2024
Genetic 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 collectionExpression
2022
Impaired 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 MRIBasic 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
Chapter 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 variants
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 cells
2015
Prospects of immune checkpoint modulators in the treatment of glioblastoma
Preusser M, Lim M, Hafler DA, Reardon DA, Sampson JH. Prospects of immune checkpoint modulators in the treatment of glioblastoma. Nature Reviews Neurology 2015, 11: 504-514. PMID: 26260659, PMCID: PMC4782584, DOI: 10.1038/nrneurol.2015.139.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsCheckpoint inhibitorsGlioblastoma patientsMultiple immunosuppressive mechanismsMedian overall survivalImmune checkpoint modulatorsBlood-brain barrierTreatment of glioblastomaOverall survivalImmunosuppressive mechanismsAdvanced tumorsClinical benefitImmunotherapeutic agentsConventional therapyCheckpoint modulatorsLung cancerImmune systemPatientsCancerInhibitorsCurrent understandingImmunotherapyPrognosisLymphocytesTherapy
2013
The plasticity of human Treg and Th17 cells and its role in autoimmunity
Kleinewietfeld M, Hafler DA. The plasticity of human Treg and Th17 cells and its role in autoimmunity. Seminars In Immunology 2013, 25: 305-312. PMID: 24211039, PMCID: PMC3905679, DOI: 10.1016/j.smim.2013.10.009.Peer-Reviewed Original ResearchConceptsTh17 cellsT cellsMultiple sclerosisAutoimmune diseasesImmune systemPlasticity of TregsEffector T cellsRegulatory T cellsEffector cell populationsHuman autoimmune diseasesT cell subpopulationsT helper cellsParticular multiple sclerosisT cell plasticityHigh gradeInnate immune systemAdaptive immune systemStrength of stimulationT cell developmentHuman TregsHelper cellsImmune responseImmune reactionsNaive cellsTregs
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
An Innate Role for IL-17
Dominguez-Villar M, Hafler DA. An Innate Role for IL-17. Science 2011, 332: 47-48. PMID: 21454778, DOI: 10.1126/science.1205311.Peer-Reviewed Original ResearchConceptsImmune responseImmune dysregulation polyendocrinopathyAbnormal immune responseRegulatory immune cellsRegulatory T cellsHuman autoimmune disordersCytokine interleukin-17Normal immune responseTranscription factor Foxp3IL-17Interleukin-17Autoimmune disordersAutoimmune diseasesImmune cellsImmune system processFOXP3 geneFactor Foxp3T cellsImmune systemFungal infectionsGenetic mutationsHuman genetic mutationsCytokinesInfectionCell types
2010
FOXP3+ regulatory T cells in the human immune system
Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nature Reviews Immunology 2010, 10: 490-500. PMID: 20559327, DOI: 10.1038/nri2785.Peer-Reviewed Original ResearchConceptsForkhead box P3Human Treg cellsTreg cellsT cellsKey PointsRegulatory T (TReg) cellsTreg cell-based therapyAntitumour immune responseRegulatory T cellsExpression of CD45RAPromising therapeutic perspectiveHuman immune systemAutoimmune pathogenesisDominant toleranceBox P3HLA-DRCell-based therapiesAutoimmune diseasesImmune homeostasisImmune responseImmune diseasesSuppressive functionPotent mediatorCancer growthImmune systemTherapeutic perspectivesIL-12 induces human CD4+CD45RA-CD25hiCD127low/neg regulatory T cells to secrete IFNγ and IL-10 and acquire a non-regulatory effector phenotype (138.9)
Dominguez-Villar M, Hafler D, Baecher-Allan C. IL-12 induces human CD4+CD45RA-CD25hiCD127low/neg regulatory T cells to secrete IFNγ and IL-10 and acquire a non-regulatory effector phenotype (138.9). The Journal Of Immunology 2010, 184: 138.9-138.9. DOI: 10.4049/jimmunol.184.supp.138.9.Peer-Reviewed Original ResearchRegulatory T cellsT cellsEffector phenotypeTreg functionIL-10Immune responseHuman Treg functionCD4 T cellsT cell responsesIL-12 familyIL-12 inducesTreg suppressionPeripheral toleranceCytokine milieuT-betIFN-gammaTregsImmune systemCell responsesCytokinesRecent evidencePivotal roleCellsPhenotypeDistinct effects
2009
Monocytes from Patients with Type 1 Diabetes Spontaneously Secrete Proinflammatory Cytokines Inducing Th17 Cells
Bradshaw EM, Raddassi K, Elyaman W, Orban T, Gottlieb PA, Kent SC, Hafler DA. Monocytes from Patients with Type 1 Diabetes Spontaneously Secrete Proinflammatory Cytokines Inducing Th17 Cells. The Journal Of Immunology 2009, 183: 4432-4439. PMID: 19748982, PMCID: PMC2770506, DOI: 10.4049/jimmunol.0900576.Peer-Reviewed Original ResearchConceptsT cellsT1D subjectsImmune systemIL-17-secreting cellsIL-17-secreting T cellsProinflammatory cytokines IL-1betaProinflammatory T cellsEffector T cellsMemory T cellsLong-term patientsHealthy control subjectsCytokines IL-1betaIL-1R antagonistType 1 diabetesInnate immune systemAdaptive immune systemTh1/T1D patientsAutoimmune diseasesIL-6Control subjectsIL-1betaHealthy controlsMonocytesType 1Use of a genetic isolate to identify rare disease variants: C7 on 5p associated with MS
