2024
B cell and aquaporin‐4 antibody relationships with neuromyelitis optica spectrum disorder activity
Bennett J, Pittock S, Paul F, Kim H, Irani S, O'Connor K, Patterson K, Smith M, Gunsior M, Mittereder N, Rees W, Cimbora D, Cree B. B cell and aquaporin‐4 antibody relationships with neuromyelitis optica spectrum disorder activity. Annals Of Clinical And Translational Neurology 2024, 11: 2792-2798. PMID: 39222408, PMCID: PMC11514900, DOI: 10.1002/acn3.52171.Peer-Reviewed Original ResearchNeuromyelitis optica spectrum disorderAquaporin-4B cellsAquaporin-4 immunoglobulin GCirculating B cell subsetsAQP4-IgG titerN-MOmentum studyB-cell countsB cell subsetsBaseline to timePost hoc analysisInebilizumab treatmentAQP4-IgGCD20<sup>+</sup>Subset countsGene signatureHoc analysisInebilizumabNo differenceImmunoglobulin GNeuromyelitisBaselineDisordered activityTitersSpectrum disorder
2023
The 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 muscleDermatomyositisPolymyositisMyositisPlasmablasts from the past: Nostalgic B cells can't let go.
Ohashi S, O'Connor K. Plasmablasts from the past: Nostalgic B cells can't let go. Science Immunology 2023, 8: eadh3115. PMID: 36867677, DOI: 10.1126/sciimmunol.adh3115.Peer-Reviewed Original ResearchPrecision targeting of autoantigen-specific B cells in muscle-specific tyrosine kinase myasthenia gravis with chimeric autoantibody receptor T cells
Oh S, Mao X, Manfredo-Vieira S, Lee J, Patel D, Choi E, Alvarado A, Cottman-Thomas E, Maseda D, Tsao P, Ellebrecht C, Khella S, Richman D, O’Connor K, Herzberg U, Binder G, Milone M, Basu S, Payne A. Precision targeting of autoantigen-specific B cells in muscle-specific tyrosine kinase myasthenia gravis with chimeric autoantibody receptor T cells. Nature Biotechnology 2023, 41: 1229-1238. PMID: 36658341, PMCID: PMC10354218, DOI: 10.1038/s41587-022-01637-z.Peer-Reviewed Original ResearchConceptsMuscle‐specific tyrosine kinase myasthenia gravisReceptor T cellsB cellsT cellsMyasthenia gravisChimeric autoantibody receptor T cellsCD19 chimeric antigen receptor T cellsAutoantigen-specific B cellsChimeric antigen receptor T cellsAntigen receptor T cellsAnti-MuSK antibodiesB-cell depletionTotal IgG levelsClinical study designInvestigational new drug applicationChronic immunosuppressionIgG levelsMuscle weaknessAutoimmune diseasesCell depletionCurrent therapiesSimilar efficacyCytolytic activityMouse modelNew drug applications
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
2020
The B cell immunobiology that underlies CNS autoantibody-mediated diseases
Sun B, Ramberger M, O’Connor K, Bashford-Rogers RJM, Irani SR. The B cell immunobiology that underlies CNS autoantibody-mediated diseases. Nature Reviews Neurology 2020, 16: 481-492. PMID: 32724223, PMCID: PMC9364389, DOI: 10.1038/s41582-020-0381-z.Peer-Reviewed Original ResearchConceptsAutoantigen-specific B cellsB cellsPathogenic autoantibodiesB cell tolerance checkpointsAutoantibody-mediated diseasesB cell immunobiologyLong-term morbidityHigher serum levelsCirculation of patientsSource of autoantibodiesSite of pathologyB-cell lineageClinical relapseAvailable medicationsSerum levelsIntrathecal synthesisCNS diseaseTolerance checkpointsPlasma cellsTherapeutic effectCerebrospinal fluidGerminal centersAutoantibodiesDiseasePatientsMonovalent IgG4 autoantibodies require self-antigen driven affinity maturation to acquire pathogenic capacity
Fichtner M, Vieni C, Redler R, Jiang R, Suarez P, Nowak R, Burden S, Bhabha G, Ekiert D, O’Connor K. Monovalent IgG4 autoantibodies require self-antigen driven affinity maturation to acquire pathogenic capacity. The Journal Of Immunology 2020, 204: 224.39-224.39. DOI: 10.4049/jimmunol.204.supp.224.39.Peer-Reviewed Original ResearchMuSK myasthenia gravisMyasthenia gravisUnmutated common ancestorPathogenic capacityB-cell-mediated autoimmune diseasesAntigen-driven affinity maturationCell-mediated autoimmune diseaseMuscle-specific tyrosine kinaseSubset of patientsAutoreactive B cellsMonovalent antigen-binding fragmentsAffinity maturationHuman monoclonal autoantibodiesUnique autoantibodiesIgG4 autoantibodiesPathogenic autoantibodiesAutoimmune disordersAutoimmune responseAutoimmune diseasesSelf antigensIgG4 subclassAutoantibodiesMG autoantibodiesB cellsFab-arm exchange
