2024
Single-Cell Transcriptomic Analyses of Brain Parenchyma in Patients With New-Onset Refractory Status Epilepticus (NORSE)
Hanin A, Zhang L, Huttner A, Plu I, Mathon B, Bielle F, Navarro V, Hirsch L, Hafler D. Single-Cell Transcriptomic Analyses of Brain Parenchyma in Patients With New-Onset Refractory Status Epilepticus (NORSE). Neurology Neuroimmunology & Neuroinflammation 2024, 11: e200259. PMID: 38810181, PMCID: PMC11139018, DOI: 10.1212/nxi.0000000000200259.Peer-Reviewed Original ResearchConceptsNew-onset refractory status epilepticusTemporal lobe epilepsyGABAergic neuronsExcitatory neuronsInfiltrating macrophagesProportion of GABAergic neuronsChronic temporal lobe epilepsyRefractory status epilepticusInhibitory GABAergic neuronsSingle-cell transcriptome analysisDecreased expression of genesDegree of demyelinationImmune disturbancesNeuronal excitabilityImmune dysregulationNew-onsetStatus epilepticusPoor outcomeRefractory epilepsyHealthy childrenMicroglial reactivitySingle-nucleus RNA sequencingNLRP3 inflammasome activationInflammatory responseLobe epilepsy
2022
Dissection of artifactual and confounding glial signatures by single-cell sequencing of mouse and human brain
Marsh SE, Walker AJ, Kamath T, Dissing-Olesen L, Hammond TR, de Soysa TY, Young AMH, Murphy S, Abdulraouf A, Nadaf N, Dufort C, Walker AC, Lucca LE, Kozareva V, Vanderburg C, Hong S, Bulstrode H, Hutchinson PJ, Gaffney DJ, Hafler DA, Franklin RJM, Macosko EZ, Stevens B. Dissection of artifactual and confounding glial signatures by single-cell sequencing of mouse and human brain. Nature Neuroscience 2022, 25: 306-316. PMID: 35260865, DOI: 10.1038/s41593-022-01022-8.Peer-Reviewed Original ResearchConceptsSingle-cell sequencing experimentsCell type diversitySingle-cell sequencingRNA-sequencing datasetsGene expression changesGene expression signaturesVivo gene expressionTranscriptional profilesGene expressionExpression changesSequencing experimentsGlial signaturesDownstream analysisExpression signaturesTissue typesSingle cell suspensionsOptimal cell yieldIntact tissueHuman tissuesCell yieldEnzymatic dissociationHuman samplesTissue digestionPostmortem human samplesTissue
2021
NEBULA is a fast negative binomial mixed model for differential or co-expression analysis of large-scale multi-subject single-cell data
He L, Davila-Velderrain J, Sumida TS, Hafler DA, Kellis M, Kulminski AM. NEBULA is a fast negative binomial mixed model for differential or co-expression analysis of large-scale multi-subject single-cell data. Communications Biology 2021, 4: 629. PMID: 34040149, PMCID: PMC8155058, DOI: 10.1038/s42003-021-02146-6.Peer-Reviewed Original ResearchConceptsNegative binomial mixed modelsBinomial mixed modelsSingle-cell dataHigh-dimensional integralsLarge sample approximationLaplace approximationCell-level expressionMixed modelsApproximationNebulaSpeed gainData setsOrders of magnitudeMarker gene identificationIntegralsModelOverdispersionFalse positive errors
2019
Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility
