2024
Single-cell transcriptomic and proteomic analysis of Parkinson’s disease brains
Zhu B, Park J, Coffey S, Russo A, Hsu I, Wang J, Su C, Chang R, Lam T, Gopal P, Ginsberg S, Zhao H, Hafler D, Chandra S, Zhang L. Single-cell transcriptomic and proteomic analysis of Parkinson’s disease brains. Science Translational Medicine 2024, 16: eabo1997. PMID: 39475571, DOI: 10.1126/scitranslmed.abo1997.Peer-Reviewed Original ResearchConceptsProteomic analysisAlzheimer's diseasePrefrontal cortexBrain cell typesGenetics of PDParkinson's diseaseCell-cell interactionsChaperone expressionSingle-nucleus transcriptomesExpressed genesTranscriptional changesPostmortem human brainPostmortem brain tissueDiseased brainSynaptic proteinsSingle-cellDown-regulationBrain cell populationsBrain regionsCell typesNeurodegenerative disordersLate-stage PDParkinson's disease brainsDisease etiologyNeuronal vulnerabilitySingle-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
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 signsCirculating clonally expanded T cells reflect functions of tumor-infiltrating T cells
Lucca LE, Axisa PP, Lu B, Harnett B, Jessel S, Zhang L, Raddassi K, Zhang L, Olino K, Clune J, Singer M, Kluger HM, Hafler DA. Circulating clonally expanded T cells reflect functions of tumor-infiltrating T cells. Journal Of Experimental Medicine 2021, 218: e20200921. PMID: 33651881, PMCID: PMC7933991, DOI: 10.1084/jem.20200921.Peer-Reviewed Original ResearchConceptsTumor-infiltrating T cellsT cellsUnique transcriptional patternsFeatures of exhaustionLongitudinal immune monitoringPeripheral immune environmentsT cell responsesT cell functionSingle-cell levelTranscriptional patternsTCR sharingTerminal exhaustionImmune environmentImmune monitoringCancer immunotherapyMetastatic melanomaEffector functionsCell responsesTumor tissueGene signatureTumorsCell functionImmunotherapyTCRαβBlood
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 ResearchMeSH KeywordsAdultCentral Nervous SystemHumansMultiple Sclerosis, Relapsing-RemittingT-LymphocytesTranscriptomeConceptsCentral 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
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
2016
AKT isoforms modulate Th1‐like Treg generation and function in human autoimmune disease
Kitz A, de Marcken M, Gautron AS, Mitrovic M, Hafler DA, Dominguez-Villar M. AKT isoforms modulate Th1‐like Treg generation and function in human autoimmune disease. EMBO Reports 2016, 17: 1169-1183. PMID: 27312110, PMCID: PMC4967959, DOI: 10.15252/embr.201541905.Peer-Reviewed Original ResearchMeSH KeywordsAutoimmune DiseasesBiomarkersCell DifferentiationCytokinesForkhead Transcription FactorsGene Expression ProfilingGene SilencingHumansImmunomodulationInterferon-gammaPhenotypePhosphatidylinositol 3-KinasesProtein IsoformsProto-Oncogene Proteins c-aktSignal TransductionT-Lymphocyte SubsetsT-Lymphocytes, RegulatoryTranscriptomeConceptsAutoimmune diseasesIFNγ secretionHuman TregsGenome-wide gene expression approachUntreated relapsing-remitting MS patientsRelapsing-remitting MS patientsImmune suppressive functionHuman autoimmune diseasesT helper 1Inflammatory cytokines IFNγTreg suppressor functionNovel treatment paradigmEffector phenotypeMS patientsTreg generationCytokines IFNγHelper 1Multiple sclerosisTreatment paradigmSuppressive functionTregsVivo modelDiseaseSecretionSuppressor function
2014
Polarization of the Effects of Autoimmune and Neurodegenerative Risk Alleles in Leukocytes
