2024
A Noncanonical CD56dimCD16dim/- NK Cell Subset Indicative of Prior Cytotoxic Activity Is Elevated in Patients with Autoantibody-Mediated Neurologic Diseases.
Yandamuri S, Filipek B, Lele N, Cohen I, Bennett J, Nowak R, Sotirchos E, Longbrake E, Mace E, O'Connor K. A Noncanonical CD56dimCD16dim/- NK Cell Subset Indicative of Prior Cytotoxic Activity Is Elevated in Patients with Autoantibody-Mediated Neurologic Diseases. The Journal Of Immunology 2024, 212: 785-800. PMID: 38251887, PMCID: PMC10932911, DOI: 10.4049/jimmunol.2300015.Peer-Reviewed Original ResearchConceptsNeuromyelitis optica spectrum disorderAb-dependent cellular cytotoxicityNK cellsMyasthenia gravisMG patientsInduced Ab-dependent cellular cytotoxicityNK cell-mediated effector functionsPeripheral blood immune cell populationsCell-mediated effector functionsNeuromyelitis optica spectrum disorder patientsBlood immune cell populationsAb-dependent cellular cytotoxicity activityNK marker CD56NK cell markersHLA-DR expressionNK cell subsetsExpression of perforinImmune cell populationsAutoimmune myasthenia gravisElevated disease burdenHLA-DRCell subsetsCellular cytotoxicityChemokine receptorsMultiparameter immunophenotyping
2023
Remission of severe myasthenia gravis after autologous stem cell transplantation
Schlatter M, Yandamuri S, O'Connor K, Nowak R, Pham M, Obaid A, Redman C, Provost M, McSweeney P, Pearlman M, Tees M, Bowen J, Nash R, Georges G. Remission of severe myasthenia gravis after autologous stem cell transplantation. Annals Of Clinical And Translational Neurology 2023, 10: 2105-2113. PMID: 37726935, PMCID: PMC10646993, DOI: 10.1002/acn3.51898.Peer-Reviewed Original ResearchConceptsHematopoietic cell transplantationRefractory myasthenia gravisAutologous hematopoietic cell transplantationMyasthenia gravisCell transplantationAcetylcholine receptorsAutologous stem cell transplantationPhase 2 clinical trialAmerica (MGFA) clinical classificationMultiple immunomodulatory agentsRabbit antithymocyte globulinSevere myasthenia gravisAutoimmune neurological disordersHigh-dose chemotherapyMyasthenia Gravis FoundationNeuromuscular junction disordersStem cell transplantationTherapeutic plasma exchangeImmune cell subtypesDays of treatmentEffect of treatmentAntithymocyte globulinDisease activityComplete responseUnderwent treatmentIndividual myasthenia gravis autoantibody clones can efficiently mediate multiple mechanisms of pathology
Pham M, Masi G, Patzina R, Obaid A, Oxendine S, Oh S, Payne A, Nowak R, O’Connor K. Individual myasthenia gravis autoantibody clones can efficiently mediate multiple mechanisms of pathology. Acta Neuropathologica 2023, 146: 319-336. PMID: 37344701, PMCID: PMC11380498, DOI: 10.1007/s00401-023-02603-y.Peer-Reviewed Original ResearchConceptsMyasthenia gravisAntigenic modulationPathogenic mechanismsAutoimmune myasthenia gravisCurrent therapeutic approachesΑ-bungarotoxin bindingNicotinic acetylcholine receptorsReceptor blockadeSerum autoantibodiesAutoreactive clonesMonoclonal levelTherapeutic approachesMonoclonal autoantibodiesAcetylcholine receptorsComplement activationAutoantibodiesAChR subunitsJurkat cell lineDistinct molecular mechanismsPathogenic profilePathogenic capacityPathologyCell-based assaysMAbsPatientsMOGAD patient autoantibodies induce complement, phagocytosis, and cellular cytotoxicity
