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
2018
Activated β-catenin in Foxp3+ regulatory T cells links inflammatory environments to autoimmunity
Sumida T, Lincoln MR, Ukeje CM, Rodriguez DM, Akazawa H, Noda T, Naito AT, Komuro I, Dominguez-Villar M, Hafler DA. Activated β-catenin in Foxp3+ regulatory T cells links inflammatory environments to autoimmunity. Nature Immunology 2018, 19: 1391-1402. PMID: 30374130, PMCID: PMC6240373, DOI: 10.1038/s41590-018-0236-6.Peer-Reviewed Original ResearchConceptsProstaglandin E receptor 2Regulatory T cellsTreg cellsT cellsAnti-inflammatory cytokine productionIL-10 productionPeripheral immune toleranceIL-10 expressionΒ-cateninE receptor 2Treg subpopulationsTreg phenotypeIL-10Cytokines IFNImmune toleranceTreg signatureCytokine signatureMultiple sclerosisAutoimmune diseasesCytokine productionInflammatory environmentLethal autoimmunityReceptor 2Activated β-cateninIFNSingle-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
2017
Podoplanin is a negative regulator of Th17 inflammation
Nylander AN, Ponath GD, Axisa PP, Mubarak M, Tomayko M, Kuchroo VK, Pitt D, Hafler DA. Podoplanin is a negative regulator of Th17 inflammation. JCI Insight 2017, 2: e92321. PMID: 28878118, PMCID: PMC5621890, DOI: 10.1172/jci.insight.92321.Peer-Reviewed Original ResearchConceptsT cellsIL-17IL-17 secretionDistinct cytokine profilesInflammatory gene signatureTh17-polarizing conditionsTh17 cellsCytokine profileCell subsetsInflammatory responseSkin biopsiesMouse modelPDPN expressionMultiple organsSkin diseasesGene signatureInflammationLymphatic systemCLEC-2PDPNRecent dataDifferent subpopulationsCellsTranscriptional profilesShRNA gene
2015
Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cells
Hernandez AL, Kitz A, Wu C, Lowther DE, Rodriguez DM, Vudattu N, Deng S, Herold KC, Kuchroo VK, Kleinewietfeld M, Hafler DA. Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cells. Journal Of Clinical Investigation 2015, 125: 4212-4222. PMID: 26524592, PMCID: PMC4639983, DOI: 10.1172/jci81151.Peer-Reviewed Original ResearchMeSH KeywordsAdoptive TransferAnimalsAntibodies, NeutralizingAutoimmunityCD4-Positive T-LymphocytesCells, CulturedCoculture TechniquesColitisCytokinesForkhead Transcription FactorsGene Expression ProfilingGenes, ReporterGraft vs Host DiseaseHeterograftsHumansImmediate-Early ProteinsInflammationInterferon-gammaLeukocytes, MononuclearMaleMiceProtein Serine-Threonine KinasesRNA InterferenceRNA, Small InterferingSodium ChlorideSodium Chloride, DietaryT-Lymphocytes, RegulatoryConceptsHigh-salt dietTreg functionIFNγ secretionCD4 effector cellsHuman Treg functionRegulatory T cellsAdoptive transfer modelAnti-IFNγ antibodyHost disease modelType 1 diabetesInduction of proinflammatoryTreg pathwayExperimental colitisXenogeneic graftEffector cellsMultiple sclerosisProinflammatory responseT cellsTregsMurine modelSuppressive activitySuppressive functionSerum/glucocorticoid-regulated kinaseAutoimmunityGlucocorticoid-regulated kinaseGenetic variants associated with autoimmunity drive NFκB signaling and responses to inflammatory stimuli
Housley WJ, Fernandez SD, Vera K, Murikinati SR, Grutzendler J, Cuerdon N, Glick L, De Jager PL, Mitrovic M, Cotsapas C, Hafler DA. Genetic variants associated with autoimmunity drive NFκB signaling and responses to inflammatory stimuli. Science Translational Medicine 2015, 7: 291ra93. PMID: 26062845, PMCID: PMC4574294, DOI: 10.1126/scitranslmed.aaa9223.Peer-Reviewed Original ResearchMeSH KeywordsAge FactorsAllelesAutoimmunityCase-Control StudiesCD4-Positive T-LymphocytesCell NucleusCytokinesFemaleGenetic Predisposition to DiseaseHumansInflammationMaleMiddle AgedMultiple SclerosisNF-kappa BPolymorphism, Single NucleotideProtein