Featured Publications
Maturation of germinal center B cells after influenza virus vaccination in humans
McIntire K, Meng H, Lin T, Kim W, Moore N, Han J, McMahon M, Wang M, Malladi S, Mohammed B, Zhou J, Schmitz A, Hoehn K, Carreño J, Yellin T, Suessen T, Middleton W, Teefey S, Presti R, Krammer F, Turner J, Ward A, Wilson I, Kleinstein S, Ellebedy A. Maturation of germinal center B cells after influenza virus vaccination in humans. Journal Of Experimental Medicine 2024, 221: e20240668. PMID: 38935072, PMCID: PMC11211068, DOI: 10.1084/jem.20240668.Peer-Reviewed Original ResearchConceptsB cellsInfluenza vaccineGerminal centersAntigen-specific GC B cellsResponse to seasonal influenza vaccinationLong-lived bone marrow plasma cellsResponse to influenza vaccinationBone marrow plasma cellsGerminal center B cellsGC B cell clonesInfluenza virus vaccineMaturation of B cellsMarrow plasma cellsSeasonal influenza vaccineMemory B cellsHemagglutinin (HAB cell clonesGC B cellsInfluenza hemagglutinin (HAH5 HANeedle aspirationLymphoid structuresLymph nodesPlasma cellsGC reaction
2024
nf-core/airrflow: An adaptive immune receptor repertoire analysis workflow employing the Immcantation framework.
Gabernet G, Marquez S, Bjornson R, Peltzer A, Meng H, Aron E, Lee N, Jensen C, Ladd D, Polster M, Hanssen F, Heumos S, , Yaari G, Kowarik M, Nahnsen S, Kleinstein S. nf-core/airrflow: An adaptive immune receptor repertoire analysis workflow employing the Immcantation framework. PLOS Computational Biology 2024, 20: e1012265. PMID: 39058741, PMCID: PMC11305553, DOI: 10.1371/journal.pcbi.1012265.Peer-Reviewed Original ResearchImmcantation frameworkAIRR-seqAIRR-seq dataAdaptive immune receptor repertoire sequencingSingle-cell sequencing datasetsClonal inferenceSequencing errorsSequencing datasetsNextflow workflowClonal relationshipReceptor sequencesRepertoire sequencingHigh-throughput processingSequenceImmune challengeAnalysis workflowT-cell receptor sequencingNextflowB cellsSARS-CoV-2Experimental toolResponse to SARS-CoV-2Infectious diseasesPI3Kγ in B cells promotes antibody responses and generation of antibody-secreting cells
Lanahan S, Yang L, Jones K, Qi Z, Cabrera E, Cominsky L, Ramaswamy A, Barmada A, Gabernet G, Uthaya Kumar D, Xu L, Shan P, Wymann M, Kleinstein S, Rao V, Mustillo P, Romberg N, Abraham R, Lucas C. PI3Kγ in B cells promotes antibody responses and generation of antibody-secreting cells. Nature Immunology 2024, 25: 1422-1431. PMID: 38961274, DOI: 10.1038/s41590-024-01890-1.Peer-Reviewed Original ResearchAntibody-secreting cellsMemory B cellsB cellsKinase activity-dependent mannerDifferentiation of antibody-secreting cellsAntibody responseGeneration of antibody-secreting cellsInborn errors of immunityActivity-dependent mannerMouse immunization modelFate choiceT cell-dependent antigensToll-like receptor activationTranscriptional programsB cell biologyPhosphoinositide 3-kinase-gammaErrors of immunityNaive B cellsTransduce signalsActivated B cellsB lineage cellsRobust antibody responsesHumoral defectsHumoral immunityReceptor activationIntegrated longitudinal multiomics study identifies immune programs associated with acute COVID-19 severity and mortality
