2024
Cholesterol promotes IFNG mRNA expression in CD4+ effector/memory cells by SGK1 activation
Hanin A, Comi M, Sumida T, Hafler D. Cholesterol promotes IFNG mRNA expression in CD4+ effector/memory cells by SGK1 activation. Life Science Alliance 2024, 7: e202402890. PMID: 39366761, PMCID: PMC11452476, DOI: 10.26508/lsa.202402890.Peer-Reviewed Original ResearchConceptsCentral nervous systemT cellsEffector/memory cellsCentral nervous system milieuT cell environmentCD4 T cellsIFNG mRNA expressionCXCR3<sup>+</sup> cellsT cell homeostasisInhibition of SGK1Targeting lipid pathwaysMaintenance of immune surveillanceSerum/glucocorticoid-regulated kinaseImmune surveillanceHealthy donorsCytotoxic capacityEffector responsesInflammatory conditionsSGK1 activityMRNA expressionNervous systemSGK1Metabolic conditionsLipid pathwaysTissue adaptation
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 characterizationChapter 51 Multiple Sclerosis
Wesley S, Hafler D. Chapter 51 Multiple Sclerosis. 2020, 961-986. DOI: 10.1016/b978-0-12-812102-3.00051-8.Peer-Reviewed Original ResearchMultiple sclerosisModern treatment paradigmsAutoreactive T cellsPeripheral immune systemCentral nervous systemTreatable diseaseInflammatory processTreatment paradigmT cellsNervous systemDisease pathogenesisImmune systemUnknown originUntreatable diseaseSclerosisPathogenesisDiseaseGenetic haplotypesStrong evidenceComprehensive reviewMyelin
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 variantsCHAPTER 2 Genetics of Multiple Sclerosis
Abulaban A, Hafler D, Longbrake E. CHAPTER 2 Genetics of Multiple Sclerosis. 2019, 33-54. DOI: 10.1039/9781788016070-00033.ChaptersMultiple sclerosisCentral nervous systemImmune cell infiltratesComplex autoimmune diseaseEnvironmental risk factorsExtensive CNS demyelinationMS therapyAxonal damageCell infiltrateCNS demyelinationAutoimmune diseasesRisk factorsGenetic predispositionNervous systemDisease severityDiseaseSclerosisComplex genetic diseasesChapter 2 GeneticsGenetic diseasesDemyelinationInfiltratesAutoimmunityPathogenesisTherapy
2018
Regulatory T Cells: From Discovery to Autoimmunity
Kitz A, Singer E, Hafler D. Regulatory T Cells: From Discovery to Autoimmunity. Cold Spring Harbor Perspectives In Medicine 2018, 8: a029041. PMID: 29311129, PMCID: PMC6280708, DOI: 10.1101/cshperspect.a029041.Peer-Reviewed Original ResearchConceptsAutoreactive T cellsT cellsMultiple sclerosisEffector-like T cellsInterferon γ secretionEffector T cellsRegulatory T cellsTreg cell functionT-bet expressionCentral nervous systemT cell activationFunctional TregsΓ secretionProinflammatory cytokinesVitamin DAutoimmune diseasesGenetic predispositionNervous systemLoss of functionReduced suppressionConsistent findingCell functionDisease developmentActivationCellsChapter 46 Multiple sclerosis
Cotsapas C, Mitrovic M, Hafler D. Chapter 46 Multiple sclerosis. Handbook Of Clinical Neurology 2018, 148: 723-730. PMID: 29478610, DOI: 10.1016/b978-0-444-64076-5.00046-6.Peer-Reviewed Original ResearchConceptsMultiple sclerosisCentral nervous system white matterNervous system white matterAutoimmune neurologic disordersDisease-modifying therapiesImmune function modulationSpecific immune subsetsCentral nervous systemGenetic variantsImmune subsetsNeurologic symptomsAutoimmune attackLeading causeNeurologic disordersNervous systemWhite matterCommon genetic variantsOverall riskSclerosisYoung adultsEnvironmental exposuresRiskSymptomsDiseasePatients
2017
Co‐inhibitory blockade while preserving tolerance: checkpoint inhibitors for glioblastoma
Lucca LE, Hafler DA. Co‐inhibitory blockade while preserving tolerance: checkpoint inhibitors for glioblastoma. Immunological Reviews 2017, 276: 9-25. PMID: 28258696, PMCID: PMC5338636, DOI: 10.1111/imr.12529.Peer-Reviewed Original ResearchConceptsCheckpoint immunotherapyTumor rejectionCommon adult brain tumorsImmune-related side effectsCheckpoint receptor blockadeCo-inhibitory receptorsIntroduction of immunotherapyT cell exhaustionImmune regulatory pathwaysCo-inhibitory pathwaysAdult brain tumorsPrevention of autoimmunityCentral nervous systemAnti-tumor activityDifferent tumor typesCheckpoint inhibitorsReceptor blockadeAdvanced cancerTherapeutic successBrain tumorsSide effectsImmunotherapyNervous systemTherapeutic efficacyTumor types
2016
The Link Between CD6 and Autoimmunity: Genetic and Cellular Associations.
