2022
Impaired TIGIT expression on B cells drives circulating follicular helper T cell expansion in multiple sclerosis
Asashima H, Axisa PP, Pham THG, Longbrake EE, Ruff WE, Lele N, Cohen I, Raddassi K, Sumida TS, Hafler DA. Impaired TIGIT expression on B cells drives circulating follicular helper T cell expansion in multiple sclerosis. Journal Of Clinical Investigation 2022, 132: e156254. PMID: 36250467, PMCID: PMC9566906, DOI: 10.1172/jci156254.Peer-Reviewed Original ResearchConceptsRelapsing-remitting multiple sclerosisMemory B cellsCTfh cellsB cellsTIGIT expressionMultiple sclerosisT cellsFollicular helper T cellsHealthy age-matched controlsB-cell depletionT cell expansionHelper T cellsAge-matched controlsB cell functionB-cell pathwayDifferential gene expression signaturesTfh cellsDisease activityGene expression signaturesCell depletionCD40 ligandTranscription factor TCF4Disease pathogenesisImmune systemNew MRI
2021
Single cell immunophenotyping of the skin lesion erythema migrans Identifies IgM memory B cells
Jiang R, Meng H, Raddassi K, Fleming I, Hoehn KB, Dardick KR, Belperron AA, Montgomery RR, Shalek AK, Hafler DA, Kleinstein SH, Bockenstedt LK. Single cell immunophenotyping of the skin lesion erythema migrans Identifies IgM memory B cells. JCI Insight 2021, 6: e148035. PMID: 34061047, PMCID: PMC8262471, DOI: 10.1172/jci.insight.148035.Peer-Reviewed Original ResearchConceptsMemory B cellsErythema migransB cellsEM lesionsIgM memory B cellsLyme diseaseB-cell receptor sequencingSkin infection siteCell receptor sequencingEarly Lyme diseaseLocal antigen presentationSkin immune responsesB cell populationsSingle-cell immunophenotypingMHC class II genesUninvolved skinImmune cellsSpirochetal infectionAntigen presentationCell immunophenotypingT cellsImmune responseIsotype usageAntibody productionInitial signsCutting Edge: Distinct B Cell Repertoires Characterize Patients with Mild and Severe COVID-19
Hoehn KB, Ramanathan P, Unterman A, Sumida TS, Asashima H, Hafler DA, Kaminski N, Dela Cruz CS, Sealfon SC, Bukreyev A, Kleinstein SH. Cutting Edge: Distinct B Cell Repertoires Characterize Patients with Mild and Severe COVID-19. The Journal Of Immunology 2021, 206: 2785-2790. PMID: 34049971, PMCID: PMC8627528, DOI: 10.4049/jimmunol.2100135.Peer-Reviewed Original ResearchConceptsSevere COVID-19Mild COVID-19B cell responsesMemory B cellsB cell repertoireB cellsCell repertoireCOVID-19Cell responsesExtrafollicular B cell responsesLong-term immunitySymptomatic COVID-19Onset of symptomsB cell populationsGerminal center reactionProtective immunityPlasma cellsSingle-cell RNA sequencingCenter reactionPatientsCell populationsImmunityRNA sequencingCellsPostvaccination
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
B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes
Stern JN, Yaari G, Vander Heiden JA, Church G, Donahue WF, Hintzen RQ, Huttner AJ, Laman JD, Nagra RM, Nylander A, Pitt D, Ramanan S, Siddiqui BA, Vigneault F, Kleinstein SH, Hafler DA, O'Connor KC. B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes. Science Translational Medicine 2014, 6: 248ra107. PMID: 25100741, PMCID: PMC4388137, DOI: 10.1126/scitranslmed.3008879.Peer-Reviewed Original ResearchConceptsCervical lymph nodesCentral nervous systemB cellsCerebrospinal fluidLymph nodesMultiple sclerosisLymphoid tissueCNS of patientsCNS B cellsAntigen-experienced B cellsMultiple sclerosis brainSecondary lymphoid tissuesB cell compartmentB cell trafficB cell maturationImmunomodulatory therapyImmune infiltratesPeripheral bloodInflammatory diseasesLymphocyte transmigrationPeripheral tissuesNervous systemMembers of clonesCell maturationCell trafficTLR‐mediated STAT3 and ERK activation controls IL‐10 secretion by human B cells
