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 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 repertoire
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 repertoiresImmune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children
Ramaswamy A, Brodsky NN, Sumida TS, Comi M, Asashima H, Hoehn KB, Li N, Liu Y, Shah A, Ravindra NG, Bishai J, Khan A, Lau W, Sellers B, Bansal N, Guerrerio P, Unterman A, Habet V, Rice AJ, Catanzaro J, Chandnani H, Lopez M, Kaminski N, Dela Cruz CS, Tsang JS, Wang Z, Yan X, Kleinstein SH, van Dijk D, Pierce RW, Hafler DA, Lucas CL. Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children. Immunity 2021, 54: 1083-1095.e7. PMID: 33891889, PMCID: PMC8043654, DOI: 10.1016/j.immuni.2021.04.003.Peer-Reviewed Original ResearchConceptsMIS-C patientsDisease severityInflammatory syndromeTCR repertoireSARS-CoV-2-associated multisystem inflammatory syndromeAsymptomatic SARS-CoV-2 infectionSARS-CoV-2 infectionAdult COVID-19Post-infectious complicationsMultisystem inflammatory syndromeCytotoxicity genesHealthy pediatricImmune dysregulationMemory TActive infectionMyeloid dysfunctionPatientsSingle-cell RNA sequencingFlow cytometrySerum proteomicsRepertoire analysisElevated expressionSeverityAlarminsCOVID-19
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 repertoire tracing identifies rituximab-resistant B cells during myasthenia gravis relapses
Jiang R, Fichtner ML, Hoehn KB, Pham MC, Stathopoulos P, Nowak RJ, Kleinstein SH, O'Connor KC. Single-cell repertoire tracing identifies rituximab-resistant B cells during myasthenia gravis relapses. JCI Insight 2020, 5 PMID: 32573488, PMCID: PMC7453893, DOI: 10.1172/jci.insight.136471.Peer-Reviewed Original ResearchConceptsMuscle-specific kinase myasthenia gravisMemory B cellsB cell subsetsAntibody-secreting cellsB cellsCell subsetsAutoantibody-producing B cellsB-cell depleting therapyCell-depleting therapyB cell clonesB cell survivalGene expression signaturesMyasthenia gravisAutoimmune disordersRelapseB cell samplesReceptor profilingCell clonesExpression signaturesRituximabTherapyCell survivalCellsTreatmentCell samples
2019
Early 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
2015
Responsive population dynamics and wide seeding into the duodenal lamina propria of transglutaminase-2-specific plasma cells in celiac disease
Di Niro R, Snir O, Kaukinen K, Yaari G, Lundin K, Gupta N, Kleinstein S, Cols M, Cerutti A, Mäki M, Shlomchik M, Sollid L. Responsive population dynamics and wide seeding into the duodenal lamina propria of transglutaminase-2-specific plasma cells in celiac disease. Mucosal Immunology 2015, 9: 254-264. PMID: 26153762, PMCID: PMC4703456, DOI: 10.1038/mi.2015.57.Peer-Reviewed Original ResearchMeSH KeywordsAutoantibodiesBiopsyCeliac DiseaseCell CountDiet, Gluten-FreeDuodenumGene Expression RegulationGlutensGTP-Binding ProteinsHumansImmunoglobulin Heavy ChainsIntestinal MucosaLaser Capture MicrodissectionPlasma CellsProtein Glutamine gamma Glutamyltransferase 2Sequence Analysis, DNATransglutaminasesConceptsTG2-specific plasma cellsPlasma cellsCeliac diseaseLamina propriaTransglutaminase 2Antibody-mediated diseasesGluten-free dietSerum antibody levelsSerum antibody titersB cell responsesAntigen-specific antibodiesDuodenal lamina propriaGluten exposureUntreated patientsAntibody levelsAntibody titersCeliac lesionAntigen stainingSubepithelial layerAntibody productionIndividual biopsiesRepertoire analysisDiseaseGut tissueAntibodies
2014
Shared VH1-46 gene usage by pemphigus vulgaris autoantibodies indicates common humoral immune responses among patients
Cho MJ, Lo AS, Mao X, Nagler AR, Ellebrecht CT, Mukherjee EM, Hammers CM, Choi EJ, Sharma PM, Uduman M, Li H, Rux AH, Farber SA, Rubin CB, Kleinstein SH, Sachais BS, Posner MR, Cavacini LA, Payne AS. Shared VH1-46 gene usage by pemphigus vulgaris autoantibodies indicates common humoral immune responses among patients. Nature Communications 2014, 5: 4167. PMID: 24942562, PMCID: PMC4120239, DOI: 10.1038/ncomms5167.Peer-Reviewed Original ResearchMeSH KeywordsAutoantibodiesComplementarity Determining RegionsDesmoglein 3HumansImmunity, HumoralPemphigusConceptsHumoral immune responsePemphigus vulgarisGene usageImmune responseAnti-Dsg3 antibodiesSomatic mutationsRequirement of mutationsPemphigus vulgaris autoantibodiesBlistering diseasePV patientsVH gene usagePatientsDesmoglein 3Unrelated patientsAutoAbsAutoantibodiesAutoreactivityDsg3MutationsGermline sequencesAbReplacement mutationsVDJ recombinationDiseaseAntibodies
2013
Protein array–based profiling of CSF identifies RBPJ as an autoantigen in multiple sclerosis
Querol L, Clark PL, Bailey MA, Cotsapas C, Cross AH, Hafler DA, Kleinstein SH, Lee JY, Yaari G, Willis SN, O'Connor KC. Protein array–based profiling of CSF identifies RBPJ as an autoantigen in multiple sclerosis. Neurology 2013, 81: 956-963. PMID: 23921886, PMCID: PMC3888197, DOI: 10.1212/wnl.0b013e3182a43b48.Peer-Reviewed Original ResearchConceptsCSF of patientsMultiple sclerosisNeurologic diseaseEpstein-Barr virus infectionImmunoglobulin GElevated immunoglobulin GInflammatory neurologic diseasesSubset of patientsLarger validation cohortRecombination signal binding proteinImmunoglobulin kappa J regionCSF autoantibodiesValidation cohortControl subjectsSerum reactivityAutoantigen candidatesHigh prevalenceVirus infectionPatientsAutoantibodiesCSFSclerosisArray-based profilingDiseaseELISA
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