TransportReceptors, Tumor Necrosis Factor, Type IRisk FactorsSex CharacteristicsSignal TransductionTime FactorsTumor Necrosis Factor-alphaConceptsB-cell leukemia 3Multiple sclerosisNegative regulatorInflammatory stimuliGenetic variantsWide association studyDisease susceptibility variantsNaïve CD4 T cellsRapid genetic screeningCD4 T cellsActivation of p65Transcription factor nuclear factor κBExpression of NFκBNuclear factor κBApoptosis 1Cellular inhibitorGG risk genotypeDegradation of inhibitorCentral regulatorAssociation studiesCytokine blockadeUlcerative colitisAutoimmune diseasesTumor necrosisSusceptibility variantsFunctional inflammatory profiles distinguish myelin-reactive T cells from patients with multiple sclerosis
Cao Y, Goods BA, Raddassi K, Nepom GT, Kwok WW, Love JC, Hafler DA. Functional inflammatory profiles distinguish myelin-reactive T cells from patients with multiple sclerosis. Science Translational Medicine 2015, 7: 287ra74. PMID: 25972006, PMCID: PMC4497538, DOI: 10.1126/scitranslmed.aaa8038.Peer-Reviewed Original ResearchConceptsMyelin-reactive T cellsMultiple sclerosisT cellsHealthy controlsT cell librariesT helper cell 17Antigen-specific T cellsGene signatureMore IL-10More proinflammatory cytokinesAutoreactive T cellsIL-10 productionHuman autoimmune diseasesGranulocyte-macrophage colony-stimulating factorProduction of interferonColony-stimulating factorMyelin antigensTh17 cellsIL-10Inflammatory profileInterleukin-17Proinflammatory cytokinesAutoimmune diseasesDisease progressionHealthy subjects
2013
Role of “Western Diet” in Inflammatory Autoimmune Diseases
Manzel A, Muller DN, Hafler DA, Erdman SE, Linker RA, Kleinewietfeld M. Role of “Western Diet” in Inflammatory Autoimmune Diseases. Current Allergy And Asthma Reports 2013, 14: 404. PMID: 24338487, PMCID: PMC4034518, DOI: 10.1007/s11882-013-0404-6.Peer-Reviewed Original ResearchConceptsAutoimmune diseasesWestern dietInflammatory autoimmune diseaseExcess salt intakeImmunologic mechanismsMetabolic syndromeSalt intakeAutoimmune pathologyCardiovascular diseaseT cellsWesternized countriesFrequent consumptionDietary influencesInfectious diseasesDiseaseNutritional patternsFast foodPathogen exposureDietCurrent knowledgeCentral playerAutoimmunityObesitySyndromeCholesterolThe CD226/CD155 Interaction Regulates the Proinflammatory (Th1/Th17)/Anti-Inflammatory (Th2) Balance in Humans
Lozano E, Joller N, Cao Y, Kuchroo VK, Hafler DA. The CD226/CD155 Interaction Regulates the Proinflammatory (Th1/Th17)/Anti-Inflammatory (Th2) Balance in Humans. The Journal Of Immunology 2013, 191: 3673-3680. PMID: 23980210, PMCID: PMC3819731, DOI: 10.4049/jimmunol.1300945.Peer-Reviewed Original ResearchConceptsNaive T cellsT cellsInflammatory balanceIL-13IL-17-producing cellsRole of CD226IL-17 productionIL-17 secretionHuman autoimmune diseasesIFN-γ productionIL-13 secretionIFN-γ expressionProduction of IFNSTAT-6 phosphorylationT cell activationHuman T cellsLigand CD155Th17 cellsIL-17Autoimmune diseasesIL-4T-betTh1 differentiationTh17 conditionsTherapeutic approaches
2012
Induction and molecular signature of pathogenic TH17 cells
Lee Y, Awasthi A, Yosef N, Quintana FJ, Xiao S, Peters A, Wu C, Kleinewietfeld M, Kunder S, Hafler DA, Sobel RA, Regev A, Kuchroo VK. Induction and molecular signature of pathogenic TH17 cells. Nature Immunology 2012, 13: 991-999. PMID: 22961052, PMCID: PMC3459594, DOI: 10.1038/ni.2416.Peer-Reviewed Original Research
2007
Protective and therapeutic role for αB-crystallin in autoimmune demyelination
Ousman SS, Tomooka BH, van Noort JM, Wawrousek EF, O’Conner K, Hafler DA, Sobel RA, Robinson WH, Steinman L. Protective and therapeutic role for αB-crystallin in autoimmune demyelination. Nature 2007, 448: 474-479. PMID: 17568699, DOI: 10.1038/nature05935.Peer-Reviewed Original Research