2019
Characterization of pathogenic monoclonal autoantibodies derived from muscle-specific kinase myasthenia gravis patients
Takata K, Stathopoulos P, Cao M, Mané-Damas M, Fichtner ML, Benotti ES, Jacobson L, Waters P, Irani SR, Martinez-Martinez P, Beeson D, Losen M, Vincent A, Nowak RJ, O’Connor K. Characterization of pathogenic monoclonal autoantibodies derived from muscle-specific kinase myasthenia gravis patients. JCI Insight 2019, 4: e127167. PMID: 31217355, PMCID: PMC6629167, DOI: 10.1172/jci.insight.127167.Peer-Reviewed Original ResearchConceptsMyasthenia gravisMonoclonal autoantibodiesNeuromuscular junctionMuscle-specific tyrosine kinaseMuSK-MG patientsChronic autoimmune disorderMyasthenia gravis patientsSubset of patientsMouse neuromuscular junctionHuman monoclonal autoantibodiesMuSK autoantibodiesAutoimmune mechanismsGravis patientsMG patientsMost patientsPathogenic autoantibodiesAutoimmune disordersMuscle weaknessNeuromuscular transmissionMuSK phosphorylationAutoantibodiesB cellsAcetylcholine receptorsSynaptic differentiationPatientsEarly 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 ResearchConceptsNeuromyelitis 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
B cells in the pathophysiology of myasthenia gravis
Yi JS, Guptill JT, Stathopoulos P, Nowak RJ, O’Connor K. B cells in the pathophysiology of myasthenia gravis. Muscle & Nerve 2017, 57: 172-184. PMID: 28940642, PMCID: PMC5767142, DOI: 10.1002/mus.25973.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsMyasthenia gravisB cellsMuscle-specific tyrosine kinaseArchetypal autoimmune diseaseMuscle end platesProduction of autoantibodiesMost patientsPathogenic autoantibodiesAutoimmune diseasesAdaptive immunityHuman studiesAcetylcholine receptorsFunctional AChRsNeuromuscular junctionPostsynaptic proteinsAutoantibodiesCellular immunologyMolecular immunologyGravisImmunopathologyPathologyAChRImmunologyTyrosine kinaseEnd platesAutoantibody-producing plasmablasts after B cell depletion identified in muscle-specific kinase myasthenia gravis
Stathopoulos P, Kumar A, Nowak RJ, O’Connor K. Autoantibody-producing plasmablasts after B cell depletion identified in muscle-specific kinase myasthenia gravis. JCI Insight 2017, 2: e94263. PMID: 28878127, PMCID: PMC5621905, DOI: 10.1172/jci.insight.94263.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAnimalsAutoantibodiesB-LymphocytesCohort StudiesFemaleHumansImmunologic FactorsLymphocyte DepletionMaleMiceMiddle AgedMyasthenia GravisReceptor Protein-Tyrosine KinasesReceptors, CholinergicRecurrenceRemission InductionRituximabTumor Necrosis Factor Receptor Superfamily, Member 7ConceptsB-cell depletionMuSK-MG patientsMyasthenia gravisCell depletionMG patientsAutoantibody productionDisease relapseB cellsB-cell-mediated autoimmune disordersMuscle-specific kinase myasthenia gravisAntigen-driven affinity maturationCell-mediated autoimmune disordersMuscle-specific tyrosine kinaseAChR myasthenia gravisAutoantibody-producing plasmablastsMuSK myasthenia gravisRituximab-induced remissionSustained clinical improvementB cell compartmentMuSK autoantibodiesClinical improvementPathogenic autoantibodiesSuch relapsesSerum autoantibodiesClinical features
2016
Restoring immune tolerance in neuromyelitis optica
