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
Integrated 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 traps
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 repertoiresSingle 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 signsSex-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
Thymus-derived B cell clones persist in the circulation after thymectomy in myasthenia gravis
Jiang R, Hoehn KB, Lee CS, Pham MC, Homer RJ, Detterbeck FC, Aban I, Jacobson L, Vincent A, Nowak RJ, Kaminski HJ, Kleinstein SH, O'Connor KC. Thymus-derived B cell clones persist in the circulation after thymectomy in myasthenia gravis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 30649-30660. PMID: 33199596, PMCID: PMC7720237, DOI: 10.1073/pnas.2007206117.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAutoantibodiesBiomarkersB-LymphocytesClonal EvolutionClonal Selection, Antigen-MediatedDisease SusceptibilityFemaleHumansLymphocyte CountMaleMiddle AgedModels, BiologicalMyasthenia GravisRadioimmunoassayReceptors, CholinergicThymectomyThymus GlandV(D)J RecombinationYoung AdultConceptsB cell clonesMyasthenia gravisB cell repertoireB cellsCell clonesPlasma cellsCell repertoireAdditional immunosuppressive treatmentDiminished clinical responseThymic lymphofollicular hyperplasiaComplete stable remissionMajority of patientsAntigen-experienced B cellsRandomized clinical trialsClinical symptom measuresAChR autoantibodiesImmunosuppressive treatmentSteroid doseAutoantibody titersMG thymusClinical responseStable remissionClinical scoresAutoimmune diseasesClinical trialsSingle cell immune profiling of dengue virus patients reveals intact immune responses to Zika virus with enrichment of innate immune signatures
Zhao Y, Amodio M, Vander Wyk B, Gerritsen B, Kumar MM, van Dijk D, Moon K, Wang X, Malawista A, Richards MM, Cahill ME, Desai A, Sivadasan J, Venkataswamy MM, Ravi V, Fikrig E, Kumar P, Kleinstein SH, Krishnaswamy S, Montgomery RR. Single cell immune profiling of dengue virus patients reveals intact immune responses to Zika virus with enrichment of innate immune signatures. PLOS Neglected Tropical Diseases 2020, 14: e0008112. PMID: 32150565, PMCID: PMC7082063, DOI: 10.1371/journal.pntd.0008112.Peer-Reviewed Original ResearchConceptsZika virusCell subsetsDengue virusConcurrent dengue infectionInnate cell responsesInnate immune signaturesVirus-infected individualsDivergent clinical outcomesMosquito-borne human pathogenIntact immune responsePre-existing infectionInnate cell typesSingle-cell immune profilingPublic health importanceCell typesImmune signaturesVirus patientsWest Nile virusAcute patientsClinical outcomesImmune profilingDengue infectionImmune statusFunctional statusImmune cells
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 responseCD19Phenotypic and Ig Repertoire Analyses Indicate a Common Origin of IgD−CD27− Double Negative B Cells in Healthy Individuals and Multiple Sclerosis Patients
Fraussen J, Marquez S, Takata K, Beckers L, Montes Diaz G, Zografou C, Van Wijmeersch B, Villar LM, O'Connor KC, Kleinstein SH, Somers V. Phenotypic and Ig Repertoire Analyses Indicate a Common Origin of IgD−CD27− Double Negative B Cells in Healthy Individuals and Multiple Sclerosis Patients. The Journal Of Immunology 2019, 203: 1650-1664. PMID: 31391234, PMCID: PMC6736705, DOI: 10.4049/jimmunol.1801236.Peer-Reviewed Original ResearchConceptsDN B cellsDouble-negative B cellsMultiple sclerosis patientsMS patientsNegative B cellsHealthy controlsClass-switched memoryB cellsAdaptive immune receptor repertoire sequencingSclerosis patientsRepertoire sequencingFrequency of CD95Naive B cellsUnique differentiation pathwayLow CD5Proinflammatory characteristicsImmune agingCD38 expressionHealthy individualsPatientsFlow cytometryLow mutation loadCD27Repertoire analysisMaturation stateEarly B cell tolerance defects in neuromyelitis optica favour anti-AQP4 autoantibody production
