2024
An autoimmune transcriptional circuit drives FOXP3+ regulatory T cell dysfunction
Sumida T, Lincoln M, He L, Park Y, Ota M, Oguchi A, Son R, Yi A, Stillwell H, Leissa G, Fujio K, Murakawa Y, Kulminski A, Epstein C, Bernstein B, Kellis M, Hafler D. An autoimmune transcriptional circuit drives FOXP3+ regulatory T cell dysfunction. Science Translational Medicine 2024, 16: eadp1720. PMID: 39196959, DOI: 10.1126/scitranslmed.adp1720.Peer-Reviewed Original ResearchConceptsForkhead box P3Autoimmune diseasesCD4<sup>+</sup>Foxp3<sup>+</sup> regulatory T cellsMultiple sclerosisFoxp3<sup>+</sup> regulatory T cellsRegulatory T cell dysfunctionPR domain zinc finger protein 1Zinc finger protein 1Glucocorticoid-regulated kinase 1Regulatory T cellsT cell dysfunctionDisorder of young adultsAutoimmune disease multiple sclerosisDisease multiple sclerosisExpression of serumTranscriptional circuitsEpigenomic profilingShort isoformPrevent autoimmunityUpstream regulatorT cellsHuman autoimmunityEvolutionary emergenceKinase 1Molecular mechanismsMeta-analysis identifies common gut microbiota associated with multiple sclerosis
Lin Q, Dorsett Y, Mirza A, Tremlett H, Piccio L, Longbrake E, Choileain S, Hafler D, Cox L, Weiner H, Yamamura T, Chen K, Wu Y, Zhou Y. Meta-analysis identifies common gut microbiota associated with multiple sclerosis. Genome Medicine 2024, 16: 94. PMID: 39085949, PMCID: PMC11293023, DOI: 10.1186/s13073-024-01364-x.Peer-Reviewed Original ResearchConceptsRRNA gene sequence dataGroups of microbial taxaGene sequence dataMicrobiome community structureAbundance of FaecalibacteriumAbundance of PrevotellaAbundance of ActinomycesSequence dataBeta diversityMicrobial taxaGut microbiotaMicrobial compositionCommunity structureNetwork analysisGutBacterial correlationsMicrobiotaAbundanceMultiple sclerosisDiverse groupMeta-analysisDiversityTaxaFaecalibacteriumConclusionsOur meta-analysisEmerging 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
2022
A multiple sclerosis–protective coding variant reveals an essential role for HDAC7 in regulatory T cells
Axisa P, Yoshida T, Lucca L, Kasler H, Lincoln M, Pham G, Del Priore D, Carpier J, Lucas C, Verdin E, Sumida T, Hafler D. A multiple sclerosis–protective coding variant reveals an essential role for HDAC7 in regulatory T cells. Science Translational Medicine 2022, 14: eabl3651. PMID: 36516268, DOI: 10.1126/scitranslmed.abl3651.Peer-Reviewed Original ResearchConceptsExperimental autoimmune encephalitisRegulatory T cellsHistone deacetylase 7Multiple sclerosisT cellsMouse modelFunction of Foxp3CD4 T cellsHigher suppressive capacityVivo modelingAutoimmune encephalitisEAE severityImmunosuppressive subsetAutoimmune diseasesImmunomodulatory roleSuppressive capacityImmune cellsDisease onsetDistinct molecular classesSusceptibility lociGenetic susceptibility lociSingle-cell RNA sequencingDisease riskPatient samplesProtective variantsImpaired TIGIT expression on B cells drives circulating follicular helper T cell expansion in multiple sclerosis
Asashima H, Axisa PP, Pham THG, Longbrake EE, Ruff WE, Lele N, Cohen I, Raddassi K, Sumida TS, Hafler DA. Impaired TIGIT expression on B cells drives circulating follicular helper T cell expansion in multiple sclerosis. Journal Of Clinical Investigation 2022, 132: e156254. PMID: 36250467, PMCID: PMC9566906, DOI: 10.1172/jci156254.Peer-Reviewed Original ResearchConceptsRelapsing-remitting multiple sclerosisMemory B cellsCTfh cellsB cellsTIGIT expressionMultiple sclerosisT cellsFollicular helper T cellsHealthy age-matched controlsB-cell depletionT cell expansionHelper T cellsAge-matched controlsB cell functionB-cell pathwayDifferential gene expression signaturesTfh cellsDisease activityGene expression signaturesCell depletionCD40 ligandTranscription factor TCF4Disease pathogenesisImmune systemNew MRIThe CELLO trial: Protocol of a planned phase 4 study to assess the efficacy of Ocrelizumab in patients with radiologically isolated syndrome
