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
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
2015
Sodium-activated macrophages: the salt mine expands
Lucca LE, Hafler DA. Sodium-activated macrophages: the salt mine expands. Cell Research 2015, 25: 885-886. PMID: 26215700, PMCID: PMC4528060, DOI: 10.1038/cr.2015.91.Peer-Reviewed Original Research
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
2012
Immune-mediated disease genetics: the shared basis of pathogenesis
Cotsapas C, Hafler DA. Immune-mediated disease genetics: the shared basis of pathogenesis. Trends In Immunology 2012, 34: 22-26. PMID: 23031829, DOI: 10.1016/j.it.2012.09.001.Peer-Reviewed Original ResearchConceptsRecent genetic studiesGenomic lociDisease geneticsMolecular basisGenetic studiesMolecular causesMolecular defectsRisk variantsSpecific pathwaysBasis of pathogenesisActionable discoveriesGeneticsInflammatory diseasesOverall symptomatologyDisease heterogeneityLociVariantsDiseasePathwayPathogenesisHigh rateRational approachDiscoveryPathobiology
2011
Pervasive Sharing of Genetic Effects in Autoimmune Disease
Cotsapas C, Voight BF, Rossin E, Lage K, Neale BM, Wallace C, Abecasis GR, Barrett JC, Behrens T, Cho J, De Jager PL, Elder JT, Graham RR, Gregersen P, Klareskog L, Siminovitch KA, van Heel DA, Wijmenga C, Worthington J, Todd JA, Hafler DA, Rich SS, Daly MJ, . Pervasive Sharing of Genetic Effects in Autoimmune Disease. PLOS Genetics 2011, 7: e1002254. PMID: 21852963, PMCID: PMC3154137, DOI: 10.1371/journal.pgen.1002254.Peer-Reviewed Original ResearchConceptsSingle nucleotide polymorphismsSystemic lupus erythematosusImmune-mediated diseasesType 1 diabetesGenetic risk factorsMajor histocompatibility locusCommon autoimmuneCommon single nucleotide polymorphismsLupus erythematosusCrohn's diseaseRheumatoid arthritisClinical evidenceMultiple sclerosisAutoimmune diseasesRisk single nucleotide polymorphismsCeliac diseaseInflammatory diseasesRisk factorsMeta-AnalysisDisease riskDiseaseHistocompatibility locusUnderlying mechanismGenetic associationNucleotide polymorphisms
2009
The 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
2008
Lack of TIM-3 Immunoregulation in Multiple Sclerosis
Yang L, Anderson DE, Kuchroo J, Hafler DA. Lack of TIM-3 Immunoregulation in Multiple Sclerosis. The Journal Of Immunology 2008, 180: 4409-4414. PMID: 18354161, DOI: 10.4049/jimmunol.180.7.4409.Peer-Reviewed Original ResearchConceptsMultiple sclerosisT cell functionTim-3Untreated patientsTreatment of MSType 1 Th cellsBlocking Tim-3Tim-3 functionTim-3 regulationT-cell infiltratesTim-3 expressionPeripheral immune systemCell functionHuman autoimmune diseasesIFN-gamma secretionCNS white matterT cell stimulationHuman Tim-3Cell infiltrateGlatiramer acetateImmune toleranceAutoimmune diseasesControl subjectsTh cellsInflammatory diseasesIncreased IL-23 secretion and altered chemokine production by dendritic cells upon CD46 activation in patients with multiple sclerosis
Vaknin-Dembinsky A, Murugaiyan G, Hafler DA, Astier AL, Weiner HL. Increased IL-23 secretion and altered chemokine production by dendritic cells upon CD46 activation in patients with multiple sclerosis. Journal Of Neuroimmunology 2008, 195: 140-145. PMID: 18403025, PMCID: PMC2702859, DOI: 10.1016/j.jneuroim.2008.01.002.Peer-Reviewed Original ResearchConceptsMultiple sclerosisCentral nervous systemChemokine productionHealthy donorsCD46 activationPathogenesis of MSIL-23 secretionChronic inflammatory diseasePotent proinflammatory cytokineRole of CD46CCL2 levelsDC activationIL-23Dendritic cellsIL-23p19Proinflammatory cytokinesCCL5 productionInflammatory diseasesNervous systemPatientsPotential roleSclerosisCytokinesActivationElevated amounts
