2024
Fluorescence-detection size-exclusion chromatography specifically detects autoantibodies targeting the ganglionic acetylcholine receptor in patients with autoimmune autonomic ganglionopathy
Baxter L, Hopkins S, O'Connor K, Pham M, Nowak R, Monson N, Blackburn K, Hibbs R, Vernino S, Noviello C. Fluorescence-detection size-exclusion chromatography specifically detects autoantibodies targeting the ganglionic acetylcholine receptor in patients with autoimmune autonomic ganglionopathy. Journal Of Neuroimmunology 2024, 396: 578454. PMID: 39277987, DOI: 10.1016/j.jneuroim.2024.578454.Peer-Reviewed Original ResearchAutoimmune autonomic ganglionopathyGanglionic acetylcholine receptorAutonomic ganglionopathyRadioimmunoprecipitation assayFluorescence-detection size-exclusion chromatographyAcetylcholine receptorsAutoantibody detectionClinical symptomsDetect autoantibodiesAutoimmune diseasesHealthy controlsPatient seraSize-exclusion-chromatographyAutoantibodiesGAChRGanglionopathySize exclusion chromatographyPatientsReceptorsUnveiling the proteome-wide autoreactome enables enhanced evaluation of emerging CAR-T therapies in autoimmunity
Bodansky A, Yu D, Rallistan A, Kalaycioglu M, Boonyaratanakornkit J, Green D, Gauthier J, Turtle C, Zorn K, O'Donovan B, Mandel-Brehm C, Asaki J, Kortbawi H, Kung A, Rackaityte E, Wang C, Saxena A, de Dios K, Masi G, Nowak R, O'Connor K, Li H, Diaz V, Saloner R, Casaletto K, Gontrum E, Chan B, Kramer J, Wilson M, Utz P, Hill J, Jackson S, Anderson M, DeRisi J. Unveiling the proteome-wide autoreactome enables enhanced evaluation of emerging CAR-T therapies in autoimmunity. Journal Of Clinical Investigation 2024, 134: e180012. PMID: 38753445, PMCID: PMC11213466, DOI: 10.1172/jci180012.Peer-Reviewed Original ResearchB-cell maturation antigenImmunomodulatory therapyPlasma cell-targeted therapyCAR-T therapyCell-targeted therapyAutoantibody mediated diseasesCAR-TAnti-CD19Maturation antigenAutoantibody profileAutoreactive antibodiesTargeted therapyPlasma cellsAutoimmune diseasesAutoantibody repertoireTherapyMediated diseasesAutoantibodiesTherapeutic interventionsProteome-wideDisease statesDiseaseImmunological fingerprintPhIP-SeqMinimal effect
2023
Individual 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 Research
2022
Myasthenia 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 ResearchConceptsAutoantibody 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 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
Fast-acting autoantibodies muscle in on encephalitis
Fichtner M, O’Connor K. Fast-acting autoantibodies muscle in on encephalitis. Science Immunology 2019, 4 DOI: 10.1126/sciimmunol.aba3068.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsCharacterization 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 differentiationPatientsAutoantibodies 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
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 plates
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
2005
Antibodies from Inflamed Central Nervous System Tissue Recognize Myelin Oligodendrocyte Glycoprotein
O’Connor K, Appel H, Bregoli L, Call ME, Catz I, Chan JA, Moore NH, Warren KG, Wong SJ, Hafler DA, Wucherpfennig KW. Antibodies from Inflamed Central Nervous System Tissue Recognize Myelin Oligodendrocyte Glycoprotein. The Journal Of Immunology 2005, 175: 1974-1982. PMID: 16034142, PMCID: PMC4515951, DOI: 10.4049/jimmunol.175.3.1974.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAutoantibodiesBinding Sites, AntibodyCentral Nervous SystemDemyelinating Autoimmune Diseases, CNSFemaleFluoroimmunoassayHumansMaleMolecular Sequence DataMultiple SclerosisMyelin ProteinsMyelin-Associated GlycoproteinMyelin-Oligodendrocyte GlycoproteinRadioimmunoassaySolutionsConceptsMyelin oligodendrocyte glycoproteinMultiple sclerosisCNS diseaseOligodendrocyte glycoproteinCNS tissueChronic inflammatory CNS diseasesAutoantibody-mediated pathologyInflammatory CNS diseasesCentral nervous system tissueInflammatory CNS diseaseCases of encephalitisHigh-affinity autoantibodiesCases of subacuteNervous system tissueCNS parenchymaMOG autoantibodiesMS patientsOligodendrocyte lossMOG-AbCNS diseasesAutoantibodiesCerebrospinal fluidMOG proteinPostmortem casesControl tissues
2003
Myelin basic protein-reactive autoantibodies in the serum and cerebrospinal fluid of multiple sclerosis patients are characterized by low-affinity interactions
O'Connor KC, Chitnis T, Griffin DE, Piyasirisilp S, Bar-Or A, Khoury S, Wucherpfennig KW, Hafler DA. Myelin basic protein-reactive autoantibodies in the serum and cerebrospinal fluid of multiple sclerosis patients are characterized by low-affinity interactions. Journal Of Neuroimmunology 2003, 136: 140-148. PMID: 12620653, DOI: 10.1016/s0165-5728(03)00002-x.Peer-Reviewed Original ResearchConceptsMyelin basic proteinMultiple sclerosisCerebrospinal fluidSoluble myelin basic proteinSemple rabies vaccinePresence of autoantibodiesMultiple sclerosis patientsSera of patientsFraction of patientsAnti-MBP antibodiesHigh-affinity autoantibodiesBasic proteinMBP autoantibodiesRelevant autoantibodiesMS patientsSclerosis patientsAutoimmune diseasesHumoral responseRabies vaccineAutoantibodiesPatientsImmunodominant antigensSerumDiseaseSolid-phase assays