-CellRNA-SeqSARS-CoV-2Single-Cell AnalysisConceptsProgressive COVID-19B cell clonesSingle-cell analysisT cellsImmune responseMulti-omics single-cell analysisCOVID-19Cell clonesAdaptive immune interactionsSevere COVID-19Dynamic immune responsesGene expressionSARS-CoV-2 virusAdaptive immune systemSomatic hypermutation frequenciesCellular effectsProtein markersEffector CD8Immune signaturesProgressive diseaseHypermutation frequencyProgressive courseClassical monocytesClonesImmune interactions
2021
Elevated N-Linked Glycosylation of IgG V Regions in Myasthenia Gravis Disease Subtypes.
Mandel-Brehm C, Fichtner ML, Jiang R, Winton VJ, Vazquez SE, Pham MC, Hoehn KB, Kelleher NL, Nowak RJ, Kleinstein SH, Wilson MR, DeRisi JL, O'Connor KC. Elevated N-Linked Glycosylation of IgG V Regions in Myasthenia Gravis Disease Subtypes. The Journal Of Immunology 2021, 207: 2005-2014. PMID: 34544801, PMCID: PMC8492536, DOI: 10.4049/jimmunol.2100225.Peer-Reviewed Original ResearchConceptsMyasthenia gravisB-cell-mediated autoimmune diseasesBCR repertoireCell-mediated autoimmune diseaseTotal BCR repertoireTotal circulating IgGSubset of patientsB cell repertoireElevated NGene segment usageMG subtypesAutoimmune disordersAutoimmune diseasesHealthy donorsCell repertoireDisease subtypesDistinct subtypesReceptor repertoireAdaptive immune receptor repertoiresV regionsAutoantigen bindingPatientsSegment usageSubtypesImmune receptor repertoires
2020
CD4+ follicular regulatory T cells optimize the influenza virus–specific B cell response
Lu Y, Jiang R, Freyn AW, Wang J, Strohmeier S, Lederer K, Locci M, Zhao H, Angeletti D, O’Connor K, Kleinstein SH, Nachbagauer R, Craft J. CD4+ follicular regulatory T cells optimize the influenza virus–specific B cell response. Journal Of Experimental Medicine 2020, 218: e20200547. PMID: 33326020, PMCID: PMC7748821, DOI: 10.1084/jem.20200547.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibody FormationAntigensB-LymphocytesCD4 AntigensDisease Models, AnimalEpitopesForkhead Transcription FactorsGerminal CenterHumansImmunityImmunologic MemoryInfluenza, HumanInfluenzavirus BIntegrasesMice, Inbred C57BLOrthomyxoviridae InfectionsReceptors, Antigen, B-CellSpecies SpecificityT-Lymphocytes, RegulatoryVaccinationConceptsB cell responsesGerminal center B cell responsesFollicular regulatory T cellsRegulatory T cellsTfr cellsCell responsesT cellsViral challengeHumoral memoryVirus-specific B cell responsesAntigen-specific B cell responsesFollicular helper T cellsHA stalk regionHelper T cellsInfluenza virus infectionGerminal center developmentAntibody responsePlasma cellsVirus infectionImmunization modelAntibody productionBCR repertoireInfluenza virusRepeated exposureInfluenza virus glycoproteinsSomatic 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 Research
2019
Overexpression of T-bet in HIV infection is associated with accumulation of B cells outside germinal centers and poor affinity maturation
Austin JW, Buckner CM, Kardava L, Wang W, Zhang X, Melson VA, Swanson RG, Martins AJ, Zhou JQ, Hoehn KB, Fisk JN, Dimopoulos Y, Chassiakos A, O'Dell S, Smelkinson MG, Seamon CA, Kwan RW, Sneller MC, Pittaluga S, Doria-Rose NA, McDermott A, Li Y, Chun TW, Kleinstein SH, Tsang JS, Petrovas C, Moir S. Overexpression of T-bet in HIV infection is associated with accumulation of B cells outside germinal centers and poor affinity maturation. Science Translational Medicine 2019, 11 PMID: 31776286, PMCID: PMC7479651, DOI: 10.1126/scitranslmed.aax0904.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntibodies, NeutralizingAntibody AffinityAntigens, CD19B-LymphocytesCytokinesFemaleGerminal CenterHIV InfectionsHumansImmunologic MemoryLymph NodesMaleMiddle AgedMutation RatePhenotypeReceptors, Antigen, B-CellT-Box Domain ProteinsT-Lymphocytes, Helper-InducerTranscriptomeYoung AdultConceptsHIV-specific B cellsT-betGC B cellsGerminal centersB cellsLymph nodesPoor affinity maturationChronic immune activationMemory B cell compartmentAntibody-mediated immunityChronic infectious diseaseOptimal antibody responseB cell compartmentChronic human infectionsB cell receptorHIV viremiaImmunologic outcomesHIV infectionViremic individualsChronic viremiaImmune activationPeripheral bloodProtective antibodiesAntibody responseCD19Cutting Edge: Ig H Chains Are Sufficient to Determine Most B Cell Clonal Relationships.