2006
The role of inflammatory bowel disease susceptibility loci in multiple sclerosis and systemic lupus erythematosus
De Jager PL, Graham R, Farwell L, Sawcer S, Richardson A, Behrens TW, Compston A, Hafler DA, Kere J, Vyse TJ, Rioux JD. The role of inflammatory bowel disease susceptibility loci in multiple sclerosis and systemic lupus erythematosus. Genes & Immunity 2006, 7: 327-334. PMID: 16642031, DOI: 10.1038/sj.gene.6364303.Peer-Reviewed Original ResearchMeSH KeywordsChromosomes, Human, Pair 5ExonsGenetic Predisposition to DiseaseHumansInflammatory Bowel DiseasesIntracellular Signaling Peptides and ProteinsLupus Erythematosus, SystemicMembrane ProteinsMultiple SclerosisNod2 Signaling Adaptor ProteinPolymorphism, Single NucleotideTumor Suppressor ProteinsConceptsSystemic lupus erythematosusInflammatory bowel diseaseMultiple sclerosisRisk allelesLupus erythematosusInflammatory diseasesCases of SLERisk of SLECARD15/NOD2 geneGeneral susceptibility locusIBD risk allelesChronic inflammatory diseaseIBD5 locusComplex inflammatory diseaseInflammatory bowel disease susceptibility lociEvidence of associationLupus nephritisBowel diseaseSLE subjectsPooled analysisCARD15 geneSusceptibility lociNOD2 geneDiseaseErythematosus
2005
Evaluating the role of the 620W allele of protein tyrosine phosphatase PTPN22 in Crohn's disease and multiple sclerosis
De Jager PL, Sawcer S, Waliszewska A, Farwell L, Wild G, Cohen A, Langelier D, Bitton A, Compston A, Hafler DA, Rioux JD. Evaluating the role of the 620W allele of protein tyrosine phosphatase PTPN22 in Crohn's disease and multiple sclerosis. European Journal Of Human Genetics 2005, 14: 317-321. PMID: 16391555, DOI: 10.1038/sj.ejhg.5201548.Peer-Reviewed Original ResearchMeSH KeywordsAllelesCanadaCase-Control StudiesCrohn DiseaseGene FrequencyGenetic Predisposition to DiseaseGenotypeHumansInflammationModels, StatisticalMultiple SclerosisOdds RatioPolymorphism, GeneticProtein Tyrosine Phosphatase, Non-Receptor Type 1Protein Tyrosine Phosphatase, Non-Receptor Type 22Protein Tyrosine PhosphatasesRiskUnited KingdomConceptsSystemic lupus erythematosusCases of CDCrohn's diseaseMultiple sclerosisPTPN22 620W alleleAutoimmune thyroiditisRheumatoid arthritisInflammatory diseasesEvidence of associationCases of MSProtein tyrosine phosphatase PTPN22Chronic inflammatory diseaseType 1 diabetesTyrosine phosphatase PTPN22PTPN22 alleleLupus erythematosusPooled analysisControl subjectsModest odds ratiosOdds ratioDiseaseRisk allelesPhosphatase PTPN22SclerosisPossible roleApplying a new generation of genetic maps to understand human inflammatory disease
Hafler DA, Jager P. Applying a new generation of genetic maps to understand human inflammatory disease. Nature Reviews Immunology 2005, 5: 83-91. PMID: 15630431, DOI: 10.1038/nri1532.Peer-Reviewed Original Research
2004
Loss of Functional Suppression by CD4+CD25+ Regulatory T Cells in Patients with Multiple Sclerosis
Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of Functional Suppression by CD4+CD25+ Regulatory T Cells in Patients with Multiple Sclerosis. Journal Of Experimental Medicine 2004, 199: 971-979. PMID: 15067033, PMCID: PMC2211881, DOI: 10.1084/jem.20031579.Peer-Reviewed Original ResearchConceptsRegulatory T cellsMultiple sclerosisT cellsRegulatory T cell functionActivity of murineSpontaneous autoimmune diseaseT cell functionSingle cell cloning experimentsPeripheral toleranceCell cloning experimentsAutoimmune diseasesPeripheral bloodInflammatory diseasesHealthy donorsHuman CD4Effector functionsNormal controlsPatientsFunctional suppressionCell functionSignificant decreaseSclerosisProtein peptidesDiseaseActive suppression
