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 mechanismsGenetic mapping across autoimmune diseases reveals shared associations and mechanisms
Lincoln M, Connally N, Axisa P, Gasperi C, Mitrovic M, van Heel D, Wijmenga C, Withoff S, Jonkers I, Padyukov L, Rich S, Graham R, Gaffney P, Langefeld C, Vyse T, Hafler D, Chun S, Sunyaev S, Cotsapas C. Genetic mapping across autoimmune diseases reveals shared associations and mechanisms. Nature Genetics 2024, 56: 838-845. PMID: 38741015, DOI: 10.1038/s41588-024-01732-8.Peer-Reviewed Original ResearchConceptsGenetic mapResolution of genetic mappingExpression quantitative trait lociFine-mapping resolutionQuantitative trait lociGenomic lociTrait lociPolygenic disorderAllelesRisk allelesLociPathogenic mechanismsImmune systemAutoimmune mechanismsAutoimmune diseasesInflammatory diseasesTraitsMechanismDiseaseSample collectionExpressionThe regulation and differentiation of regulatory T cells and their dysfunction in autoimmune diseases
Sumida T, Cheru N, Hafler D. The regulation and differentiation of regulatory T cells and their dysfunction in autoimmune diseases. Nature Reviews Immunology 2024, 24: 503-517. PMID: 38374298, PMCID: PMC11216899, DOI: 10.1038/s41577-024-00994-x.Peer-Reviewed Original ResearchTreg cell dysfunctionTreg cellsAutoimmune diseasesCell dysfunctionSuppressive function of Treg cellsDifferentiation of regulatory T cellsFunction of Treg cellsDiscovery of Foxp3Foxp3-independent mechanismsTreg cell suppressionRegulatory T cellsTreg cell functionTranscription factor Foxp3Systemic lupus erythematosusRegulate immune responsesInflammatory bowel diseaseFOXP3 mutationsFoxp3-dependentSystemic autoinflammationRegulatory TIPEX syndromeCell lineage determinationT cellsTregsLupus erythematosus
2023
Regulatory T cells in peripheral tissue tolerance and diseases
Cheru N, Hafler D, Sumida T. Regulatory T cells in peripheral tissue tolerance and diseases. Frontiers In Immunology 2023, 14: 1154575. PMID: 37197653, PMCID: PMC10183596, DOI: 10.3389/fimmu.2023.1154575.Peer-Reviewed Original ResearchConceptsTissue-resident TregsRegulatory T cellsT cellsResident TregsTissue TregsAutoimmune diseasesCommon human autoimmune diseasesAutoreactive T cellsHuman autoimmune diseasesNon-immune cellsNon-lymphoid tissuesTissue-resident cellsTreg poolTreg studiesEffector cytokinesPeripheral toleranceTreg functionIPEX syndromeImmune homeostasisSpecific tissue environmentsTregsSuppressive functionLoss of functionResident cellsGene signature
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 variants
2020
Epigenetic fine-mapping: identification of causal mechanisms for autoimmunity
Lincoln MR, Axisa PP, Hafler DA. Epigenetic fine-mapping: identification of causal mechanisms for autoimmunity. Current Opinion In Immunology 2020, 67: 50-56. PMID: 32977183, DOI: 10.1016/j.coi.2020.09.002.Peer-Reviewed Original ResearchConceptsGenome-wide association studiesMolecular mechanismsSusceptibility lociIndividual susceptibility lociFundamental genetic basisCausal molecular mechanismsPathogenic cell typesSpecific molecular mechanismsGenetic susceptibility lociEpigenetic techniquesGenetic basisGenetic lociAssociation studiesCell typesLociRecent advancesMechanismGeneticsAutoimmune diseasesSpectrum of autoimmunityCausal mechanismsEtiological mechanismsInflammatory diseasesTranslationAutoimmunity
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 onsetAutoantibodies against Neurologic Antigens in Nonneurologic Autoimmunity