Bar-Or A, Steinman L, Behne J, Benitez-Ribas D, Chin P, Clare-Salzler M, Healey D, Kim J, Kranz D, Lutterotti A, Martin R, Schippling S, Villoslada P, Wei C, Weiner H, Zamvil S, Smith T, Yeaman M, Aktas O, Amezcua L, Appiwatanakul M, Asgari N, Banwell B, Bennett J, Bowen J, Cabre P, Chitnis T, Cohen J, De Seze J, Fujihara K, Han M, Hellwig K, Hintzen R, Hooper D, Iorio R, Jacob A, Jarius S, Kim H, Kissani N, Klawiter E, Kleiter I, Lana-Peixoto M, Leite M, Levy M, Lublin F, Draayer Y, Marignier R, Matiello M, Nakashima I, O’Connor K, Palace J, Pandit L, Paul F, Prayoonwiwat N, Riley C, Ruprecht K, Saiz A, Siritho S, Tenembaum S, Weinshenker B, Wingerchuk D, Würfel J. Restoring immune tolerance in neuromyelitis optica. Neurology Neuroimmunology & Neuroinflammation 2016, 3: &na;. PMID: 27648464, PMCID: PMC5015540, DOI: 10.1212/nxi.0000000000000277.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsNMO/SDImmune toleranceAquaporin-4Neuromyelitis optica spectrum disorderNormal host defense mechanismsOptica spectrum disorderHost defense mechanismsOral tolerizationNeuromyelitis opticaOptic nerveParticular brain regionsAutoimmune diseasesAstrocyte functionSpinal cordClinical variantsNovel therapiesDominant autoantigenClinical developmentPotential cureB cellsBrain regionsExperimental modelDiseaseCharacteristic phenotypeAutoantigens
2015
Investigating the Antigen Specificity of Multiple Sclerosis Central Nervous System-Derived Immunoglobulins
Willis SN, Stathopoulos P, Chastre A, Compton SD, Hafler DA, O’Connor K. Investigating the Antigen Specificity of Multiple Sclerosis Central Nervous System-Derived Immunoglobulins. Frontiers In Immunology 2015, 6: 600. PMID: 26648933, PMCID: PMC4663633, DOI: 10.3389/fimmu.2015.00600.Peer-Reviewed Original ResearchCentral nervous systemB cell responsesMultiple sclerosisB cellsCNS tissueCerebrospinal fluidAntigen specificityNervous systemCell responsesAntigen-driven B cell responsesImmune cell infiltrationMS central nervous systemTertiary lymphoid structuresResident B cellsAntigen-driven responseB cell clonesMS brainsLymphoid structuresCell infiltrationRecombinant human immunoglobulinNeurofilament lightCNS-derived cell linesCandidate antigensAntigen arraysDisease pathology
2014
Interleukin-10+ Regulatory B Cells Arise Within Antigen-Experienced CD40+ B Cells to Maintain Tolerance to Islet Autoantigens
Kleffel S, Vergani A, Tezza S, Nasr M, Niewczas MA, Wong S, Bassi R, D’Addio F, Schatton T, Abdi R, Atkinson M, Sayegh MH, Wen L, Wasserfall CH, O’Connor K, Fiorina P. Interleukin-10+ Regulatory B Cells Arise Within Antigen-Experienced CD40+ B Cells to Maintain Tolerance to Islet Autoantigens. Diabetes 2014, 64: 158-171. PMID: 25187361, PMCID: PMC4274804, DOI: 10.2337/db13-1639.Peer-Reviewed Original ResearchConceptsIslet autoantigensB cellsT1D patientsInterleukin-10IL-10-producing B cellsHyperglycemic nonobese diabetic miceRegulatory B-cell responsesAutoreactive T cell responsesT cell-mediated responsesRole of BregsB-cell depletionRegulatory B cellsNonobese diabetic (NOD) miceNOD mouse modelT cell responsesB cell responsesType 1 diabetesB cell receptorAdoptive transferDiabetic miceAutoimmune diseasesHuman ILHyperglycemic miceMouse modelBregs
2013
Specific peripheral B cell tolerance defects in patients with multiple sclerosis
Kinnunen T, Chamberlain N, Morbach H, Cantaert T, Lynch M, Preston-Hurlburt P, Herold KC, Hafler DA, O’Connor K, Meffre E. Specific peripheral B cell tolerance defects in patients with multiple sclerosis. Journal Of Clinical Investigation 2013, 123: 2737-2741. PMID: 23676463, PMCID: PMC3668812, DOI: 10.1172/jci68775.Peer-Reviewed Original ResearchConceptsB cell tolerance checkpointsB cell tolerance defectsMultiple sclerosisRheumatoid arthritisTolerance checkpointsB cellsPeripheral B cell tolerance checkpointsTolerance defectsAutoreactive B cell clonesMature naive B cellsType 1 diabetesAutoreactive B cellsB cell toleranceCentral nervous systemNaive B cellsB cell clonesB cell selectionEarly B cell developmentIPEX patientsMost patientsTreg functionHomeostatic proliferationAutoimmune diseasesPatientsHealthy individuals
2010
A unique antibody gene signature is prevalent in the central nervous system of patients with multiple sclerosis
