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
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
2015
Imaging robust microglial activation after lipopolysaccharide administration in humans with PET
Sandiego CM, Gallezot JD, Pittman B, Nabulsi N, Lim K, Lin SF, Matuskey D, Lee JY, O’Connor K, Huang Y, Carson RE, Hannestad J, Cosgrove KP. Imaging robust microglial activation after lipopolysaccharide administration in humans with PET. Proceedings Of The National Academy Of Sciences Of The United States Of America 2015, 112: 12468-12473. PMID: 26385967, PMCID: PMC4603509, DOI: 10.1073/pnas.1511003112.Peer-Reviewed Original ResearchConceptsMicroglial activationBrain microglial activationLPS administrationInflammatory cytokinesLPS challengeRobust microglial activationSystemic LPS challengeActivation of microgliaInnate immune cellsVital sign changesHealthy male subjectsEscherichia coli lipopolysaccharidePositron emission tomography (PET) radiotracerNeuroinflammatory responseSystemic inflammationLipopolysaccharide administrationAntiinflammatory effectsBlood levelsImmune cellsNew medicationsSystemic administrationColi lipopolysaccharidePET scansPsychiatric diseasesMale subjects11C-PBR28 imaging in multiple sclerosis patients and healthy controls: test-retest reproducibility and focal visualization of active white matter areas
Park E, Gallezot JD, Delgadillo A, Liu S, Planeta B, Lin SF, O’Connor K, Lim K, Lee JY, Chastre A, Chen MK, Seneca N, Leppert D, Huang Y, Carson RE, Pelletier D. 11C-PBR28 imaging in multiple sclerosis patients and healthy controls: test-retest reproducibility and focal visualization of active white matter areas. European Journal Of Nuclear Medicine And Molecular Imaging 2015, 42: 1081-1092. PMID: 25833352, DOI: 10.1007/s00259-015-3043-4.Peer-Reviewed Original ResearchConceptsNormal-appearing white matterVolume of distributionTest-retest variabilityWhole brain white matterHealthy controlsMicroglial activationTest-retest reproducibilityGray matterMultiple sclerosisMS subjectsWhite matterWhole brain gray matterGood test-retest reproducibilityAbsolute test-retest variabilityActive MS patientsPositron emission tomography (PET) ligandMultiple sclerosis patientsMain outcome measuresWhite matter areasMS WM lesionsBrain gray matterDemyelinating injuryTest-retest resultsVT valuesMS patients
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
The neuroinflammation marker translocator protein is not elevated in individuals with mild-to-moderate depression: A [11C]PBR28 PET study
Hannestad J, DellaGioia N, Gallezot JD, Lim K, Nabulsi N, Esterlis I, Pittman B, Lee JY, O’Connor K, Pelletier D, Carson RE. The neuroinflammation marker translocator protein is not elevated in individuals with mild-to-moderate depression: A [11C]PBR28 PET study. Brain Behavior And Immunity 2013, 33: 131-138. PMID: 23850810, PMCID: PMC3899398, DOI: 10.1016/j.bbi.2013.06.010.Peer-Reviewed Original ResearchConceptsLevels of TSPOControl subjectsSystemic inflammationPositron emission tomographyModerate depressionTSPO levelsActivation of microgliaTranslocator protein 18Total ligand bindingAcute episodePrimary outcomePostmortem studiesSevere depressionMajor depressionPET scansTSPO genotypeBrain regionsEmission tomographySubject factorsPET studiesArterial input functionInflammationElevated levelsProtein 18DepressionSerum 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
2010
Elevated Intrathecal Myelin Oligodendrocyte Glycoprotein Antibodies in Multiple Sclerosis
Klawiter EC, Piccio L, Lyons JA, Mikesell R, O’Connor K, Cross AH. Elevated Intrathecal Myelin Oligodendrocyte Glycoprotein Antibodies in Multiple Sclerosis. JAMA Neurology 2010, 67: 1102-1108. PMID: 20837855, PMCID: PMC3051403, DOI: 10.1001/archneurol.2010.197.Peer-Reviewed Original ResearchConceptsMultiple sclerosisMyelin oligodendrocyte glycoproteinCerebrospinal fluidClinical disabilityMS patientsCSF markersAntibody productionForms of MSProspective case-controlled seriesMyelin oligodendrocyte glycoprotein antibodyDiagnosis of MSImmunoglobulin G indexNoninflammatory neurologic diseasesRoutine CSF testingProgressive multiple sclerosisAcademic referral centerRelapsing-remitting MSRadiographic outcome measuresMagnetic resonance metricsCase-control seriesReferral centerAlbumin levelsIgG indexCSF testingGlycoprotein antibodiesA 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
Epstein–Barr virus infection is not a characteristic feature of multiple sclerosis brain
Willis SN, Stadelmann C, Rodig SJ, Caron T, Gattenloehner S, Mallozzi SS, Roughan JE, Almendinger SE, Blewett MM, Brück W, Hafler DA, O’Connor K. Epstein–Barr virus infection is not a characteristic feature of multiple sclerosis brain. Brain 2009, 132: 3318-3328. PMID: 19638446, PMCID: PMC2792367, DOI: 10.1093/brain/awp200.Peer-Reviewed Original ResearchConceptsMultiple sclerosis brainEpstein-Barr virus infectionEBV infectionWhite matter lesionsMultiple sclerosisCentral nervous systemMatter lesionsVirus infectionSecond cohortEBV infected cellsB cell infiltrationB cell aggregatesInflammatory demyelinating diseaseB-cell infiltratesReal-time polymerase chain reaction methodologyCNS immunopathologyCNS lymphomaDemyelinating diseaseCell infiltrateSitu hybridizationCell infiltrationLarge cohortBrain pathologyNervous systemPolymerase chain reaction methodology
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