Gygi J, Maguire C, Patel R, Shinde P, Konstorum A, Shannon C, Xu L, Hoch A, Jayavelu N, Haddad E, Network I, Reed E, Kraft M, McComsey G, Metcalf J, Ozonoff A, Esserman D, Cairns C, Rouphael N, Bosinger S, Kim-Schulze S, Krammer F, Rosen L, van Bakel H, Wilson M, Eckalbar W, Maecker H, Langelier C, Steen H, Altman M, Montgomery R, Levy O, Melamed E, Pulendran B, Diray-Arce J, Smolen K, Fragiadakis G, Becker P, Sekaly R, Ehrlich L, Fourati S, Peters B, Kleinstein S, Guan L. Integrated longitudinal multiomics study identifies immune programs associated with acute COVID-19 severity and mortality. Journal Of Clinical Investigation 2024, 134: e176640. PMID: 38690733, PMCID: PMC11060740, DOI: 10.1172/jci176640.Peer-Reviewed Original ResearchConceptsClinical outcomesImmune cascadeElevated levels of inflammatory cytokinesDisease severityLevels of inflammatory cytokinesFormation of neutrophil extracellular trapsAcute COVID-19 severityCritically ill patientsNeutrophil extracellular trapsDevelopment of therapiesCOVID-19 cohortCOVID-19 severityViral clearanceImmunosuppressive metabolitesDeep immunophenotypingMultiomic modelIFN-stimulated genesImmunophenotypic assessmentB cellsDisease courseEarly upregulationInflammatory cytokinesDisease progressionIFN inhibitorsExtracellular trapsCD23+IgG1+ memory B cells are poised to switch to pathogenic IgE production in food allergy
Ota M, Hoehn K, Fernandes-Braga W, Ota T, Aranda C, Friedman S, Miranda-Waldetario M, Redes J, Suprun M, Grishina G, Sampson H, Malbari A, Kleinstein S, Sicherer S, Curotto de Lafaille M. CD23+IgG1+ memory B cells are poised to switch to pathogenic IgE production in food allergy. Science Translational Medicine 2024, 16: eadi0673. PMID: 38324641, PMCID: PMC11008013, DOI: 10.1126/scitranslmed.adi0673.Peer-Reviewed Original ResearchConceptsMemory B cellsB cellsIgE-producing cellsPeanut allergySerum peanut-specific IgEFood allergyInterleukin-4 (IL-4)-B cell memoryPeanut-specific IgEAllergen-specific immunoglobulin EHigh-affinity B cellsPersistent IgE responsesConcentration of IgESingle-cell RNA sequencing experimentsMemory populationRNA sequencing experimentsIgE productionImmune responseImmunoglobulin ECirculating concentrationsIgE responseAllergySequencing experimentsAra h 2Long-term persistenceMemory B cell subsets have divergent developmental origins that are coupled to distinct imprinted epigenetic states
Callahan D, Smita S, Joachim S, Hoehn K, Kleinstein S, Weisel F, Chikina M, Shlomchik M. Memory B cell subsets have divergent developmental origins that are coupled to distinct imprinted epigenetic states. Nature Immunology 2024, 25: 562-575. PMID: 38200277, DOI: 10.1038/s41590-023-01721-9.Peer-Reviewed Original ResearchGerminal center B cellsDistinct genomic featuresDP cellsDevelopmental originsEpigenetic stateFunctional diversityEpigenetic patternsTranscriptional profilingGenomic featuresDN cellsDistinct developmental historiesB cellsReporter miceFunctional responseCellsMemory B cellsChromatinB cell subsetsCell-dependent responsesMultiple approachesProgenyDiversityT cell-dependent responsesGerminal centersDevelopmental history
2023
Prior cycles of anti-CD20 antibodies affect antibody responses after repeated SARS-CoV-2 mRNA vaccination