2006
Comprehensive Phenotyping in Multiple Sclerosis: Discovery Based Proteomics and the Current Understanding of Putative Biomarkers
O’Connor K, Roy SM, Becker CH, Hafler DA, Kantor AB. Comprehensive Phenotyping in Multiple Sclerosis: Discovery Based Proteomics and the Current Understanding of Putative Biomarkers. Disease Markers 2006, 22: 213-225. PMID: 17124343, PMCID: PMC3851054, DOI: 10.1155/2006/670439.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsMeSH KeywordsAutoantibodiesBiomarkersHumansInflammationMultiple SclerosisNeurodegenerative DiseasesPhenotypeProteomicsConceptsMultiple sclerosisMagnetic resonance imagingPutative biomarkersComprehensive phenotypingMonitoring of progressionComponent expression levelsClinical evaluationCSF proteinAccurate biomarkersCerebrospinal fluid chemistryControl groupTherapeutic interventionsPatient careAccurate diagnosisResonance imagingDisease pathologyFurther evaluationBiomarkersPreliminary dataExpression levelsSclerosisDiagnosisCSFSingle testNovel assessment
2005
Evaluating the role of the 620W allele of protein tyrosine phosphatase PTPN22 in Crohn's disease and multiple sclerosis
De Jager PL, Sawcer S, Waliszewska A, Farwell L, Wild G, Cohen A, Langelier D, Bitton A, Compston A, Hafler DA, Rioux JD. Evaluating the role of the 620W allele of protein tyrosine phosphatase PTPN22 in Crohn's disease and multiple sclerosis. European Journal Of Human Genetics 2005, 14: 317-321. PMID: 16391555, DOI: 10.1038/sj.ejhg.5201548.Peer-Reviewed Original ResearchMeSH KeywordsAllelesCanadaCase-Control StudiesCrohn DiseaseGene FrequencyGenetic Predisposition to DiseaseGenotypeHumansInflammationModels, StatisticalMultiple SclerosisOdds RatioPolymorphism, GeneticProtein Tyrosine Phosphatase, Non-Receptor Type 1Protein Tyrosine Phosphatase, Non-Receptor Type 22Protein Tyrosine PhosphatasesRiskUnited KingdomConceptsSystemic lupus erythematosusCases of CDCrohn's diseaseMultiple sclerosisPTPN22 620W alleleAutoimmune thyroiditisRheumatoid arthritisInflammatory diseasesEvidence of associationCases of MSProtein tyrosine phosphatase PTPN22Chronic inflammatory diseaseType 1 diabetesTyrosine phosphatase PTPN22PTPN22 alleleLupus erythematosusPooled analysisControl subjectsModest odds ratiosOdds ratioDiseaseRisk allelesPhosphatase PTPN22SclerosisPossible roleApplying a new generation of genetic maps to understand human inflammatory disease
Hafler DA, Jager P. Applying a new generation of genetic maps to understand human inflammatory disease. Nature Reviews Immunology 2005, 5: 83-91. PMID: 15630431, DOI: 10.1038/nri1532.Peer-Reviewed Original Research
2003
Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the target organ of patients with rheumatoid arthritis
Cao D, Malmström V, Baecher‐Allan C, Hafler D, Klareskog L, Trollmo C. Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the target organ of patients with rheumatoid arthritis. European Journal Of Immunology 2003, 33: 215-223. PMID: 12594850, DOI: 10.1002/immu.200390024.Peer-Reviewed Original ResearchConceptsT cellsRegulatory cellsRheumatoid arthritisSynovial fluidTarget organsSuch regulatory T cellsFunctional regulatory cellsInflamed knee jointsPathological T cellsActive rheumatoid arthritisAutologous T cellsRegulatory T cellsExperimental animal modelsPeripheral blood originAutoimmune manifestationsRA patientsAutoimmune diseasesPeripheral bloodSame patientAnimal modelsPatientsKnee jointBlood originDiseaseArthritis
2000
Enhanced B7 costimulatory molecule expression in inflammatory human sural nerve biopsies