Kofler DM, Farkas A, von Bergwelt-Baildon M, Hafler DA. The Link Between CD6 and Autoimmunity: Genetic and Cellular Associations. Current Drug Targets 2016, 17: 651-65. PMID: 26844569, DOI: 10.2174/1389450117666160201105934.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, CDAntigens, Differentiation, T-LymphocyteArthritis, RheumatoidAutoimmunityCD4-Positive T-LymphocytesCell Adhesion Molecules, NeuronalClinical Trials as TopicDisease Models, AnimalFetal ProteinsGenetic Predisposition to DiseaseHumansMultiple SclerosisPolymorphism, Single NucleotideConceptsMultiple sclerosisRheumatoid arthritisCentral nervous systemNervous systemSingle nucleotide polymorphismsDevelopment of MSTreatment of RARole of CD6T cell traffickingT cell functionGenetic risk factorsEndothelial cell barrierCD6 geneClinical responseGenetic associationClinical featuresAutoimmune diseasesSynovial cellsRisk factorsTumor necrosisSynovial fibroblastsPossible common mechanismT cellsT lymphocytesLeukocyte trafficking
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 pathology
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
Regulatory T Cells in MS
Gawlik B, Hafler D. Regulatory T Cells in MS. 2013, 27-47. DOI: 10.1007/978-1-4614-7953-6_2.Peer-Reviewed Original ResearchRegulatory T cellsAutoreactive T cellsT cellsCentral nervous systemMultiple sclerosisTreg cellsHealthy individualsPathogenic autoreactive T cellsMultifocal demyelinating diseaseDemyelinating diseaseCNS lesionsMS patientsAutoimmune responseAutoimmune diseasesPeripheral bloodImmune homeostasisImmune responseNervous systemSusceptible individualsProgressive neurodegenerationDiseaseKey regulatorCellsIndividualsHigher number
2012
Regulatory T cells in the central nervous system
Lowther DE, Hafler DA. Regulatory T cells in the central nervous system. Immunological Reviews 2012, 248: 156-169. PMID: 22725960, DOI: 10.1111/j.1600-065x.2012.01130.x.Peer-Reviewed Original ResearchConceptsRegulatory T cellsTreg functionAutoimmune diseasesT cellsForkhead box protein 3Central nervous system diseaseBox protein 3Nervous system diseasesCentral nervous systemPotential therapeutic targetHuman immune systemTreg biologyPeripheral toleranceMultiple sclerosisCNS diseaseImmune surveillanceImmune responseSystem diseasesTherapeutic targetNervous systemImmune systemProtein 3DiseaseTregsCells
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 ResearchConceptsB 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 hypermutationInjuryBrainReceptors
2009
Epstein–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 methodologyT-Cells in Multiple Sclerosis
Severson C, Hafler DA. T-Cells in Multiple Sclerosis. 2009, 51: 1-24. PMID: 19582415, DOI: 10.1007/400_2009_12.Peer-Reviewed Original ResearchConceptsMultiple sclerosisT cellsMultifocal demyelinating diseaseMultiple cell subtypesRegulatory T cellsT cell subsetsT cell functionCentral nervous systemRational therapeutic strategiesT cell activationDemyelinating diseaseMS pathogenesisMS pathophysiologyCell subsetsAdaptive immunityEffective treatmentTherapeutic strategiesNervous systemCell activationCell subtypesEvidence implicateSpecific toleranceFunctional defectsIntrinsic cellsCell functionT-Cells in Multiple Sclerosis
Severson C, Hafler D. T-Cells in Multiple Sclerosis. Results And Problems In Cell Differentiation 2009, 51: 75-98. DOI: 10.1007/400_2009_9012.Peer-Reviewed Original ResearchMultiple sclerosisT cellsMultifocal demyelinating diseaseMultiple cell subtypesRegulatory T cellsT cell subsetsT cell functionCentral nervous systemRational therapeutic strategiesT cell activationDemyelinating diseaseMS pathogenesisMS pathophysiologyCell subsetsAdaptive immunityEffective treatmentTherapeutic strategiesNervous systemCell activationCell subtypesEvidence implicateSpecific toleranceFunctional defectsIntrinsic cellsCell functionThe role of the CD58 locus in multiple sclerosis
De Jager PL, Baecher-Allan C, Maier LM, Arthur AT, Ottoboni L, Barcellos L, McCauley JL, Sawcer S, Goris A, Saarela J, Yelensky R, Price A, Leppa V, Patterson N, de Bakker PI, Tran D, Aubin C, Pobywajlo S, Rossin E, Hu X, Ashley CW, Choy E, Rioux JD, Pericak-Vance MA, Ivinson A, Booth DR, Stewart GJ, Palotie A, Peltonen L, Dubois B, Haines JL, Weiner HL, Compston A, Hauser SL, Daly MJ, Reich D, Oksenberg JR, Hafler DA. The role of the CD58 locus in multiple sclerosis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2009, 106: 5264-5269. PMID: 19237575, PMCID: PMC2664005, DOI: 10.1073/pnas.0813310106.Peer-Reviewed Original ResearchConceptsMultiple sclerosisMS subjectsMononuclear cellsCD58 expressionProtective effectMRNA expressionPeripheral blood mononuclear cellsRegulatory T cellsBlood mononuclear cellsTranscription factor Foxp3Dose-dependent increaseCentral nervous systemLymphoblastic cell linesClinical remissionAxonal lossControl subjectsInflammatory diseasesFactor Foxp3T cellsWhole-genome association scansLFA-3Nervous systemProtective allelesPotential mechanismsSclerosis