Cotzomi E, Stathopoulos P, Lee CS, Ritchie AM, Soltys JN, Delmotte FR, Oe T, Sng J, Jiang R, K A, Vander Heiden JA, Kleinstein SH, Levy M, Bennett JL, Meffre E, O’Connor K. Early B cell tolerance defects in neuromyelitis optica favour anti-AQP4 autoantibody production. Brain 2019, 142: 1598-1615. PMID: 31056665, PMCID: PMC6536857, DOI: 10.1093/brain/awz106.Peer-Reviewed Original ResearchMeSH KeywordsAdultAquaporin 4AutoantibodiesB-LymphocytesFemaleHumansMaleMiddle AgedNeuromyelitis OpticaOptic NerveConceptsNeuromyelitis optica spectrum disorderB cell tolerance checkpointsNMOSD patientsNaïve B cellsAQP4 autoantibodiesTolerance checkpointsHealthy donorsB cellsEarly B cell tolerance checkpointsPeripheral B cell tolerance checkpointsMature naïve B cellsB cell tolerance defectsSeropositive NMOSD patientsOptica spectrum disorderRare autoimmune disorderNaïve B-cell compartmentB cell compartmentB cell populationsAquaporin-4 water channelsPathogenic autoantibodiesAutoantibody productionOptic nerveAutoimmune disordersSevere inflammationSpinal cord
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
2016
Autoreactive T Cells from Patients with Myasthenia Gravis Are Characterized by Elevated IL-17, IFN-γ, and GM-CSF and Diminished IL-10 Production
Cao Y, Amezquita RA, Kleinstein SH, Stathopoulos P, Nowak RJ, O'Connor KC. Autoreactive T Cells from Patients with Myasthenia Gravis Are Characterized by Elevated IL-17, IFN-γ, and GM-CSF and Diminished IL-10 Production. The Journal Of Immunology 2016, 196: 2075-2084. PMID: 26826242, PMCID: PMC4761502, DOI: 10.4049/jimmunol.1501339.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAutoimmunityCD4-Positive T-LymphocytesCell SeparationCytokinesEnzyme-Linked Immunosorbent AssayFemaleGranulocyte-Macrophage Colony-Stimulating FactorHumansInterferon-gammaInterleukin-10Interleukin-17MaleMiddle AgedMyasthenia GravisPhenotypePolymerase Chain ReactionT-Lymphocyte SubsetsConceptsAutoreactive T cellsT cell compartmentHealthy control subjectsMyasthenia gravisT cellsMG patientsIL-17Control subjectsT cell librariesB cellsGM-CSFMemory T cell compartmentElevated IL-17Prototypical autoimmune diseaseIL-10 productionMemory T cellsCell compartmentIL-10 expressionB cell compartmentPathogenic phenotypeMG cohortPathogenic autoantibodiesAutoimmune responseClinical manifestationsProinflammatory phenotype
2015
Neutralizing antibodies against West Nile virus identified directly from human B cells by single-cell analysis and next generation sequencing
Tsioris K, Gupta NT, Ogunniyi AO, Zimnisky RM, Qian F, Yao Y, Wang X, Stern JN, Chari R, Briggs AW, Clouser CR, Vigneault F, Church GM, Garcia MN, Murray KO, Montgomery RR, Kleinstein SH, Love JC. Neutralizing antibodies against West Nile virus identified directly from human B cells by single-cell analysis and next generation sequencing. Integrative Biology 2015, 7: 1587-1597. PMID: 26481611, PMCID: PMC4754972, DOI: 10.1039/c5ib00169b.Peer-Reviewed Original ResearchConceptsHumoral responseNext-generation sequencingB cellsWest Nile virus infectionSevere neurological illnessMemory B cellsAntibody-secreting cellsCohort of subjectsWNV-specific antibodiesHuman B cellsMosquito-borne diseaseWest Nile virusAnamnestic responseAntibody responseAvailable treatmentsClinical severityAntibody isotypesNeurological illnessVaccine studiesVirus infectionGeneration sequencingInfectious diseasesPrevious exposureTherapeutic antibodiesAntibodies
2014
Systems Immunology Reveals Markers of Susceptibility to West Nile Virus Infection
Qian F, Goel G, Meng H, Wang X, You F, Devine L, Raddassi K, Garcia MN, Murray KO, Bolen CR, Gaujoux R, Shen-Orr SS, Hafler D, Fikrig E, Xavier R, Kleinstein SH, Montgomery RR. Systems Immunology Reveals Markers of Susceptibility to West Nile Virus Infection. MSphere 2014, 22: 6-16. PMID: 25355795, PMCID: PMC4278927, DOI: 10.1128/cvi.00508-14.Peer-Reviewed Original ResearchConceptsWest Nile virus infectionVirus infectionMyeloid dendritic cellsMarker of susceptibilityPotential therapeutic strategySeverity of infectionSevere neurological diseaseOlder patientsAcute infectionDendritic cellsCXCL10 expressionDetectable yearsImmunity-related genesStratified cohortWNV infectionTherapeutic strategiesPathogenic mechanismsAnimal studiesNeurological diseasesDisease severityVivo infectionPredictive signatureInfectionProminent alterationsPrimary cellsInfluence 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 exposureB cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes
