2023
Precision 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
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 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 centersAutoantibodiesDiseasePatients
2019
Autoantibodies 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 ResearchConceptsSystemic 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
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
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
2007
A Local Antigen-Driven Humoral Response Is Present in the Inflammatory Myopathies
Bradshaw EM, Orihuela A, McArdel SL, Salajegheh M, Amato AA, Hafler DA, Greenberg SA, O’Connor K. A Local Antigen-Driven Humoral Response Is Present in the Inflammatory Myopathies. The Journal Of Immunology 2007, 178: 547-556. PMID: 17182595, DOI: 10.4049/jimmunol.178.1.547.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAmino Acid SequenceAntibody FormationAutoantigensB-Lymphocyte SubsetsFemaleGenes, Immunoglobulin Heavy ChainHumansImmunoglobulin Switch RegionImmunoglobulin Variable RegionMaleMicrodissectionMiddle AgedMolecular Sequence DataMutationMyocardiumMyositisReceptors, Antigen, B-CellSyndecan-1Transcription, GeneticConceptsInclusion body myositisLaser capture microdissectionBody myositisCapture microdissectionInflammatory myopathiesMuscle tissueInsertions/deletionsT cell-mediated diseaseGene sequencesCell-mediated diseaseGene transcriptsInflamed muscle tissueAg-specific responsesAg receptorB cell maturationPlasma cell populationPutative autoimmune disordersControl muscle tissueSignificant somatic mutationsIndividual cellsVariable region gene sequencesOligoclonal expansionInflammatory infiltrateSomatic mutationsMuscle weakness
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 cellsPolymyositisMyositis