Liu B, Cao Y, Huizinga TW, Hafler DA, Toes RE. TLR‐mediated STAT3 and ERK activation controls IL‐10 secretion by human B cells. European Journal Of Immunology 2014, 44: 2121-2129. PMID: 24737107, DOI: 10.1002/eji.201344341.Peer-Reviewed Original ResearchConceptsIL-10 productionIL-10-producing B cellsB cellsHuman B cellsIL-10IL-10 secretionPotent immunoregulatory cytokineType I IFNERK activationType I IFN familyInhibition of STAT3TLR-MyD88Activation of STAT3Immunoregulatory cytokinesTLR signalingPotent productionMouse modelI IFNCD40 ligationAntibody productionTLRSTAT3 pathwayIFNIFN familyPotential target
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
Class II MHC Self-Antigen Presentation in Human B and T Lymphocytes
Costantino CM, Spooner E, Ploegh HL, Hafler DA. Class II MHC Self-Antigen Presentation in Human B and T Lymphocytes. PLOS ONE 2012, 7: e29805. PMID: 22299025, PMCID: PMC3267721, DOI: 10.1371/journal.pone.0029805.Peer-Reviewed Original ResearchMeSH KeywordsAntigen PresentationAntigen-Antibody ComplexAutoantigensBlood DonorsB-LymphocytesCase-Control StudiesCD4-Positive T-LymphocytesCell Line, TransformedHistocompatibility Antigens Class IIHLA-DR AntigensHumansModels, BiologicalPeptidesProteomeSpectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationTandem Mass SpectrometryT-LymphocytesConceptsHLA-DRT cellsPeptide repertoireSelf-antigen presentationAntigen presenting cellsEndogenous peptide repertoireB cell repertoireT-cell processMHC-peptide complexesIL-2Presenting cellsAPC typesT lymphocytesCell repertoireNovel epitopesB cellsHuman BEndogenous epitopesClass II MHC-peptide complexesPeptide epitopesEpitopesCellsCell processesCell-specific proteomesVast majority
2011
Related B cell clones populate the meninges and parenchyma of patients with multiple sclerosis
Lovato L, Willis SN, Rodig SJ, Caron T, Almendinger SE, Howell OW, Reynolds R, O’Connor K, Hafler DA. Related B cell clones populate the meninges and parenchyma of patients with multiple sclerosis. Brain 2011, 134: 534-541. PMID: 21216828, PMCID: PMC3030766, DOI: 10.1093/brain/awq350.Peer-Reviewed Original ResearchMeSH KeywordsB-LymphocytesCentral Nervous SystemClone CellsHumansImmunoglobulin Variable RegionMeningesMultiple SclerosisConceptsB cell clonesB cell aggregatesMultiple sclerosisCentral nervous systemParenchymal infiltratesCell clonesNervous systemMeningeal B cell aggregatesRelated B cell clonesProgressive multiple sclerosisB-cell infiltratesCerebral spinal fluidInflammatory plaquesCell infiltrateImmune compartmentParenchymal lesionsLymphoid tissueSclerosisSpinal fluidWhite matterPatientsGray matterBrain tissueInfiltratesMeninges
2010
A 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 hypermutationInjuryBrainReceptorsFunctionally defective germline variants of sialic acid acetylesterase in autoimmunity
Surolia I, Pirnie SP, Chellappa V, Taylor KN, Cariappa A, Moya J, Liu H, Bell DW, Driscoll DR, Diederichs S, Haider K, Netravali I, Le S, Elia R, Dow E, Lee A, Freudenberg J, De Jager PL, Chretien Y, Varki A, MacDonald ME, Gillis T, Behrens TW, Bloch D, Collier D, Korzenik J, Podolsky DK, Hafler D, Murali M, Sands B, Stone JH, Gregersen PK, Pillai S. Functionally defective germline variants of sialic acid acetylesterase in autoimmunity. Nature 2010, 466: 243-247. PMID: 20555325, PMCID: PMC2900412, DOI: 10.1038/nature09115.Peer-Reviewed Original ResearchMeSH KeywordsAcetylationAcetylesteraseAllelesAnimalsAntibodies, AntinuclearArthritis, RheumatoidAutoimmune DiseasesAutoimmunityBiocatalysisB-LymphocytesCarboxylic Ester HydrolasesCase-Control StudiesCell LineDiabetes Mellitus, Type 1EuropeExonsGenetic Predisposition to DiseaseGerm-Line MutationHumansMiceN-Acetylneuraminic AcidOdds RatioPolymorphism, Single NucleotideSample SizeSequence Analysis, DNA