Longbrake EE, Hua LH, Mowry EM, Gauthier SA, Alvarez E, Cross AH, Pei J, Priest J, Raposo C, Hafler DA, Winger RC. The CELLO trial: Protocol of a planned phase 4 study to assess the efficacy of Ocrelizumab in patients with radiologically isolated syndrome. Multiple Sclerosis And Related Disorders 2022, 68: 104143. PMID: 36031693, PMCID: PMC9772048, DOI: 10.1016/j.msard.2022.104143.Peer-Reviewed Original ResearchConceptsEfficacy of ocrelizumabMultiple sclerosisImmunologic biomarkersClinical trialsTransient B-cell depletionClinical multiple sclerosisCSF immune cellsEffects of ocrelizumabMS disease pathophysiologyNew brain lesionsOvert neurological symptomsB-cell depletionPlacebo-controlled studyPhase 4 studyLong-term outcomesPatient-reported outcomesPrimary progressive MSHumanized monoclonal antibodyFirst-degree relativesB cell biologySubtle cognitive impairmentEligible patientsImmune recoveryProgressive MSWeek 48Fatty Acid Metabolism and T Cells in Multiple Sclerosis
Pompura SL, Hafler DA, Dominguez-Villar M. Fatty Acid Metabolism and T Cells in Multiple Sclerosis. Frontiers In Immunology 2022, 13: 869197. PMID: 35603182, PMCID: PMC9116144, DOI: 10.3389/fimmu.2022.869197.Peer-Reviewed Original ResearchConceptsT cell functionT cellsMultiple sclerosisSpecific lipid speciesEffector T cellsRegulatory T cellsCell functionT helper subsetsMetabolic programsT cell activationT cell transitionLipid speciesFatty acid metabolismTh subsetsHelper subsetsEffector stateBody of evidenceCell activationDisease settingsDisease statesFunctional phenotypeOrganismal levelAcid metabolismMetabolic remodelingNutrient availability
2021
Oleic acid restores suppressive defects in tissue-resident FOXP3 regulatory T cells from patients with multiple sclerosis
Pompura SL, Wagner A, Kitz A, Laperche J, Yosef N, Dominguez-Villar M, Hafler D. Oleic acid restores suppressive defects in tissue-resident FOXP3 regulatory T cells from patients with multiple sclerosis. Journal Of Clinical Investigation 2021, 131 PMID: 33170805, PMCID: PMC7810477, DOI: 10.1172/jci138519.Peer-Reviewed Original ResearchConceptsMultiple sclerosisAdipose tissueFoxp3 regulatory T cellsExpression of Foxp3Regulatory T cellsTreg suppressive functionProinflammatory arachidonic acidHuman adipose tissuePhosphorylation of STAT5Treg homeostasisFatty acidsPeripheral bloodTissue residencyHealthy donorsInflammatory signalsT cellsTregsFree fatty acidsSuppressive functionArachidonic acidPatientsOleic acidOxidative phosphorylationTranscriptomic programsFoxp3
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
CXCR3+ T cells in multiple sclerosis correlate with reduced diversity of the gut microbiome
Choileáin SN, Kleinewietfeld M, Raddassi K, Hafler DA, Ruff WE, Longbrake EE. CXCR3+ T cells in multiple sclerosis correlate with reduced diversity of the gut microbiome. Journal Of Translational Autoimmunity 2019, 3: 100032. PMID: 32743517, PMCID: PMC7388357, DOI: 10.1016/j.jtauto.2019.100032.Peer-Reviewed Original ResearchInflammatory T cell subsetsCentral nervous systemT cell subsetsMultiple sclerosisT cellsGut microbiomeCell subsetsCNS-reactive T cellsRelapsing-remitting MS patientsGrey matter inflammationGut-immune axisExpression of CXCR3CD8 T cellsAltered gut microbiomeAutoreactive T cellsMultiple sclerosis correlateGut microbiome compositionInflammatory subsetMS pathogenesisMS patientsTh1 phenotypeAxonal degenerationAutoimmune diseasesCascade of eventsDisease onsetSiponimod Chips Away at Progressive MS