Yandamuri S, Filipek B, Obaid A, Lele N, Thurman J, Makhani N, Nowak R, Guo Y, Lucchinetti C, Flanagan E, Longbrake E, O’Connor K. MOGAD patient autoantibodies induce complement, phagocytosis, and cellular cytotoxicity. JCI Insight 2023, 8: e165373. PMID: 37097758, PMCID: PMC10393237, DOI: 10.1172/jci.insight.165373.Peer-Reviewed Original ResearchConceptsMyelin oligodendrocyte glycoprotein antibody-associated diseaseAntibody-dependent cellular phagocytosisAntibody-dependent cellular cytotoxicityComplement-dependent cytotoxicityMOG autoantibodiesPatient seraCellular cytotoxicityEffector functionsComplement activityAntibody-associated diseaseMultiple mechanismsNK cellsPatient autoantibodiesCytotoxic capacityLesion histologyCellular phagocytosisFuture relapseIgG subclassesCerebrospinal fluidAutoantibodiesCNS conditionsMOGSerumRelapseCytotoxicityClinicoserological insights into patients with immune checkpoint inhibitor‐induced myasthenia gravis
Masi G, Pham M, Karatz T, Oh S, Payne A, Nowak R, Howard J, Guptill J, Juel V, O'Connor K. Clinicoserological insights into patients with immune checkpoint inhibitor‐induced myasthenia gravis. Annals Of Clinical And Translational Neurology 2023, 10: 825-831. PMID: 36924454, PMCID: PMC10187728, DOI: 10.1002/acn3.51761.Peer-Reviewed Original ResearchMeSH KeywordsAutoantibodiesComplement ActivationHumansImmune Checkpoint InhibitorsMyasthenia GravisReceptors, CholinergicPrecision 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 repertoireNovel pathophysiological insights in autoimmune myasthenia gravis
Masi G, O’Connor K. Novel pathophysiological insights in autoimmune myasthenia gravis. Current Opinion In Neurology 2022, 35: 586-596. PMID: 35942663, PMCID: PMC9458626, DOI: 10.1097/wco.0000000000001088.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsAutoimmune myasthenia gravisMyasthenia gravisMG patientsClinical responseMuscle-specific tyrosine kinaseSpecific therapeutic strategiesNovel pathophysiological insightsMG pathologyMG subtypesAutoantibody repertoireTreatment optionsCancer immunotherapyPredictive biomarkersSuch therapyImmunological heterogeneityPathophysiological insightsMG phenotypeTherapeutic strategiesClinical observationsTherapeutic outcomesAcetylcholine receptorsDisease subtypesTherapeutic perspectivesSubtypesDevelopment of assaysMyasthenia gravis complement activity is independent of autoantibody titer and disease severity
Fichtner ML, Hoarty MD, Vadysirisack DD, Munro-Sheldon B, Nowak RJ, O’Connor K. Myasthenia gravis complement activity is independent of autoantibody titer and disease severity. PLOS ONE 2022, 17: e0264489. PMID: 35290370, PMCID: PMC8923450, DOI: 10.1371/journal.pone.0264489.Peer-Reviewed Original ResearchMeSH KeywordsAutoantibodiesComplement System ProteinsHumansMyasthenia GravisReceptors, CholinergicSeverity of Illness IndexConceptsAutoantibody titersComplement activityDisease activityMyasthenia gravisComplement pathwayAcetylcholine receptor autoantibodiesAutoimmune myasthenia gravisSecondary complement deficiencyClassical complement pathwayAChR autoantibodiesReceptor autoantibodiesClinical statusAutoimmune diseasesHealthy controlsComplement deficiencyPatients associatesStudy subjectsCandidate biomarkersDisease statusDisease severitySignificant associationDisease pathologyTitersAutoantibodiesPatients
2020
Affinity maturation is required for pathogenic monovalent IgG4 autoantibody development in myasthenia gravis