Patsopoulos N, Baranzini S, Santaniello A, Shoostari P, Cotsapas C, Wong G, Beecham A, James T, Replogle J, Vlachos I, McCabe C, Pers T, Brandes A, White C, Keenan B, Cimpean M, Winn P, Panteliadis I, Robbins A, Andlauer T, Zarzycki O, Dubois B, Goris A, Søndergaard H, Sellebjerg F, Sorensen P, Ullum H, Thørner L, Saarela J, Cournu-Rebeix I, Damotte V, Fontaine B, Guillot-Noel L, Lathrop M, Vukusic S, Berthele A, Pongratz V, Buck D, Gasperi C, Graetz C, Grummel V, Hemmer B, Hoshi M, Knier B, Korn T, Lill C, Luessi F, Mühlau M, Zipp F, Dardiotis E, Agliardi C, Amoroso A, Barizzone N, Benedetti M, Bernardinelli L, Cavalla P, Clarelli F, Comi G, Cusi D, Esposito F, Ferrè L, Galimberti D, Guaschino C, Leone M, Martinelli V, Moiola L, Salvetti M, Sorosina M, Vecchio D, Zauli A, Santoro S, Mancini N, Zuccalà M, Mescheriakova J, van Duijn C, Bos S, Celius E, Spurkland A, Comabella M, Montalban X, Alfredsson L, Bomfim I, Gomez-Cabrero D, Hillert J, Jagodic M, Lindén M, Piehl F, Jelčić I, Martin R, Sospedra M, Baker A, Ban M, Hawkins C, Hysi P, Kalra S, Karpe F, Khadake J, Lachance G, Molyneux P, Neville M, Thorpe J, Bradshaw E, Caillier S, Calabresi P, Cree B, Cross A, Davis M, de Bakker P, Delgado S, Dembele M, Edwards K, Fitzgerald K, Frohlich I, Gourraud P, Haines J, Hakonarson H, Kimbrough D, Isobe N, Konidari I, Lathi E, Lee M, Li T, An D, Zimmer A, Madireddy L, Manrique C, Mitrovic M, Olah M, Patrick E, Pericak-Vance M, Piccio L, Schaefer C, Weiner H, Lage K, Compston A, Hafler D, Harbo H, Hauser S, Stewart G, D’Alfonso S, Hadjigeorgiou G, Taylor B, Barcellos L, Booth D, Hintzen R, Kockum I, Martinelli-Boneschi F, McCauley J, Oksenberg J, Oturai A, Sawcer S, Ivinson A, Olsson T, De Jager P. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science 2019, 365 PMID: 31604244, PMCID: PMC7241648, DOI: 10.1126/science.aav7188.Peer-Reviewed Original ResearchMeSH KeywordsCase-Control StudiesCell Cycle ProteinsChromosome MappingChromosomes, Human, XGene FrequencyGenetic LociGenome-Wide Association StudyGenomicsGTPase-Activating ProteinsHumansInheritance PatternsMajor Histocompatibility ComplexMicrogliaMultiple SclerosisPolymorphism, Single NucleotideQuantitative Trait LociRNA-SeqTranscriptomeConceptsMajor histocompatibility complexMultiple sclerosisImmune cellsBrain-resident immune cellsPeripheral immune cellsPeripheral immune responseCentral nervous systemExtended major histocompatibility complexAutoimmune processControl subjectsHuman microgliaImmune responseNervous systemImmune systemHistocompatibility complexPutative susceptibility genesMicrogliaX variantGenetic architectureSusceptibility genesGenomic mapGenetic dataExpression profilesM geneSusceptibility variants
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
2016
TGF-β1 modulates microglial phenotype and promotes recovery after intracerebral hemorrhage
Taylor RA, Chang CF, Goods BA, Hammond MD, Mac Grory B, Ai Y, Steinschneider AF, Renfroe SC, Askenase MH, McCullough LD, Kasner SE, Mullen MT, Hafler DA, Love JC, Sansing LH. TGF-β1 modulates microglial phenotype and promotes recovery after intracerebral hemorrhage. Journal Of Clinical Investigation 2016, 127: 280-292. PMID: 27893460, PMCID: PMC5199690, DOI: 10.1172/jci88647.Peer-Reviewed Original ResearchConceptsIntracerebral hemorrhageTGF-β1 treatmentTGF-β1Functional recoveryBrain injuryMurine modelPlasma TGF-β1 concentrationResolution phasePhenotype of microgliaTissue-resident microgliaAcute brain injuryBlood-derived macrophagesTGF-β1 concentrationsRapid inflammatory reactionIL6 gene expressionLongitudinal transcriptional profilingInflammatory profileMicroglial phenotypeFunctional outcomeBrain parenchymaInflammatory reactionPromotes recoveryMicrogliaTherapeutic targetDevastating form