Kiefer R, Dangond F, Mueller M, Toyka KV, Hafler DA, Hartung HP. Enhanced B7 costimulatory molecule expression in inflammatory human sural nerve biopsies. Journal Of Neurology Neurosurgery & Psychiatry 2000, 69: 362. PMID: 10945811, PMCID: PMC1737105, DOI: 10.1136/jnnp.69.3.362.Peer-Reviewed Original ResearchConceptsChronic inflammatory demyelinating polyneuropathyGuillain-Barré syndromeSural nerve biopsyPeripheral nervous systemB7-1Nerve biopsyB7-2 mRNAB7 moleculesPolymerase chain reactionB7-2Nervous systemCases of GBSNon-inflammatory control groupCostimulatory molecules B7-1B7-1 mRNANon-inflammatory controlsTh-2 phenotypeInflammatory demyelinating polyneuropathyB7-1 proteinCostimulatory molecule expressionT cell responsesEffective antigen presentationCases of neuroborreliosisHuman sural nerve biopsiesCIDP cases
1994
T cell anergy
Lasalle J, Hafler D. T cell anergy. The FASEB Journal 1994, 8: 601-608. PMID: 8005388, DOI: 10.1096/fasebj.8.9.8005388.Peer-Reviewed Original ResearchConceptsImmunologic self toleranceAutoreactive T cellsT cell anergyMHC class IIT cellsClonal anergyT cell presentationT cell clonal anergySelf antigensCell anergySelf toleranceCell presentationClass IIAutologous T cellsAbsence of costimulationHuman T cellsSecondary unresponsivenessHigh extracellular concentrationsAntigenic stimulationAntigen presentationAntigen resultsAnergyPrimary proliferationPeptide antigensAntigen
1991
Restricted T cell expression of IL-2/IFN-gamma mRNA in human inflammatory disease.
Brod SA, Benjamin D, Hafler DA. Restricted T cell expression of IL-2/IFN-gamma mRNA in human inflammatory disease. The Journal Of Immunology 1991, 147: 810-5. PMID: 1907306, DOI: 10.4049/jimmunol.147.3.810.Peer-Reviewed Original ResearchConceptsPeripheral bloodCSF of subjectsIL-5 mRNAT cell clonesIFN-gamma mRNAIL-4Inflammatory diseasesIFN-gammaIL-2Systemic inflammationT cellsTh1 T cell clonesTh2-type T cellsT cell cytokine profilesIL-2/ILDistinct T cell populationsCell clonesT cell populationsT cell expressionType T cellsTNF-alpha mRNAHuman inflammatory diseasesIL-2 mRNACytokine profileImmune compartment
1989
Inflammatory cerebrospinal fluid t cells have activation requirements characteristic of cd4+cd45ra‐ t cells
Chofflon M, González V, Weiner H, Hafler D. Inflammatory cerebrospinal fluid t cells have activation requirements characteristic of cd4+cd45ra‐ t cells. European Journal Of Immunology 1989, 19: 1791-1795. PMID: 2479560, DOI: 10.1002/eji.1830191005.Peer-Reviewed Original ResearchConceptsCSF T cellsPhorbol myristate acetateMononuclear cellsCSF mononuclear cellsT cellsCerebrospinal fluidCerebrospinal fluid T cellsCSF of subjectsProtein kinase CCD3/T cell receptor complexInflammatory brain diseasesBlood mononuclear cellsT cell populationsSorted T cellsInterleukin-2 receptorInterleukin-2 secretionCD2 activation pathwayT cell receptor complexKinase CInflammatory compartmentMultiple sclerosisCNS diseaseCell receptor complexImmune responseNormal subjects
1987
T Cells in Multiple Sclerosis and Inflammatory Central Nervous System Diseases
Hafler D, Weiner H. T Cells in Multiple Sclerosis and Inflammatory Central Nervous System Diseases. Immunological Reviews 1987, 100: 307-332. PMID: 3326824, DOI: 10.1111/j.1600-065x.1987.tb00537.x.Peer-Reviewed Original ResearchConceptsT cellsInflammatory responseCNS tissueInflammatory central nervous system diseasesProgressive multiple sclerosis patientsCentral nervous system diseaseClass II MHC antigensMonoclonal antibodiesT-cell receptor gene rearrangementsCSF T cellsOngoing inflammatory responseTotal T cellsInflammatory CNS diseaseMultiple sclerosis patientsAntigen-presenting cellsAnti-measles antibodiesChronic disease processesAntigen-specific cellsNervous system diseasesReceptor gene rearrangementsMurine monoclonal antibodiesSelective accumulationAlpha beta chainsCNS damageSclerosis patients