2024
Emerging Cerebrospinal Fluid Biomarkers of Disease Activity and Progression in Multiple Sclerosis
Cross A, Gelfand J, Thebault S, Bennett J, von Büdingen H, Cameron B, Carruthers R, Edwards K, Fallis R, Gerstein R, Giacomini P, Greenberg B, Hafler D, Ionete C, Kaunzner U, Kodama L, Lock C, Longbrake E, Musch B, Pardo G, Piehl F, Weber M, Yuen S, Ziemssen T, Bose G, Freedman M, Anania V, Ramesh A, Winger R, Jia X, Herman A, Harp C, Bar-Or A. Emerging Cerebrospinal Fluid Biomarkers of Disease Activity and Progression in Multiple Sclerosis. JAMA Neurology 2024, 81: 373-383. PMID: 38466277, PMCID: PMC10928543, DOI: 10.1001/jamaneurol.2024.0017.Peer-Reviewed Original ResearchPrimary progressive MSGlial fibrillary acidic proteinNeurofilament heavy chainRelapsing MSCerebrospinal fluidTest cohortMultiple sclerosisDisease-modifying MS therapyMulticenter study of patientsBiomarkers of disease activityAnti-CD20 treatmentCentral nervous system biologyClinical follow-upConfirmation cohortT2 lesion volumeStudy of patientsHeavy chainCSF-GFAP levelsMS disease progressionMagnetic resonance imaging measuresNeurofilament light chainActivated glial markersStudy assessed dataFibrillary acidic proteinAnti-CD20
2023
Cytokines in New‐Onset Refractory Status Epilepticus Predict Outcomes
Hanin A, Cespedes J, Dorgham K, Pulluru Y, Gopaul M, Gorochov G, Hafler D, Navarro V, Gaspard N, Hirsch L. Cytokines in New‐Onset Refractory Status Epilepticus Predict Outcomes. Annals Of Neurology 2023, 94: 75-90. PMID: 36871188, DOI: 10.1002/ana.26627.Peer-Reviewed Original ResearchConceptsNew-onset refractory status epilepticusCytokines/chemokinesFebrile infection-related epilepsy syndromePro-inflammatory cytokines/chemokinesRefractory status epilepticusCerebrospinal fluidStatus epilepticusCryptogenic new-onset refractory status epilepticusSerum cytokines/chemokinesSpecific anti-inflammatory interventionsCytokine/chemokine levelsCytokine/chemokine profilesAnti-inflammatory interventionsCXCL8/ILLong-term outcomesPro-inflammatory cytokinesAnn NeurolChemokine levelsCytokine levelsChemokine profilesEpilepsy syndromesMIP-1αIL-6Predicts outcomeWorse outcomes
2022
Basic principles of neuroimmunology
Yoshida TM, Wang A, Hafler DA. Basic principles of neuroimmunology. Seminars In Immunopathology 2022, 44: 685-695. PMID: 35732977, DOI: 10.1007/s00281-022-00951-7.Peer-Reviewed Original ResearchConceptsNeuro-immune interactionsCentral nervous systemImmune privilegeCerebrospinal fluidCNS-resident immune cellsImmune-derived cytokinesResident T cellsImmune cell infiltrationImmune-privileged organMeningeal lymphatic systemIntroduction of antigenImmune compartmentNeuroinflammatory diseasesNeurological functionCNS homeostasisCell infiltrationHarmful inflammationImmune cellsPeripheral organsT cellsImmune responseLeukocyte traffickingNervous systemImmune systemLymphatic system
2020
Transcriptomic and clonal characterization of T cells in the human central nervous system
Pappalardo JL, Zhang L, Pecsok MK, Perlman K, Zografou C, Raddassi K, Abulaban A, Krishnaswamy S, Antel J, van Dijk D, Hafler DA. Transcriptomic and clonal characterization of T cells in the human central nervous system. Science Immunology 2020, 5 PMID: 32948672, PMCID: PMC8567322, DOI: 10.1126/sciimmunol.abb8786.Peer-Reviewed Original ResearchConceptsCentral nervous systemCSF of patientsT cellsCerebrospinal fluidMultiple sclerosisImmune surveillanceNervous systemCSF T cellsHuman central nervous systemHealthy human donorsT cell activationImmune dysfunctionNeuroinflammatory diseasesCytotoxic capacityHealthy donorsHealthy individualsCell activationHuman donorsTissue adaptationPatientsClonal characterizationExpression of genesCellsSurveillanceFurther characterization
2019
Ocrelizumab treatment reduced levels of neurofilament light chain and numbers of B cells in the cerebrospinal fluid of patients with relapsing multiple sclerosis in the OBOE study (S56.008)