Stathopoulos P, Chastre A, Waters P, Irani S, Fichtner ML, Benotti ES, Guthridge JM, Seifert J, Nowak RJ, Buckner JH, Holers VM, James JA, Hafler DA, O’Connor K. Autoantibodies against Neurologic Antigens in Nonneurologic Autoimmunity. The Journal Of Immunology 2019, 202: ji1801295. PMID: 30824481, PMCID: PMC6452031, DOI: 10.4049/jimmunol.1801295.Peer-Reviewed Original ResearchConceptsSystemic lupus erythematosusRheumatoid arthritisControl cohortNeuromyelitis optica spectrum disorderSurface AgOptica spectrum disorderMyelin oligodendrocyte glycoproteinHealthy donor seraType 1 diabetesB cell toleranceNeurologic autoimmunitySLE patientsLupus erythematosusSuch autoantibodiesT1D patientsAutoimmune diseasesHigh titer AbsOligodendrocyte glycoproteinSystemic autoimmunityDonor seraLarge cohortRare caseAutoantibodiesAquaporin-4Cell toleranceLatent autoimmunity across disease-specific boundaries in at-risk first-degree relatives of SLE and RA patients
James JA, Chen H, Young KA, Bemis EA, Seifert J, Bourn RL, Deane KD, Demoruelle MK, Feser M, O'Dell JR, Weisman MH, Keating RM, Gaffney PM, Kelly JA, Langefeld CD, Harley JB, Robinson W, Hafler DA, O'Connor KC, Buckner J, Guthridge JM, Norris JM, Holers VM. Latent autoimmunity across disease-specific boundaries in at-risk first-degree relatives of SLE and RA patients. EBioMedicine 2019, 42: 76-85. PMID: 30952617, PMCID: PMC6491794, DOI: 10.1016/j.ebiom.2019.03.063.Peer-Reviewed Original ResearchConceptsSystemic lupus erythematosusFirst-degree relativesGenetic risk scoreRA patientsRheumatoid arthritisSLE patientsT1D patientsAutoantibody-positive systemic lupus erythematosusRisk first-degree relativesOrgan-specific autoimmune diseasesType 1 diabetes patientsAutoimmune disease preventionAnti-tissue transglutaminaseDisease-associated autoantibodiesDisease prevention studiesUnaffected first-degree relativesCross-sectional studyLatent autoimmunityLupus erythematosusAutoimmune diseasesDiabetes patientsPrevention StudyRisk scoreAutoimmunityPreclinical periodTIGIT 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
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-cateninIFNRegulatory T cells in autoimmune disease
Dominguez-Villar M, Hafler DA. Regulatory T cells in autoimmune disease. Nature Immunology 2018, 19: 665-673. PMID: 29925983, PMCID: PMC7882196, DOI: 10.1038/s41590-018-0120-4.Peer-Reviewed Original ResearchConceptsAutoimmune diseasesTreg cellsRegulatory T cell biologyRegulatory T cellsNon-immune cellsTreg cell plasticityTreg cell biologyNew therapeutic strategiesT cell biologyTreg cell instabilityDisease outcomeT cellsTherapeutic strategiesDiseaseCell plasticityCell biologyCellsAutoimmunityPathogenesisSpecific tissuesRegulatory 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 developmentActivationCells
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 functionThe 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
Genetic 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 variantsGenetic basis of autoimmunity
Marson A, Housley WJ, Hafler DA. Genetic basis of autoimmunity. Journal Of Clinical Investigation 2015, 125: 2234-2241. PMID: 26030227, PMCID: PMC4497748, DOI: 10.1172/jci78086.Peer-Reviewed Original ResearchConceptsGenetic basisInterpretation of GWASMultiple genomic datasetsWide association studyCommon human autoimmune diseasesRelevant cell typesCellular conditionsCellular phenotypesGenomic datasetsGene expressionDense genotypingBiological pathwaysAssociation studiesHuman autoimmune diseasesNucleotide variantsCell typesAutoimmune diseasesPrimary immune cellsUnbiased viewMonogenic mutationsPolygenic risk factorsEssential mechanismComplex disorderEnvironmental factorsNovel diagnosticsFunctional 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 subjectsMultiple sclerosis—a quiet revolution
Ransohoff RM, Hafler DA, Lucchinetti CF. Multiple sclerosis—a quiet revolution. Nature Reviews Neurology 2015, 11: 134-142. PMID: 25686758, PMCID: PMC4556342, DOI: 10.1038/nrneurol.2015.14.Peer-Reviewed Original ResearchConceptsTreatment optionsMajor unmet medical needMultiple sclerosis susceptibilityUnmet medical needNeural tissue injuryGenetic variantsMS therapeuticsAcetate therapyMS riskInflammatory aspectsMultiple sclerosisAutoimmune diseasesTreatable diseaseTissue injuryIndividual patientsDisease evolutionClinical phenotypeMedical needPatientsDisease susceptibilityDiseaseGenetic componentSclerosisIFNOptions