Fichtner ML, Vieni C, Redler RL, Kolich L, Jiang R, Takata K, Stathopoulos P, Suarez PA, Nowak RJ, Burden SJ, Ekiert DC, O’Connor K. Affinity maturation is required for pathogenic monovalent IgG4 autoantibody development in myasthenia gravis. Journal Of Experimental Medicine 2020, 217: e20200513. PMID: 32820331, PMCID: PMC7953735, DOI: 10.1084/jem.20200513.Peer-Reviewed Original ResearchConceptsMyasthenia gravisUnmutated common ancestorPathogenic capacityMuscle-specific tyrosine kinaseAffinity maturationMuSK myasthenia gravisAutoimmune myasthenia gravisMonovalent antigen-binding fragmentsUnique autoantibodiesIgG4 autoantibodiesAutoantibody developmentAutoantibodiesFab-arm exchangeMonoclonal autoantibodiesAntigen-binding fragmentsGravisSomatic mutationsSubnanomolar affinityMAbsMonovalent FabTyrosine kinaseMaturationImmunopathologyAutoimmunityThe 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 ResearchMeSH KeywordsAnimalsAutoantibodiesAutoantigensAutoimmune DiseasesB-LymphocytesCentral Nervous System DiseasesHumansImmunotherapyConceptsAutoantigen-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 centersAutoantibodiesDiseasePatientsAutoimmune Pathology in Myasthenia Gravis Disease Subtypes Is Governed by Divergent Mechanisms of Immunopathology
Fichtner ML, Jiang R, Bourke A, Nowak RJ, O’Connor K. Autoimmune Pathology in Myasthenia Gravis Disease Subtypes Is Governed by Divergent Mechanisms of Immunopathology. Frontiers In Immunology 2020, 11: 776. PMID: 32547535, PMCID: PMC7274207, DOI: 10.3389/fimmu.2020.00776.Peer-Reviewed Original ResearchConceptsLipoprotein receptor-related protein 4Chronic inflammatory demyelinating polyneuropathyMuSK myasthenia gravisMyasthenia gravisDisease subtypesPathogenic autoantibodiesNeuromyelitis opticaPemphigus vulgarisFab-arm exchangeNeuromuscular junctionAChR myasthenia gravisDistinct immune mechanismsInflammatory demyelinating polyneuropathyAutoimmune myasthenia gravisContribution of complementMuscle-specific kinaseNicotinic acetylcholine receptorsSubtype of diseaseDemyelinating polyneuropathyMG subtypesMG patientsAutoantibody productionClinical benefitAutoimmune diseasesAutoimmune pathology
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 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 cordAutoantibodies against Neurologic Antigens in Nonneurologic Autoimmunity
Stathopoulos P, Chastre A, Waters P, Irani S, Fichtner ML, Benotti ES, Guthridge JM, Seifert J, Nowak RJ, Buckner JH, Holers VM, James JA, Hafler DA, O’Connor K. Autoantibodies against Neurologic Antigens in Nonneurologic Autoimmunity. The Journal Of Immunology 2019, 202: ji1801295. PMID: 30824481, PMCID: PMC6452031, DOI: 10.4049/jimmunol.1801295.Peer-Reviewed Original ResearchMeSH KeywordsAutoantibodiesAutoantigensAutoimmune DiseasesB-LymphocytesFemaleHEK293 CellsHumansMaleMiddle AgedNerve Tissue ProteinsConceptsSystemic lupus erythematosusRheumatoid arthritisControl cohortNeuromyelitis optica spectrum disorderSurface AgOptica spectrum disorderMyelin oligodendrocyte glycoproteinHealthy donor seraType 1 diabetesB cell toleranceNeurologic autoimmunitySLE patientsLupus erythematosusSuch autoantibodiesT1D patientsAutoimmune diseasesHigh titer AbsOligodendrocyte glycoproteinSystemic autoimmunityDonor seraLarge cohortRare caseAutoantibodiesAquaporin-4Cell tolerance
2017
Autoantibody-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 featuresDurability of the Rituximab Response in Acetylcholine Receptor Autoantibody–Positive Myasthenia Gravis