Cross A, Bennett J, von Büdingen H, Carruthers R, Edwards K, Fallis R, Fiore D, Gelfand J, Giacomini P, Greenberg B, Hafler D, Harp C, Assman B, Herman A, Ionete C, Kaunzner U, Lock C, Ma X, Musch B, Pardo G, Piehl F, Weber M, Ziemssen T, Bar-Or A. Ocrelizumab treatment reduced levels of neurofilament light chain and numbers of B cells in the cerebrospinal fluid of patients with relapsing multiple sclerosis in the OBOE study (S56.008). Neurology 2019, 92 DOI: 10.1212/wnl.92.15_supplement.s56.008.Peer-Reviewed Original Research
2018
Single-cell RNA sequencing reveals microglia-like cells in cerebrospinal fluid during virologically suppressed HIV
Farhadian SF, Mehta SS, Zografou C, Robertson K, Price RW, Pappalardo J, Chiarella J, Hafler DA, Spudich SS. Single-cell RNA sequencing reveals microglia-like cells in cerebrospinal fluid during virologically suppressed HIV. JCI Insight 2018, 3: e121718. PMID: 30232286, PMCID: PMC6237230, DOI: 10.1172/jci.insight.121718.Peer-Reviewed Original ResearchConceptsCerebrospinal fluidHIV infectionImmune activationAntiretroviral therapyNeuronal injuryCentral nervous system immune activationLong-term suppressive antiretroviral therapySingle-cell RNA sequencingCNS immune activationDisease-associated microgliaSuppressive antiretroviral therapyImmune cell subsetsMicroglia-like cellsGene expression signaturesNeuronal damageNeuroinflammatory diseasesRNA sequencingCell subsetsCNS cellsNeurological conditionsRare subsetNeurocognitive impairmentMyeloid cellsCellular subsetsInfection
2015
Investigating the Antigen Specificity of Multiple Sclerosis Central Nervous System-Derived Immunoglobulins
Willis SN, Stathopoulos P, Chastre A, Compton SD, Hafler DA, O’Connor K. Investigating the Antigen Specificity of Multiple Sclerosis Central Nervous System-Derived Immunoglobulins. Frontiers In Immunology 2015, 6: 600. PMID: 26648933, PMCID: PMC4663633, DOI: 10.3389/fimmu.2015.00600.Peer-Reviewed Original ResearchCentral nervous systemB cell responsesMultiple sclerosisB cellsCNS tissueCerebrospinal fluidAntigen specificityNervous systemCell responsesAntigen-driven B cell responsesImmune cell infiltrationMS central nervous systemTertiary lymphoid structuresResident B cellsAntigen-driven responseB cell clonesMS brainsLymphoid structuresCell infiltrationRecombinant human immunoglobulinNeurofilament lightCNS-derived cell linesCandidate antigensAntigen arraysDisease pathologyBiomarkers in multiple sclerosis
Housley WJ, Pitt D, Hafler DA. Biomarkers in multiple sclerosis. Clinical Immunology 2015, 161: 51-58. PMID: 26143623, DOI: 10.1016/j.clim.2015.06.015.Peer-Reviewed Original ResearchConceptsMultiple sclerosisB cell chemoattractant CXCL13Myelin-reactive T cellsMacrophage marker CD163Reactive T cellsMarkers of neurodegenerationKIR4.1 antibodiesMS seraClinical outcomesOligoclonal bandsYKL-40Disease progressionT cellsMS susceptibilityCerebrospinal fluidPotential biomarkersViral titersClinical useBiomarkersBiomarker researchSclerosisProgressionDisease diagnosisCD163CXCL13
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 traffic
2013
PhIP-Seq characterization of autoantibodies from patients with multiple sclerosis, type 1 diabetes and rheumatoid arthritis
Larman HB, Laserson U, Querol L, Verhaeghen K, Solimini NL, Xu GJ, Klarenbeek PL, Church GM, Hafler DA, Plenge RM, Nigrovic PA, De Jager PL, Weets I, Martens GA, O'Connor KC, Elledge SJ. PhIP-Seq characterization of autoantibodies from patients with multiple sclerosis, type 1 diabetes and rheumatoid arthritis. Journal Of Autoimmunity 2013, 43: 1-9. PMID: 23497938, PMCID: PMC3677742, DOI: 10.1016/j.jaut.2013.01.013.Peer-Reviewed Original ResearchConceptsType 1 diabetes patientsRheumatoid arthritis patientsMultiple sclerosis patientsLoss of tolerancePhage immunoprecipitation sequencingType 1 diabetesNeurological autoimmunitySeropositivity statusArthritis patientsRheumatoid arthritisSclerosis patientsMultiple sclerosisAutoimmune diseasesDiabetes patientsCerebrospinal fluidGeneral populationSynovial fluidHealthy seraPatientsSusceptible individualsAntibody specificityDiseaseReceptor specificitySerumHuman peptidome