2009
Age-Dependent B Cell Autoimmunity to a Myelin Surface Antigen in Pediatric Multiple Sclerosis
McLaughlin KA, Chitnis T, Newcombe J, Franz B, Kennedy J, McArdel S, Kuhle J, Kappos L, Rostasy K, Pohl D, Gagne D, Ness JM, Tenembaum S, O'Connor KC, Viglietta V, Wong SJ, Tavakoli NP, de Seze J, Idrissova Z, Khoury SJ, Bar-Or A, Hafler DA, Banwell B, Wucherpfennig KW. Age-Dependent B Cell Autoimmunity to a Myelin Surface Antigen in Pediatric Multiple Sclerosis. The Journal Of Immunology 2009, 183: 4067-4076. PMID: 19687098, PMCID: PMC2795331, DOI: 10.4049/jimmunol.0801888.Peer-Reviewed Original ResearchConceptsMyelin oligodendrocyte glycoproteinMultiple sclerosisB cell autoimmunityCell autoimmunityMOG-AbNative myelin oligodendrocyte glycoproteinPediatric-onset multiple sclerosisEarly onsetSurface AgPediatric MS casesPediatric-onset MSPediatric multiple sclerosisAdult-onset patientsCNS white matterHuman CNS white matterYears of ageAdult-onset diseaseDifferent myelin proteinsImmunological mechanismsPediatric patientsSerum AbsSuch autoantibodiesOligodendrocyte glycoproteinDisease onsetGlial cellsEpstein–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 methodologyCathepsin S Regulates Class II MHC Processing in Human CD4+ HLA-DR+ T Cells
Costantino CM, Ploegh HL, Hafler DA. Cathepsin S Regulates Class II MHC Processing in Human CD4+ HLA-DR+ T Cells. The Journal Of Immunology 2009, 183: 945-952. PMID: 19553543, PMCID: PMC2752291, DOI: 10.4049/jimmunol.0900921.Peer-Reviewed Original ResearchConceptsT cellsCathepsin S expressionSelf-Ag presentationClass II MHC moleculesClass II MHCT cell clonesCathepsin SII MHC moleculesCLIP expressionProfessional APCsConsequence of activationII MHCHuman CD4Presentation pathwayB cellsMHC moleculesEx vivoHLACell clonesInvariant chain proteolysisLysosomal proteasesS expressionCellsActivationCell surface
2008
Lysosomal Cysteine and Aspartic Proteases Are Heterogeneously Expressed and Act Redundantly to Initiate Human Invariant Chain Degradation
Costantino CM, Hang HC, Kent SC, Hafler DA, Ploegh HL. Lysosomal Cysteine and Aspartic Proteases Are Heterogeneously Expressed and Act Redundantly to Initiate Human Invariant Chain Degradation. The Journal Of Immunology 2008, 180: 2876-2885. PMID: 18292509, DOI: 10.4049/jimmunol.180.5.2876.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAntigen PresentationAntigens, Differentiation, B-LymphocyteAspartic Acid EndopeptidasesB-LymphocytesCD4-Positive T-LymphocytesCell Line, TransformedClone CellsCoculture TechniquesCysteine EndopeptidasesGene Expression Regulation, EnzymologicGenetic HeterogeneityHistocompatibility Antigens Class IIHLA-D AntigensHumansLysosomesMolecular Sequence DataProtease InhibitorsProtein Processing, Post-TranslationalConceptsAsparagine endopeptidasePeptide AgClass II MHC productsMyelin basic protein epitopeClass II MHCClass II invariant chainInvariant chain cleavageInvariant chain degradationPresentation of AgInvariant chain processingAEP inhibitionB cell linesDistinct allelic variantsII MHCMHC productsDifferent EBVMHC dimersAllelic variantsHuman AgInvariant chainAltered regulation
2007
Polyspecificity of T cell and B cell receptor recognition