Raj T, Rothamel K, Mostafavi S, Ye C, Lee MN, Replogle JM, Feng T, Lee M, Asinovski N, Frohlich I, Imboywa S, Von Korff A, Okada Y, Patsopoulos NA, Davis S, McCabe C, Paik HI, Srivastava GP, Raychaudhuri S, Hafler DA, Koller D, Regev A, Hacohen N, Mathis D, Benoist C, Stranger BE, De Jager PL. Polarization of the Effects of Autoimmune and Neurodegenerative Risk Alleles in Leukocytes. Science 2014, 344: 519-523. PMID: 24786080, PMCID: PMC4910825, DOI: 10.1126/science.1249547.Peer-Reviewed Original ResearchMeSH KeywordsAdaptive ImmunityAllelesAlzheimer DiseaseAutoimmune DiseasesAutoimmunityCD4-Positive T-LymphocytesEthnicityGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansImmunity, InnateMonocytesMultiple SclerosisNeurodegenerative DiseasesParkinson DiseasePolymorphism, Single NucleotideQuantitative Trait LociRheumatic FeverTranscriptomeConceptsSpecific immune cell typesHuman immune functionImmune cell typesMulti-ethnic cohortCell-autonomous effectsAutoimmune diseasesT cellsImmune functionParkinson's diseaseHealthy individualsInnate immunityRisk allelesDiseaseExpression quantitative trait loci (eQTL) studiesQuantitative trait loci studiesSusceptibility allelesPutative functional assignmentsCausal regulatory variantsDisease-associated lociDisease susceptibility variantsCell typesSusceptibility variantsTrans-eQTLsFunctional assignmentRegulatory variantsCommon Genetic Variants Modulate Pathogen-Sensing Responses in Human Dendritic Cells
Lee MN, Ye C, Villani AC, Raj T, Li W, Eisenhaure TM, Imboywa SH, Chipendo PI, Ran FA, Slowikowski K, Ward LD, Raddassi K, McCabe C, Lee MH, Frohlich IY, Hafler DA, Kellis M, Raychaudhuri S, Zhang F, Stranger BE, Benoist CO, De Jager PL, Regev A, Hacohen N. Common Genetic Variants Modulate Pathogen-Sensing Responses in Human Dendritic Cells. Science 2014, 343: 1246980. PMID: 24604203, PMCID: PMC4124741, DOI: 10.1126/science.1246980.Peer-Reviewed Original ResearchMeSH KeywordsAdultAutoimmune DiseasesCommunicable DiseasesDendritic CellsEscherichia coliFemaleGene-Environment InteractionGenetic LociGenome-Wide Association StudyHEK293 CellsHost-Pathogen InteractionsHumansInfluenza A virusInterferon Regulatory Factor-7Interferon-betaLipopolysaccharidesMaleMiddle AgedPolymorphism, Single NucleotideQuantitative Trait LociSTAT Transcription FactorsTranscriptomeYoung AdultConceptsGenetic variationPathogen-responsive genesHuman genetic variationGenetic variantsIRF transcription factorsCommon genetic variantsType I IFN inductionFunctional annotationExpression responsesTranscription factorsI IFN inductionCausal variantsPathogen sensingEnvironmental stimuliComplex diseasesCommon variantsCommon allelesIFN inductionComputational approachVariantsCellsInductionGenesInterindividual variationSTAT
2012
An RNA Profile Identifies Two Subsets of Multiple Sclerosis Patients Differing in Disease Activity
Ottoboni L, Keenan BT, Tamayo P, Kuchroo M, Mesirov JP, Buckle GJ, Khoury SJ, Hafler DA, Weiner HL, De Jager PL. An RNA Profile Identifies Two Subsets of Multiple Sclerosis Patients Differing in Disease Activity. Science Translational Medicine 2012, 4: 153ra131. PMID: 23019656, PMCID: PMC3753678, DOI: 10.1126/scitranslmed.3004186.Peer-Reviewed Original ResearchConceptsGlatiramer acetateDisease activityPatient populationFirst-line disease-modifying treatmentsMultiple sclerosis (MS) patient populationPeripheral blood mononuclear cellsMS patient populationDisease-modifying treatmentsMultiple sclerosis patientsBlood mononuclear cellsSubset of subjectsDisease courseSclerosis patientsMS subjectsMononuclear cellsInflammatory eventsTreatment responseUntreated subjectsAdditional groupHigh expressionTranscriptional signatureSubjectsRNA profilesTreatmentTranscriptional profiles