Asashima H, Kim D, Wang K, Lele N, Buitrago-Pocasangre N, Lutz R, Cruz I, Raddassi K, Ruff W, Racke M, Wilson J, Givens T, Grifoni A, Weiskopf D, Sette A, Kleinstein S, Montgomery R, Shaw A, Li F, Fan R, Hafler D, Tomayko M, Longbrake E. Prior cycles of anti-CD20 antibodies affect antibody responses after repeated SARS-CoV-2 mRNA vaccination. JCI Insight 2023, 8: e168102. PMID: 37606046, PMCID: PMC10543713, DOI: 10.1172/jci.insight.168102.Peer-Reviewed Original ResearchConceptsSARS-CoV-2 mRNA vaccinationB-cell-depleted patientsB-cell depletionAntibody responseMRNA vaccinationThird doseCell depletionT cellsClaude D. Pepper Older Americans Independence CenterB cellsNational Multiple Sclerosis SocietyAnti-CD20 antibodySpike-specific antibodiesMultiple Sclerosis SocietyLow cumulative exposureLogistic regression modelsImportant clinical needCD20 therapyCD20 treatmentMost patientsThird vaccineSerologic responseVaccine dosesMRNA vaccinesVaccination strategiesTracking B cell responses to the SARS-CoV-2 mRNA-1273 vaccine
de Assis F, Hoehn K, Zhang X, Kardava L, Smith C, Merhebi O, Buckner C, Trihemasava K, Wang W, Seamon C, Chen V, Schaughency P, Cheung F, Martins A, Chiang C, Li Y, Tsang J, Chun T, Kleinstein S, Moir S. Tracking B cell responses to the SARS-CoV-2 mRNA-1273 vaccine. Cell Reports 2023, 42: 112780. PMID: 37440409, PMCID: PMC10529190, DOI: 10.1016/j.celrep.2023.112780.Peer-Reviewed Original ResearchConceptsMemory B cellsB cell receptorB cellsAtypical memory B cellsInfection-naïve individualsTwo-dose SARSSARS-CoV-2 mRNAB cell responsesAntibody-secreting cellsMonth 6Protective immunityCell responsesCell receptorClonal expansionImmunoglobulin GEarly timepointsLater timepointsPlasmablastsVaccinationCD71TimepointsSurface proteinsCellsMultimodal single-cell analysisMRNAHigh-throughput single-cell profiling of B cell responses following inactivated influenza vaccination in young and older adults
Wang M, Jiang R, Mohanty S, Meng H, Shaw A, Kleinstein S. High-throughput single-cell profiling of B cell responses following inactivated influenza vaccination in young and older adults. Aging 2023, 15: 9250-9274. PMID: 37367734, PMCID: PMC10564424, DOI: 10.18632/aging.204778.Peer-Reviewed Original ResearchConceptsB cellsActivated B cellsB cell receptorOlder adultsInfluenza vaccinationAge groupsPeripheral blood B cellsYoung adultsInactivated influenza vaccineB cell responsesSubstantial disease burdenBlood B cellsMemory B cellsInfluenza vaccination responsesStrong antibody responseAge-related changesInfluenza vaccineVaccination responseSeasonal influenzaAntibody responseHospital visitsDisease burdenSomatic hypermutation frequenciesVaccinationCell responsesThe 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 ResearchConceptsInclusion 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 muscleDermatomyositisPolymyositisMyositisAge-associated B cells are heterogeneous and dynamic drivers of autoimmunity in mice
Nickerson K, Smita S, Hoehn K, Marinov A, Thomas K, Kos J, Yang Y, Bastacky S, Watson C, Kleinstein S, Shlomchik M. Age-associated B cells are heterogeneous and dynamic drivers of autoimmunity in mice. Journal Of Experimental Medicine 2023, 220: e20221346. PMID: 36828389, PMCID: PMC9997508, DOI: 10.1084/jem.20221346.Peer-Reviewed Original ResearchPD-1highCXCR5–CD4+ peripheral helper T cells promote CXCR3+ plasmablasts in human acute viral infection