Wucherpfennig KW, Allen PM, Celada F, Cohen IR, De Boer R, Garcia KC, Goldstein B, Greenspan R, Hafler D, Hodgkin P, Huseby ES, Krakauer DC, Nemazee D, Perelson AS, Pinilla C, Strong RK, Sercarz EE. Polyspecificity of T cell and B cell receptor recognition. Seminars In Immunology 2007, 19: 216-224. PMID: 17398114, PMCID: PMC2034306, DOI: 10.1016/j.smim.2007.02.012.Peer-Reviewed Original Research
2001
Immunological Memory: Contribution of Memory B Cells Expressing Costimulatory Molecules in the Resting State
Bar-Or A, Oliveira E, Anderson D, Krieger J, Duddy M, O’Connor K, Hafler D. Immunological Memory: Contribution of Memory B Cells Expressing Costimulatory Molecules in the Resting State. The Journal Of Immunology 2001, 167: 5669-5677. PMID: 11698439, DOI: 10.4049/jimmunol.167.10.5669.Peer-Reviewed Original ResearchConceptsMemory B cellsB cell subsetsB cellsCell subsetsCostimulatory moleculesB cell memory compartmentMemory responsesImmune memory responseDistinct B cell subsetsHuman memory B cellsHumoral memory responsesHuman B cellsTh cellsImmunological memoryT cellsMemory compartmentPoor APCsMurine systemNovel subpopulationRelative paucityCellsThe Neuroimmunology of Multiple Sclerosis: Possible Roles of T and B Lymphocytes in Immunopathogenesis
O'connor K, Bar-Or A, Hafler D. The Neuroimmunology of Multiple Sclerosis: Possible Roles of T and B Lymphocytes in Immunopathogenesis. Journal Of Clinical Immunology 2001, 21: 81-92. PMID: 11332657, DOI: 10.1023/a:1011064007686.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsMultiple sclerosisT cellsB cellsImmunopathology of MSMyelin-reactive T cellsCentral nervous system white matterNervous system white matterAutoreactive T cellsMS immunopathologyImmunosuppressive therapyCNS pathogenesisTolerance breakdownAutoreactive cellsInflammatory diseasesPathological studiesAnimal modelsB lymphocytesWhite matterMajor mediatorDisease pathologyNonhuman primatesDiseaseEvidence supportImmunopathologySclerosisImmune Tolerance and the Nervous System
Anderson D, Hafler D. Immune Tolerance and the Nervous System. Advances In Experimental Medicine And Biology 2001, 490: 79-98. PMID: 11505978, DOI: 10.1007/978-1-4615-1243-1_9.Peer-Reviewed Original ResearchConceptsT cellsB cellsInnate immunityForeign microbial antigensPrior viral infectionSpecific immune responseClass I moleculesNK cellsImmune toleranceMicrobial antigensImmune responseViral infectionNervous systemInfectious agentsSecondary exposureImmune systemInfectious virusParticular antigenSpecific receptorsTumor cellsAntigenI moleculesInfectionInnate mechanismsImmunity
1996
Complementary mutations in an antigenic peptide allow for crossreactivity of autoreactive T-cell clones
Ausubel L, Kwan C, Sette A, Kuchroo V, Hafler D. Complementary mutations in an antigenic peptide allow for crossreactivity of autoreactive T-cell clones. Proceedings Of The National Academy Of Sciences Of The United States Of America 1996, 93: 15317-15322. PMID: 8986809, PMCID: PMC26402, DOI: 10.1073/pnas.93.26.15317.Peer-Reviewed Original ResearchConceptsT cell clonesT cell receptorAutoreactive T cell clonesSpecific T cell clonesAntigenic peptidesMajor histocompatibility complex moleculesSpecific peptide antigenContext of MHCT cell recognitionTCR contact residuesMHC-antigen complexesHistocompatibility complex moleculesMHC-peptide complexesSingle conservative amino acid substitutionTCR-MHCT cellsReceptor plasticityPeptide antigensFunctional pocketStimulating peptideCrossreactivityAntigenTrimolecular complexAmino acid substitutionsConservative amino acid substitutions