Zhou JQ, Kleinstein SH. Cutting Edge: Ig H Chains Are Sufficient to Determine Most B Cell Clonal Relationships. The Journal Of Immunology 2019, 203: 1687-1692. PMID: 31484734, PMCID: PMC6865802, DOI: 10.4049/jimmunol.1900666.Peer-Reviewed Original Research
2018
The CAIRR Pipeline for Submitting Standards-Compliant B and T Cell Receptor Repertoire Sequencing Studies to the National Center for Biotechnology Information Repositories
Bukhari SAC, O’Connor M, Martínez-Romero M, Egyedi AL, Willrett D, Graybeal J, Musen MA, Rubelt F, Cheung KH, Kleinstein SH. The CAIRR Pipeline for Submitting Standards-Compliant B and T Cell Receptor Repertoire Sequencing Studies to the National Center for Biotechnology Information Repositories. Frontiers In Immunology 2018, 9: 1877. PMID: 30166985, PMCID: PMC6105692, DOI: 10.3389/fimmu.2018.01877.Peer-Reviewed Original ResearchConceptsMetadata qualityInformation repositoryAdaptive immune receptor repertoiresLarge-scale dataWeb–based templateSoftware frameworkData annotationData standardsEffective sharingAIRR-seq dataReceptor repertoireData submittersCell receptorSequence filesAdaptive immune responsesRepositoryImmune receptor repertoiresMetadataData setsT cell receptorArchive databaseB cell receptorOptimized Threshold Inference for Partitioning of Clones From High-Throughput B Cell Repertoire Sequencing Data
Nouri N, Kleinstein SH. Optimized Threshold Inference for Partitioning of Clones From High-Throughput B Cell Repertoire Sequencing Data. Frontiers In Immunology 2018, 9: 1687. PMID: 30093903, PMCID: PMC6070604, DOI: 10.3389/fimmu.2018.01687.Peer-Reviewed Original Research
2017
Dysregulation of B Cell Repertoire Formation in Myasthenia Gravis Patients Revealed through Deep Sequencing
Vander Heiden JA, Stathopoulos P, Zhou JQ, Chen L, Gilbert TJ, Bolen CR, Barohn RJ, Dimachkie MM, Ciafaloni E, Broering TJ, Vigneault F, Nowak RJ, Kleinstein SH, O'Connor KC. Dysregulation of B Cell Repertoire Formation in Myasthenia Gravis Patients Revealed through Deep Sequencing. The Journal Of Immunology 2017, 198: 1460-1473. PMID: 28087666, PMCID: PMC5296243, DOI: 10.4049/jimmunol.1601415.Peer-Reviewed Original ResearchConceptsDeep sequencing
2015
Practical guidelines for B-cell receptor repertoire sequencing analysis
Yaari G, Kleinstein SH. Practical guidelines for B-cell receptor repertoire sequencing analysis. Genome Medicine 2015, 7: 121. PMID: 26589402, PMCID: PMC4654805, DOI: 10.1186/s13073-015-0243-2.Peer-Reviewed Original ResearchMeSH KeywordsComputational BiologyGuidelines as TopicHigh-Throughput Nucleotide SequencingHumansReceptors, Antigen, B-CellSequence AnalysisThe 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
2011
Activated germinal centre B cells undergo directed migration.
O'Connor MJ, Hauser AE, Haberman AM, Kleinstein SH. Activated germinal centre B cells undergo directed migration. International Journal Of Data Mining And Bioinformatics 2011, 5: 321-31. PMID: 21805826, PMCID: PMC4343311, DOI: 10.1504/ijdmb.2011.040387.Peer-Reviewed Original Research
2006
Mutation parameters from DNA sequence data using graph theoretic measures on lineage trees
Magori-Cohen R, Louzoun Y, Kleinstein SH. Mutation parameters from DNA sequence data using graph theoretic measures on lineage trees. Bioinformatics 2006, 22: e332-e340. PMID: 16873490, DOI: 10.1093/bioinformatics/btl239.Peer-Reviewed Original ResearchConceptsLineage treesDNA sequencesDNA sequence dataSomatic hypermutationMaximum likelihood analysisTree shapeBioinformatics methodsSequence dataLethal mutationsMutation rateNumber of generationsLikelihood analysisMutation parametersB cellsSynthetic treeClonal expansionTreesSequenceMutationsHypermutationAffinity maturationCellsImportant linkClonesUnexpected locations