Longbrake EE, Hafler DA. Siponimod Chips Away at Progressive MS. Cell 2019, 179: 1440. PMID: 31951523, PMCID: PMC8023412, DOI: 10.1016/j.cell.2019.11.034.Peer-Reviewed Original ResearchConceptsProgressive multiple sclerosisGadolinium-enhancing MRI lesionsInflammatory disease activityImmunomodulatory medicationsDisability progressionDisease activityMRI lesionsProgressive MSNeurologic disabilityPMS patientsMultiple sclerosisSiponimodMedicationsSclerosisPatientsLesionsBedsideProgressionMultiple 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 variantsOcrelizumab 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 ResearchMultiple sclerosis enters a grey area
Pappalardo JL, Hafler DA. Multiple sclerosis enters a grey area. Nature 2019, 566: 465-466. PMID: 30809050, DOI: 10.1038/d41586-019-00563-6.Peer-Reviewed Original ResearchTIGIT signaling restores suppressor function of Th1 Tregs
Lucca LE, Axisa PP, Singer ER, Nolan NM, Dominguez-Villar M, Hafler DA. TIGIT signaling restores suppressor function of Th1 Tregs. JCI Insight 2019, 4: e124427. PMID: 30728325, PMCID: PMC6413794, DOI: 10.1172/jci.insight.124427.Peer-Reviewed Original ResearchIL-12Multiple sclerosisHuman autoimmune disordersT-bet expressionProinflammatory cytokine secretionProduction of IFNType 1 diabetesReduced suppressor activitySuppressor functionRepression of AktFOXO1 nuclear localizationTh1 programTIGIT pathwayCoinhibitory receptorsImmunomodulatory therapyTh17 responsesAutoimmune disordersAutoimmune diseasesSuppressor defectCytokine secretionTregsTIGITProtective effectFunctional inhibitionAkt pathwayCHAPTER 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
Enhanced astrocyte responses are driven by a genetic risk allele associated with multiple sclerosis
Ponath G, Lincoln MR, Levine-Ritterman M, Park C, Dahlawi S, Mubarak M, Sumida T, Airas L, Zhang S, Isitan C, Nguyen TD, Raine CS, Hafler DA, Pitt D. Enhanced astrocyte responses are driven by a genetic risk allele associated with multiple sclerosis. Nature Communications 2018, 9: 5337. PMID: 30559390, PMCID: PMC6297228, DOI: 10.1038/s41467-018-07785-8.Peer-Reviewed Original ResearchConceptsMultiple sclerosisAstrocyte responseRisk variantsLocal autoimmune inflammationPeripheral immune cellsCentral nervous system cellsPeripheral immune systemCultured human astrocytesNervous system cellsNF-κB signalingCNS accessDysfunctional lymphocytesAstroglial functionAutoimmune inflammationLymphocytic infiltrateLymphocyte recruitmentImmune cellsGenetic risk allelesGenetic risk variantsMS lesionsMS susceptibilityHuman astrocytesLesion sizeImmune systemSystem cellsActivated 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-cateninIFNFingolimod modulates T cell phenotype and regulatory T cell plasticity in vivo
Dominguez-Villar M, Raddassi K, Danielsen AC, Guarnaccia J, Hafler DA. Fingolimod modulates T cell phenotype and regulatory T cell plasticity in vivo. Journal Of Autoimmunity 2018, 96: 40-49. PMID: 30122421, PMCID: PMC7882197, DOI: 10.1016/j.jaut.2018.08.002.Peer-Reviewed Original ResearchConceptsT cellsMultiple sclerosisT cell effector phenotypeRelapsing-remitting multiple sclerosisRegulatory T cell populationTh1-like phenotypeRegulatory T cellsPro-inflammatory cytokinesT-cell phenotypeT cell populationsExpression of Th1Immune cell functionRegulatory T cell plasticityT cell plasticityCentral nervous systemExpression of markersCell migratory capacityImportant immunomodulatory functionsExcessive Th1Fingolimod treatmentExhaustion markersTh17 cytokinesEffector phenotypeLymph nodesSerum levels