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 assays
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 kinaseMaturationImmunopathologyAutoimmunityMonovalent 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 differentiationPatients
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