Ligocki AJ, Lovato L, Xiang D, Guidry P, Scheuermann RH, Willis SN, Almendinger S, Racke MK, Frohman EM, Hafler DA, O'Connor KC, Monson NL. A unique antibody gene signature is prevalent in the central nervous system of patients with multiple sclerosis. Journal Of Neuroimmunology 2010, 226: 192-193. PMID: 20655601, PMCID: PMC2937103, DOI: 10.1016/j.jneuroim.2010.06.016.Peer-Reviewed Original ResearchConceptsMultiple sclerosisB cellsGene signatureMS brain tissueCSF of patientsCNS tissue samplesEnriched B cellsCentral nervous systemB cell receptorMS brainsTissue injuryNervous systemBrain tissueCell receptorTissue samplesSclerosisPatientsCSFUnique accumulationCellsSomatic hypermutationInjuryBrainReceptors
2009
The Microenvironment of Germ Cell Tumors Harbors a Prominent Antigen-Driven Humoral Response
Willis SN, Mallozzi SS, Rodig SJ, Cronk KM, McArdel SL, Caron T, Pinkus GS, Lovato L, Shampain KL, Anderson DE, Anderson RC, Bruce JN, O'Connor KC. The Microenvironment of Germ Cell Tumors Harbors a Prominent Antigen-Driven Humoral Response. The Journal Of Immunology 2009, 182: 3310-3317. PMID: 19234230, DOI: 10.4049/jimmunol.0803424.Peer-Reviewed Original ResearchConceptsImmune cell infiltratesGerm cell tumorsHumoral immune responseCell infiltrateB cellsCell tumorsImmune responseGerm cell tumor biologyGerm cell tumor subtypesTumor-associated B cellsTumor-infiltrating B cellsTumor microenvironmentSpecific humoral immune responseRole B cellsB cell clonal expansionB-cell infiltratesB cell responsesCell clonal expansionB cell maturationSignificant somatic mutationsLymphoid folliclesHumoral responsePeripheral bloodTumor subtypesCardinal features
2005
Plasma cells in muscle in inclusion body myositis and polymyositis
Greenberg S, Bradshaw E, Pinkus J, Pinkus G, Burleson T, Due B, Bregoli L, O’Connor K, Amato A. Plasma cells in muscle in inclusion body myositis and polymyositis. Neurology 2005, 65: 1782-1787. PMID: 16344523, DOI: 10.1212/01.wnl.0000187124.92826.20.Peer-Reviewed Original ResearchMeSH KeywordsAntigens, SurfaceAutoantigensBiomarkersBiopsyB-LymphocytesCell DifferentiationCell LineageHumansImmunoglobulinsImmunohistochemistryLymphocyte ActivationMembrane GlycoproteinsMuscle, SkeletalMyositis, Inclusion BodyPlasma CellsPolymyositisProteoglycansRNA, MessengerSyndecan-1SyndecansT-LymphocytesConceptsInclusion body myositisBody myositisB cellsImmunoglobulin gene transcriptsPlasma cellsImmunohistochemical studyCell-mediated immune mechanismsMore T cellsT cell populationsMuscles of patientsMuscle biopsy specimensPrevious immunohistochemical studiesB cell activationDifferentiated B cellsB-cell lineageCell surface markersImmunoglobulin gene rearrangementsUntreated patientsHumoral mechanismsBiopsy specimensImmune mechanismsLaser capture microdissectionT cellsPolymyositisMyositisMultiple sclerosis
Hafler DA, Slavik JM, Anderson DE, O'Connor KC, De Jager P, Baecher‐Allan C. Multiple sclerosis. Immunological Reviews 2005, 204: 208-231. PMID: 15790361, DOI: 10.1111/j.0105-2896.2005.00240.x.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsMultiple sclerosisT cellsB cellsImmunopathology of MSCentral nervous system white matterNervous system white matterRegulatory T cellsHallmark of inflammationImmunosuppressive therapyAutoimmune processImmunomodulatory therapeuticsAnimal modelsMS researchWhite matterDisease pathologyClonal expansionDiseaseMajor histocompatibility complex (MHC) genesMolecular pathologyRNA expressionSclerosisInflammationTherapyPathologyComplex genetic diseases
2001
Immunological Memory: Contribution of Memory B Cells Expressing Costimulatory Molecules in the Resting State
Bar-Or A, Oliveira E, Anderson D, Krieger J, Duddy M, O’Connor K, Hafler D. Immunological Memory: Contribution of Memory B Cells Expressing Costimulatory Molecules in the Resting State. The Journal Of Immunology 2001, 167: 5669-5677. PMID: 11698439, DOI: 10.4049/jimmunol.167.10.5669.Peer-Reviewed Original ResearchConceptsMemory B cellsB cell subsetsB cellsCell subsetsCostimulatory moleculesB cell memory compartmentMemory responsesImmune memory responseDistinct B cell subsetsHuman memory B cellsHumoral memory responsesHuman B cellsTh cellsImmunological memoryT cellsMemory compartmentPoor APCsMurine systemNovel subpopulationRelative paucityCells