2011
Related B cell clones that populate the CSF and CNS of patients with multiple sclerosis produce CSF immunoglobulin
Obermeier B, Lovato L, Mentele R, Brück W, Forne I, Imhof A, Lottspeich F, Turk KW, Willis SN, Wekerle H, Hohlfeld R, Hafler DA, O'Connor KC, Dornmair K. Related B cell clones that populate the CSF and CNS of patients with multiple sclerosis produce CSF immunoglobulin. Journal Of Neuroimmunology 2011, 233: 245-248. PMID: 21353315, PMCID: PMC3090654, DOI: 10.1016/j.jneuroim.2011.01.010.Peer-Reviewed Original Research
2009
Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid
Owens GP, Bennett JL, Lassmann H, O'Connor KC, Ritchie AM, Shearer A, Lam C, Yu X, Birlea M, DuPree C, Williamson RA, Hafler DA, Burgoon MP, Gilden D. Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid. Annals Of Neurology 2009, 65: 639-649. PMID: 19557869, PMCID: PMC2843543, DOI: 10.1002/ana.21641.Peer-Reviewed Original ResearchConceptsMS cerebrospinal fluidMyelin oligodendrocyte glycoproteinMultiple sclerosisCerebrospinal fluidMyelin basic proteinMyelin antigensOligodendrocyte glycoproteinMultiple sclerosis cerebrospinal fluidOligoclonal B cell responseB cell clonal expansionIntrathecal IgG synthesisB cell responsesPlasma cell cloneB lymphocyte clonesHuman brain tissue sectionsTissue sectionsProteolipid proteinIndividual myelin proteinsBasic proteinBrain tissue sectionsIgG synthesisInflammatory cellsHumoral responseControl brainsPlasma cells
2006
Dysregulated T cell expression of TIM3 in multiple sclerosis
Koguchi K, Anderson DE, Yang L, O'Connor KC, Kuchroo VK, Hafler DA. Dysregulated T cell expression of TIM3 in multiple sclerosis. Journal Of Experimental Medicine 2006, 203: 1413-1418. PMID: 16754722, PMCID: PMC2118310, DOI: 10.1084/jem.20060210.Peer-Reviewed Original ResearchConceptsIFN-gamma secretionCSF clonesT cell expressionMultiple sclerosisT cellsHuman T cellsTIM3 expressionControl subjectsCerebrospinal fluidCell expressionMucin-domain-containing moleculesPathogenesis of MSEx vivo CD4Human autoimmune diseasesT helper cellsT-cell immunoglobulinT cell clonesVivo CD4Costimulatory blockadeTh1 responseCytokine profileCell surface moleculesAutoimmune diseasesHelper cellsInterleukin-12
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
1995
Increased frequency of gamma delta T cells in cerebrospinal fluid and peripheral blood of patients with multiple sclerosis. Reactivity, cytotoxicity, and T cell receptor V gene rearrangements.
Stinissen P, Vandevyver C, Medaer R, Vandegaer L, Nies J, Tuyls L, Hafler DA, Raus J, Zhang J. Increased frequency of gamma delta T cells in cerebrospinal fluid and peripheral blood of patients with multiple sclerosis. Reactivity, cytotoxicity, and T cell receptor V gene rearrangements. The Journal Of Immunology 1995, 154: 4883-94. PMID: 7722338, DOI: 10.4049/jimmunol.154.9.4883.Peer-Reviewed Original ResearchConceptsGamma delta T cell clonesGamma delta T cellsDelta T cellsT cell clonesGamma delta clonesMultiple sclerosisPeripheral bloodT cellsCerebrospinal fluidMS patientsOND patientsCell clonesControl subjectsNormal individualsBacterial superantigen staphylococcal enterotoxin BCentral nervous system demyelinationCSF of patientsSuperantigen staphylococcal enterotoxin BToxic shock syndrome toxin-1Nervous system demyelinationClonal originSecondary inflammatory processesV gene usageSyndrome toxin-1Staphylococcal enterotoxin B
1994
Increased frequency of interleukin 2-responsive T cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis.