Asashima H, Mohanty S, Comi M, Ruff W, Hoehn K, Wong P, Klein J, Lucas C, Cohen I, Coffey S, Lele N, Greta L, Raddassi K, Chaudhary O, Unterman A, Emu B, Kleinstein S, Montgomery R, Iwasaki A, Dela Cruz C, Kaminski N, Shaw A, Hafler D, Sumida T. PD-1highCXCR5–CD4+ peripheral helper T cells promote CXCR3+ plasmablasts in human acute viral infection. Cell Reports 2023, 42: 111895. PMID: 36596303, PMCID: PMC9806868, DOI: 10.1016/j.celrep.2022.111895.Peer-Reviewed Original ResearchConceptsAcute viral infectionTph cellsViral infectionCXCR3 expressionClinical outcomesHelper TSevere viral infectionsB cell helpBetter clinical outcomesProtective humoral immunityT cell-B cell interactionsKey immune responsesPlasmablast expansionB cell differentiationCell subsetsHumoral immunityCell helpImmune responseInterferon γPlasmablast differentiationB cellsPlasmablastsCell responsesInfectionCD4
2022
Adaptive immune responses to SARS-CoV-2 persist in the pharyngeal lymphoid tissue of children
Xu Q, Milanez-Almeida P, Martins A, Radtke A, Hoehn K, Oguz C, Chen J, Liu C, Tang J, Grubbs G, Stein S, Ramelli S, Kabat J, Behzadpour H, Karkanitsa M, Spathies J, Kalish H, Kardava L, Kirby M, Cheung F, Preite S, Duncker P, Kitakule M, Romero N, Preciado D, Gitman L, Koroleva G, Smith G, Shaffer A, McBain I, McGuire P, Pittaluga S, Germain R, Apps R, Schwartz D, Sadtler K, Moir S, Chertow D, Kleinstein S, Khurana S, Tsang J, Mudd P, Schwartzberg P, Manthiram K. Adaptive immune responses to SARS-CoV-2 persist in the pharyngeal lymphoid tissue of children. Nature Immunology 2022, 24: 186-199. PMID: 36536106, PMCID: PMC10777159, DOI: 10.1038/s41590-022-01367-z.Peer-Reviewed Original ResearchConceptsT cell receptorImmune responseGerminal centersPrevious SARS-CoV-2 infectionSARS-CoV-2 infectionB-cell receptor sequencingTissue-specific immunityCell receptor sequencingAdaptive immune responsesUpper respiratory tractMemory B cellsT cell clonotypesSite of infectionSARS-CoV-2Pharyngeal lymphoid tissuePeripheral bloodLymphocyte populationsLymphoid tissueRespiratory tractCell clonotypesAdaptive immunityB cellsCDR3 sequencesAdenoidsCell receptorReemergence 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 ResearchConceptsB 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 Research
2021
Intranasal priming induces local lung-resident B cell populations that secrete protective mucosal antiviral IgA
Oh JE, Song E, Moriyama M, Wong P, Zhang S, Jiang R, Strohmeier S, Kleinstein SH, Krammer F, Iwasaki A. Intranasal priming induces local lung-resident B cell populations that secrete protective mucosal antiviral IgA. Science Immunology 2021, 6: eabj5129. PMID: 34890255, PMCID: PMC8762609, DOI: 10.1126/sciimmunol.abj5129.Peer-Reviewed Original ResearchConceptsVirus infectionIgA secretionB cellsMucosal surfacesIgA-secreting B cellsIgA-expressing cellsRole of IgARespiratory virus infectionsIgA-secreting cellsLower respiratory tractInfluenza virus infectionEffective immune protectionHeterologous virus infectionMemory B cellsSecretory immunoglobulin AProtein-based vaccinesB cell populationsPredominant Ig isotypeSite of entryIntranasal primingBronchoalveolar spaceProtective immunityVaccine strategiesRespiratory mucosaImmune protectionHuman B cell lineages associated with germinal centers following influenza vaccination are measurably evolving