Kallio SP, Jakkula E, Purcell S, Suvela M, Koivisto K, Tienari PJ, Elovaara I, Pirttilä T, Reunanen M, Bronnikov D, Viander M, Meri S, Hillert J, Lundmark F, Harbo HF, Lorentzen Å, De Jager PL, Daly MJ, Hafler DA, Palotie A, Peltonen L, Saarela J. Use of a genetic isolate to identify rare disease variants: C7 on 5p associated with MS. Human Molecular Genetics 2009, 18: 1670-1683. PMID: 19221116, PMCID: PMC2667286, DOI: 10.1093/hmg/ddp073.Peer-Reviewed Original Research
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
2006
Innate Immunity in Multiple Sclerosis: Myeloid Dendritic Cells in Secondary Progressive Multiple Sclerosis Are Activated and Drive a Proinflammatory Immune Response
Karni A, Abraham M, Monsonego A, Cai G, Freeman GJ, Hafler D, Khoury SJ, Weiner HL. Innate Immunity in Multiple Sclerosis: Myeloid Dendritic Cells in Secondary Progressive Multiple Sclerosis Are Activated and Drive a Proinflammatory Immune Response. The Journal Of Immunology 2006, 177: 4196-4202. PMID: 16951385, DOI: 10.4049/jimmunol.177.6.4196.Peer-Reviewed Original ResearchConceptsMyeloid dendritic cellsDendritic cellsMultiple sclerosisInnate immune systemRR-MSImmune responseImmune systemT cell-mediated autoimmune diseaseSecondary progressive multiple sclerosisCell-mediated autoimmune diseaseStages of MSIncreased percentageProgressive phaseNeuronal degenerative changesSecondary progressive phaseSP-MS patientsProgressive multiple sclerosisProinflammatory immune responsePrimary immune responseNaive T cellsImmunologic basisTh1 responseClinical patternMS patientsPD-L1Human regulatory T cells and their role in autoimmune disease
Baecher‐Allan C, Hafler DA. Human regulatory T cells and their role in autoimmune disease. Immunological Reviews 2006, 212: 203-216. PMID: 16903916, DOI: 10.1111/j.0105-2896.2006.00417.x.Peer-Reviewed Original ResearchConceptsRegulatory T cellsAutoimmune diseasesSelf-reactive cellsT cellsHealthy individualsHuman natural regulatory T cellsSelf-reactive T cellsNatural regulatory T cellsHuman regulatory T cellsPathologic T cellsReduced inhibitory functionSpecific autoimmune diseasesT cell populationsMature T cellsT cell maturationNon-responsive stateRegulatory cellsNatural CD4Peripheral circulationImmune systemPatientsDiseaseInhibitory functionNumber of mechanismsCells
2001
Decreases in Interleukin-4 Secretion by Invariant CD4−CD8−Vα24JαQ T Cells in Peripheral Blood of Patients with Relapsing–Remitting Multiple Sclerosis
Gausling R, Trollmo C, Hafler D. Decreases in Interleukin-4 Secretion by Invariant CD4−CD8−Vα24JαQ T Cells in Peripheral Blood of Patients with Relapsing–Remitting Multiple Sclerosis. Clinical Immunology 2001, 98: 11-17. PMID: 11141321, DOI: 10.1006/clim.2000.4942.Peer-Reviewed Original ResearchConceptsRelapsing-remitting multiple sclerosisT cell receptorIFN-gamma secretionMultiple sclerosisT cell clonesT cellsCytokine profilePeripheral bloodIL-4Cell clonesProgressive multiple sclerosisRR-MS patientsCytokine secretion patternsRelapsing-remitting MSInterleukin-4 secretionT cell functionalityCytokine secretionHealthy controlsSecretion patternPatientsCP-MSImmune systemControl individualsCell receptorSecretionImmune Tolerance and the Nervous System
Anderson D, Hafler D. Immune Tolerance and the Nervous System. Advances In Experimental Medicine And Biology 2001, 490: 79-98. PMID: 11505978, DOI: 10.1007/978-1-4615-1243-1_9.Peer-Reviewed Original ResearchConceptsT cellsB cellsInnate immunityForeign microbial antigensPrior viral infectionSpecific immune responseClass I moleculesNK cellsImmune toleranceMicrobial antigensImmune responseViral infectionNervous systemInfectious agentsSecondary exposureImmune systemInfectious virusParticular antigenSpecific receptorsTumor cellsAntigenI moleculesInfectionInnate mechanismsImmunity
1998
Extreme Th1 bias of invariant Vα24JαQ T cells in type 1 diabetes
Wilson S, Kent S, Patton K, Orban T, Jackson R, Exley M, Porcelli S, Schatz D, Atkinson M, Balk S, Strominger J, Hafler D. Extreme Th1 bias of invariant Vα24JαQ T cells in type 1 diabetes. Nature 1998, 391: 177-181. PMID: 9428763, DOI: 10.1038/34419.Peer-Reviewed Original ResearchConceptsType 1 diabetesT cellsMajor histocompatibility complexIL-4T cell-mediated destructionNon-diabetic siblingsAutoreactive T cellsHigher serum levelsTwins/tripletsType1 diabetic patientsDiabetic patientsSerum levelsTh1 biasDiabetic siblingsImmune systemTissue damageIncomplete concordanceDiabetesHistocompatibility complexIDDMIdentical twinsIFNDiseaseRiskCells