Zhang J, Markovic-Plese S, Lacet B, Raus J, Weiner HL, Hafler DA. Increased frequency of interleukin 2-responsive T cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis. Journal Of Experimental Medicine 1994, 179: 973-984. PMID: 7509366, PMCID: PMC2191414, DOI: 10.1084/jem.179.3.973.Peer-Reviewed Original ResearchConceptsMyelin-reactive T cellsFrequency of MBPMBP-reactive T cell linesMBP-reactive T cellsMyelin basic proteinT cellsCerebrospinal fluidT cell linesMS patientsProteolipid proteinPLP-reactive T cellsNormal individualsFrequency of interleukinAutoreactive T cellsPathogenesis of MSMultiple sclerosis patientsIL-2-responsive cellsRIL-2 stimulationCentral nervous systemCell linesBasic proteinSclerosis patientsMultiple sclerosisPeripheral bloodPathogenic role
1992
T cell vaccination in multiple sclerosis: A preliminary report
Hafler D, Cohen I, Benjamin D, Weiner H. T cell vaccination in multiple sclerosis: A preliminary report. Clinical Immunology 1992, 62: 307-313. PMID: 1541056, DOI: 10.1016/0090-1229(92)90108-z.Peer-Reviewed Original ResearchConceptsT cell clonesMultiple sclerosisAutoimmune diseasesCell clonesAutologous T cell clonesAutoreactive T cell clonesAutologous mixed lymphocyte responseProgressive multiple sclerosisExperimental autoimmune diseasesT cell vaccinationFurther clinical trialsMixed lymphocyte responseUntoward side effectsCentral nervous systemPhase one trialsCell vaccinationMyelin autoantigensImmunologic effectsLymphocyte responsesClinical trialsImmunologic studiesAutoreactive clonesCerebrospinal fluidSide effectsNervous systemAutoreactive T Cells in Multiple Sclerosis
Zhang J, Weiner H, Hafler D. Autoreactive T Cells in Multiple Sclerosis. International Reviews Of Immunology 1992, 9: 183-201. PMID: 1285060, DOI: 10.3109/08830189209061790.Peer-Reviewed Original ResearchConceptsCentral nervous systemMultiple sclerosisInflammatory processT cellsCerebrospinal fluidNervous systemAcute MS plaquesActive inflammatory processAutoreactive T cellsChronic inflammatory diseaseCNS inflammatory processesIL-2 receptorPeripheral nervous systemActivated T cellsNeurologic disabilityNeurological functionMS plaquesSensory deficitsInflammatory diseasesOligoclonal immunoglobulinsPositive macrophagesT lymphocytesWhite matterVisual problemsDemyelination
1991
Common T‐cell receptor Vβ usage in oligoclonal T lymphocytes derived from cerebrospinal fluid and blood of patients with multiple sclerosis
Lee S, Wucherpfennig K, Brod S, Benjamin D, Weiner H, Hafler D. Common T‐cell receptor Vβ usage in oligoclonal T lymphocytes derived from cerebrospinal fluid and blood of patients with multiple sclerosis. Annals Of Neurology 1991, 29: 33-40. PMID: 1847614, DOI: 10.1002/ana.410290109.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAgedBase SequenceBlotting, SouthernChild, PreschoolClone CellsDNA ProbesFemaleGene Rearrangement, beta-Chain T-Cell Antigen ReceptorGene Rearrangement, gamma-Chain T-Cell Antigen ReceptorHumansMaleMiddle AgedMolecular Sequence DataMultiple SclerosisPhenotypePolymerase Chain ReactionT-LymphocytesConceptsT cell populationsT cell clonesCerebrospinal fluidMultiple sclerosisT cellsT cell receptor Vβ usageNeurological diseasesOligoclonal T-cell populationsT cell receptor V beta genesOligoclonal T lymphocytesOligoclonal T cellsSame T cell receptorBlood of patientsNormal control subjectsT cell receptor beta chainProgenitor T cellsT cell receptorIndividual T cellsGamma chain geneImmune compartmentVβ usageControl subjectsReceptor beta chainT lymphocytesPatients