Robeson KR, Kumar A, Keung B, DiCapua DB, Grodinsky E, Patwa HS, Stathopoulos PA, Goldstein JM, O’Connor K, Nowak RJ. Durability of the Rituximab Response in Acetylcholine Receptor Autoantibody–Positive Myasthenia Gravis. JAMA Neurology 2017, 74: 60-66. PMID: 27893014, DOI: 10.1001/jamaneurol.2016.4190.Peer-Reviewed Original ResearchConceptsDurability of responseMyasthenia gravisRituximab treatmentAnti-AChR antibody levelsB cell-targeted therapiesLong-term clinical responseRetrospective case series studyTreatment of MGEvidence-based practice parametersLast rituximab treatmentRefractory myasthenia gravisSerum cytokine levelsComplete stable remissionSubset of patientsCase series studyMyasthenia Gravis FoundationMG clinicPharmacologic remissionRituximab cyclesSustained remissionAutoantibody levelsInflammatory markersRituximab therapyClinical improvementClinical response
2013
Serum autoantibodies to myelin peptides distinguish acute disseminated encephalomyelitis from relapsing– remitting multiple sclerosis
Van Haren K, Tomooka BH, Kidd BA, Banwell B, Bar-Or A, Chitnis T, Tenembaum SN, Pohl D, Rostasy K, Dale RC, O’Connor K, Hafler DA, Steinman L, Robinson WH. Serum autoantibodies to myelin peptides distinguish acute disseminated encephalomyelitis from relapsing– remitting multiple sclerosis. Multiple Sclerosis Journal 2013, 19: 1726-1733. PMID: 23612879, PMCID: PMC4411183, DOI: 10.1177/1352458513485653.Peer-Reviewed Original ResearchConceptsAcute disseminated encephalomyelitisMyelin basic proteinDisseminated encephalomyelitisMyelin peptidesMultiple sclerosisIgM autoantibodiesIsotype-specific secondary antibodiesPediatric acute disseminated encephalomyelitisRelapsing-remitting multiple sclerosisPediatric multiple sclerosisProteolipid proteinMicroarrays softwareBasic proteinMyelin antigensLaboratory featuresPeptide autoantibodiesMS seraSerum autoantibodiesIgG autoantibodiesAutoantibody biomarkersSerum IgGOligodendrocyte-specific proteinAutoantibody reactivityAdult MSAutoantibodies
2012
Autoantibodies Produced at the Site of Tissue Damage Provide Evidence of Humoral Autoimmunity in Inclusion Body Myositis
Ray A, Amato AA, Bradshaw EM, Felice KJ, DiCapua DB, Goldstein JM, Lundberg IE, Nowak RJ, Ploegh HL, Spooner E, Wu Q, Willis SN, O’Connor K. Autoantibodies Produced at the Site of Tissue Damage Provide Evidence of Humoral Autoimmunity in Inclusion Body Myositis. PLOS ONE 2012, 7: e46709. PMID: 23071619, PMCID: PMC3465259, DOI: 10.1371/journal.pone.0046709.Peer-Reviewed Original ResearchConceptsInclusion body myositisHumoral immune responseImmune responsePlasma cellsTissue damageBody myositisAntibody-secreting plasma cellsCell linesSingle plasma cellsMajor intermediate filament proteinMuscle tissueIBM patientsHumoral autoimmunityInflammatory myopathiesHuman-derived cell linesIBM muscleMuscle tissue sectionsMuscle tissue homogenatesMuscle diseaseTissue homogenatesTissue sectionsIntermediate filament proteinsMyositisAutoantibodiesDisease
2006
Comprehensive Phenotyping in Multiple Sclerosis: Discovery Based Proteomics and the Current Understanding of Putative Biomarkers
O’Connor K, Roy SM, Becker CH, Hafler DA, Kantor AB. Comprehensive Phenotyping in Multiple Sclerosis: Discovery Based Proteomics and the Current Understanding of Putative Biomarkers. Disease Markers 2006, 22: 213-225. PMID: 17124343, PMCID: PMC3851054, DOI: 10.1155/2006/670439.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsMeSH KeywordsAutoantibodiesBiomarkersHumansInflammationMultiple SclerosisNeurodegenerative DiseasesPhenotypeProteomicsConceptsMultiple sclerosisMagnetic resonance imagingPutative biomarkersComprehensive phenotypingMonitoring of progressionComponent expression levelsClinical evaluationCSF proteinAccurate biomarkersCerebrospinal fluid chemistryControl groupTherapeutic interventionsPatient careAccurate diagnosisResonance imagingDisease pathologyFurther evaluationBiomarkersPreliminary dataExpression levelsSclerosisDiagnosisCSFSingle testNovel assessment