2007
Promotion of Tissue Inflammation by the Immune Receptor Tim-3 Expressed on Innate Immune Cells
Anderson AC, Anderson DE, Bregoli L, Hastings WD, Kassam N, Lei C, Chandwaskar R, Karman J, Su EW, Hirashima M, Bruce JN, Kane LP, Kuchroo VK, Hafler DA. Promotion of Tissue Inflammation by the Immune Receptor Tim-3 Expressed on Innate Immune Cells. Science 2007, 318: 1141-1143. PMID: 18006747, DOI: 10.1126/science.1148536.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAstrocytesCD11b AntigenCentral Nervous System NeoplasmsDendritic CellsEncephalomyelitis, Autoimmune, ExperimentalGalectinsGlioblastomaHepatitis A Virus Cellular Receptor 2HumansImmunity, InnateInflammation MediatorsLipopolysaccharidesMacrophagesMembrane ProteinsMiceMicrogliaMultiple SclerosisRatsReceptors, ImmunologicReceptors, VirusSignal TransductionTh1 CellsT-LymphocytesToll-Like ReceptorsConceptsImmune receptor Tim-3Tim-3Immune cellsT helper 1 cellsAdaptive immune cellsInnate immune cellsToll-like receptorsInduced Immune ResponsesInnate immune systemTh1 immunityDendritic cellsTissue inflammationInflammatory conditionsT cellsImmune responseImmune systemImportant mediatorAntibody agonistsInflammationCell typesLatter findingNumerous pathwaysCellsDifferential expressionCD4
1999
The distinction blurs between an autoimmune versus microbial hypothesis in multiple sclerosis
Hafler DA. The distinction blurs between an autoimmune versus microbial hypothesis in multiple sclerosis. Journal Of Clinical Investigation 1999, 104: 527-529. PMID: 10487765, PMCID: PMC483283, DOI: 10.1172/jci8193.Peer-Reviewed Original ResearchAnimalsAntigen PresentationAntigens, ViralAutoantigensAutoimmune DiseasesCardiovirus InfectionsCross ReactionsDemyelinating DiseasesDisease Models, AnimalDisease ProgressionEncephalomyelitis, Autoimmune, ExperimentalEpitopesHuman T-lymphotropic virus 1HumansMiceMicrogliaModels, ImmunologicalMolecular MimicryMultiple SclerosisMyelin ProteinsParaparesis, Tropical SpasticTheilovirusT-Lymphocyte SubsetsVirus Diseases
1997
Constitutive expression of costimulatory molecules by human microglia and its relevance to CNS autoimmunity
Dangond F, Windhagen A, Groves C, Hafler D. Constitutive expression of costimulatory molecules by human microglia and its relevance to CNS autoimmunity. Journal Of Neuroimmunology 1997, 76: 132-138. PMID: 9184642, DOI: 10.1016/s0165-5728(97)00043-x.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAutoimmunityB7-1 AntigenBrainCells, CulturedChild, PreschoolFemaleHumansMaleMicrogliaConceptsCentral nervous systemCostimulatory moleculesHuman microgliaMyelin-reactive T cellsTh1 T cell responsesExpression of B7.1Reactive T cellsT cell responsesMultiple sclerosis plaquesT cell surface moleculesB7.2 costimulatory moleculesMHC-antigen complexesT cell activationT cell receptorCNS autoimmunityCNS inflammationB7.2 expressionBiopsy specimensB7 familyT cellsNormal brainMicrogliaNervous systemB7.1High expression