Stern JN, Yaari G, Vander Heiden JA, Church G, Donahue WF, Hintzen RQ, Huttner AJ, Laman JD, Nagra RM, Nylander A, Pitt D, Ramanan S, Siddiqui BA, Vigneault F, Kleinstein SH, Hafler DA, O'Connor KC. B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes. Science Translational Medicine 2014, 6: 248ra107. PMID: 25100741, PMCID: PMC4388137, DOI: 10.1126/scitranslmed.3008879.Peer-Reviewed Original ResearchConceptsCervical lymph nodesCentral nervous systemB cellsCerebrospinal fluidLymph nodesMultiple sclerosisLymphoid tissueCNS of patientsCNS B cellsAntigen-experienced B cellsMultiple sclerosis brainSecondary lymphoid tissuesB cell compartmentB cell trafficB cell maturationImmunomodulatory therapyImmune infiltratesPeripheral bloodInflammatory diseasesLymphocyte transmigrationPeripheral tissuesNervous systemMembers of clonesCell maturationCell trafficImmune Markers Associated with Host Susceptibility to Infection with West Nile Virus
Qian F, Thakar J, Yuan X, Nolan M, Murray KO, Lee WT, Wong SJ, Meng H, Fikrig E, Kleinstein SH, Montgomery RR. Immune Markers Associated with Host Susceptibility to Infection with West Nile Virus. Viral Immunology 2014, 27: 39-47. PMID: 24605787, PMCID: PMC3949440, DOI: 10.1089/vim.2013.0074.Peer-Reviewed Original ResearchConceptsWest Nile virusSevere infectionsImmune markersIL-4IL-4 levelsSerum cytokine levelsSerum IL-4Nile virusSignificant risk factorsImmune system statusPeripheral blood cellsSevere neurological diseaseCytokine levelsAntibody levelsImmune statusRisk factorsHealthy subjectsStratified cohortWNV infectionNeurological diseasesInfectionAltered expression levelsBlood cellsAltered gene expression patternsHost susceptibility
2012
The Blood Transcriptional Signature of Chronic Hepatitis C Virus Is Consistent with an Ongoing Interferon-Mediated Antiviral Response
Bolen CR, Robek MD, Brodsky L, Schulz V, Lim JK, Taylor MW, Kleinstein SH. The Blood Transcriptional Signature of Chronic Hepatitis C Virus Is Consistent with an Ongoing Interferon-Mediated Antiviral Response. Journal Of Interferon & Cytokine Research 2012, 33: 15-23. PMID: 23067362, PMCID: PMC3539252, DOI: 10.1089/jir.2012.0037.Peer-Reviewed Original ResearchConceptsPeripheral blood mononuclear cellsHCV patientsHealthy volunteersChronic hepatitis C virus (HCV) infectionChronic hepatitis C virusInfected individualsTreatment-naïve HCV patientsHepatitis C virus infectionBlood transcriptional profilesBlood transcriptional signaturesC virus infectionChronic HCV infectionOngoing immune responseBlood mononuclear cellsHepatitis C virusBlood transcriptional profilingDrug treatment responseHCV infectionSubset of IFNMononuclear cellsC virusIFN signatureHealthy controlsTreatment responseVirus infection
2011
Altered Folate Availability Modifies the Molecular Environment of the Human Colorectum: Implications for Colorectal Carcinogenesis
Protiva P, Mason JB, Liu Z, Hopkins ME, Nelson C, Marshall JR, Lambrecht RW, Pendyala S, Kopelovich L, Kim M, Kleinstein SH, Laird PW, Lipkin M, Holt PR. Altered Folate Availability Modifies the Molecular Environment of the Human Colorectum: Implications for Colorectal Carcinogenesis. Cancer Prevention Research 2011, 4: 530-543. PMID: 21321062, PMCID: PMC3742550, DOI: 10.1158/1940-6207.capr-10-0143.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedBiological AvailabilityCell Transformation, NeoplasticColonColorectal NeoplasmsDietary SupplementsDNA BreaksDNA MethylationFemaleFolic AcidFolic Acid DeficiencyGene ExpressionGene Expression ProfilingHumansMaleMiddle AgedOligonucleotide Array Sequence AnalysisPromoter Regions, GeneticRectumReverse Transcriptase Polymerase Chain ReactionTumor Suppressor Protein p53ConceptsFolate supplementationFolate deliveryFolate depletionImmune responseColorectal carcinogenesisDNA strand breaksHuman colonColorectal cancer riskFolic acidSupplemental folic acidLow-folate dietLow folate statusImmune response pathwaysImmune-related pathwaysFirst studyRectosigmoid biopsiesRisk volunteersPrimary endpointGene array analysisPromoter-specific DNA methylationRepletion protocolFolate dietFolate levelsSecond studyFolate status