Hoehn KB, Turner JS, Miller FI, Jiang R, Pybus OG, Ellebedy A, Kleinstein SH. Human B cell lineages associated with germinal centers following influenza vaccination are measurably evolving. ELife 2021, 10: e70873. PMID: 34787567, PMCID: PMC8741214, DOI: 10.7554/elife.70873.Peer-Reviewed Original ResearchConceptsSeasonal influenza vaccinationInfluenza vaccinationB-cell lineageGerminal centersB cell evolutionPoor efficacyB cellsSeasonal influenza virus vaccinationSeasonal influenza virus vaccinesVaccine-induced B cell responsesInfluenza virus vaccinationInfluenza virus vaccinePre-existing immunityB cell responsesMemory B cellsCell lineagesGC B cellsSeasonal vaccinationHIV infectionVirus vaccinationVirus vaccineVaccinationVaccine antigensCell responsesSignificant heterogeneityB Cell Mobilization, Dissemination, Fine Tuning of Local Antigen Specificity and Isotype Selection in Asthma
Ohm-Laursen L, Meng H, Hoehn KB, Nouri N, Jiang Y, Clouser C, Johnstone TG, Hause R, Sandhar BS, Upton NEG, Chevretton EB, Lakhani R, Corrigan CJ, Kleinstein SH, Gould HJ. B Cell Mobilization, Dissemination, Fine Tuning of Local Antigen Specificity and Isotype Selection in Asthma. Frontiers In Immunology 2021, 12: 702074. PMID: 34721376, PMCID: PMC8552043, DOI: 10.3389/fimmu.2021.702074.Peer-Reviewed Original ResearchConceptsLower respiratory tractRespiratory tractB cellsAtopic asthmaPlasma cellsCommon respiratory tract diseaseB-cell mobilizationNon-atopic controlsRespiratory tract mucosaUpper respiratory tractRespiratory tract diseaseOrgan-specific diseasesAntibody repertoireB cell clonesAdaptive immune receptor repertoire sequencingBronchial mucosaNasal mucosaTract diseaseCell mobilizationIsotype selectionAntigen specificityAdult volunteersMucosal surfacesImmune systemAsthmaSingle cell immunophenotyping of the skin lesion erythema migrans Identifies IgM memory B cells
Jiang R, Meng H, Raddassi K, Fleming I, Hoehn KB, Dardick KR, Belperron AA, Montgomery RR, Shalek AK, Hafler DA, Kleinstein SH, Bockenstedt LK. Single cell immunophenotyping of the skin lesion erythema migrans Identifies IgM memory B cells. JCI Insight 2021, 6: e148035. PMID: 34061047, PMCID: PMC8262471, DOI: 10.1172/jci.insight.148035.Peer-Reviewed Original ResearchConceptsMemory B cellsErythema migransB cellsEM lesionsIgM memory B cellsLyme diseaseB-cell receptor sequencingSkin infection siteCell receptor sequencingEarly Lyme diseaseLocal antigen presentationSkin immune responsesB cell populationsSingle-cell immunophenotypingMHC class II genesUninvolved skinImmune cellsSpirochetal infectionAntigen presentationCell immunophenotypingT cellsImmune responseIsotype usageAntibody productionInitial signsCutting Edge: Distinct B Cell Repertoires Characterize Patients with Mild and Severe COVID-19
Hoehn KB, Ramanathan P, Unterman A, Sumida TS, Asashima H, Hafler DA, Kaminski N, Dela Cruz CS, Sealfon SC, Bukreyev A, Kleinstein SH. Cutting Edge: Distinct B Cell Repertoires Characterize Patients with Mild and Severe COVID-19. The Journal Of Immunology 2021, 206: 2785-2790. PMID: 34049971, PMCID: PMC8627528, DOI: 10.4049/jimmunol.2100135.Peer-Reviewed Original ResearchConceptsSevere COVID-19Mild COVID-19B cell responsesMemory B cellsB cell repertoireB cellsCell repertoireCOVID-19Cell responsesExtrafollicular B cell responsesLong-term immunitySymptomatic COVID-19Onset of symptomsB cell populationsGerminal center reactionProtective immunityPlasma cellsSingle-cell RNA sequencingCenter reactionPatientsCell populationsImmunityRNA sequencingCellsPostvaccination