2003
CTLA-4 dysregulation in the activation of myelin basic protein reactive T cells may distinguish patients with multiple sclerosis from healthy controls
Oliveira EM, Bar-Or A, Waliszewska AI, Cai G, Anderson DE, Krieger JI, Hafler DA. CTLA-4 dysregulation in the activation of myelin basic protein reactive T cells may distinguish patients with multiple sclerosis from healthy controls. Journal Of Autoimmunity 2003, 20: 71-81. PMID: 12604314, DOI: 10.1016/s0896-8411(02)00106-3.Peer-Reviewed Original ResearchConceptsMultiple sclerosisT cellsMyelin basic proteinHealthy controlsMyelin basic protein-reactive T cellsMBP-reactive T cellsPathogenesis of MSPeripheral blood mononuclear cellsCTLA-4 blockadeReactive T cellsBlood mononuclear cellsCo-stimulatory pathwaysNaïve T cellsCo-stimulatory signalsCentral nervous systemCTLA-4 engagementCytokine responsesAutoimmune responseMononuclear cellsInflammatory diseasesB7-CD28Proliferative responseNervous systemPatientsMyelin sheath
2001
The Neuroimmunology of Multiple Sclerosis: Possible Roles of T and B Lymphocytes in Immunopathogenesis
O'connor K, Bar-Or A, Hafler D. The Neuroimmunology of Multiple Sclerosis: Possible Roles of T and B Lymphocytes in Immunopathogenesis. Journal Of Clinical Immunology 2001, 21: 81-92. PMID: 11332657, DOI: 10.1023/a:1011064007686.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsMultiple sclerosisT cellsB cellsImmunopathology of MSMyelin-reactive T cellsCentral nervous system white matterNervous system white matterAutoreactive T cellsMS immunopathologyImmunosuppressive therapyCNS pathogenesisTolerance breakdownAutoreactive cellsInflammatory diseasesPathological studiesAnimal modelsB lymphocytesWhite matterMajor mediatorDisease pathologyNonhuman primatesDiseaseEvidence supportImmunopathologySclerosis
1999
Molecular pathogenesis of multiple sclerosis
Bar-Or A, Oliveira E, Anderson D, Hafler D. Molecular pathogenesis of multiple sclerosis. Journal Of Neuroimmunology 1999, 100: 252-259. PMID: 10695735, DOI: 10.1016/s0165-5728(99)00193-9.Peer-Reviewed Original ResearchConceptsMultiple sclerosisT cellsMyelin-reactive T cellsCentral nervous system white matterB7 costimulatory pathwayNervous system white matterDifferential activation statesMacrophage infiltratesMS patientsAxonal injuryNeurological functionProinflammatory cellsProinflammatory cytokinesCostimulatory pathwayInflammatory diseasesMS lesionsMolecular pathogenesisWhite matterMolecular mimicryMatrix metalloproteinasesNormal individualsAdhesion moleculesSelective expressionSclerosisActivation state
1998
Expansion of autoreactive T cells in multiple sclerosis is independent of exogenous B7 costimulation.
Scholz C, Patton K, Anderson D, Freeman G, Hafler D. Expansion of autoreactive T cells in multiple sclerosis is independent of exogenous B7 costimulation. The Journal Of Immunology 1998, 160: 1532-8. PMID: 9570577, DOI: 10.4049/jimmunol.160.3.1532.Peer-Reviewed Original ResearchMeSH KeywordsAbataceptAntigens, CDAntigens, DifferentiationAutoantigensB7-1 AntigenB7-2 AntigenClone CellsCTLA-4 AntigenEpitopes, T-LymphocyteHumansImmunoconjugatesImmunoglobulin Fc FragmentsImmunosuppressive AgentsInterleukin-4Lymphocyte ActivationMembrane GlycoproteinsMultiple SclerosisMyelin Basic ProteinRecombinant Fusion ProteinsT-Lymphocyte SubsetsTetanus ToxoidThymidineConceptsCD4 T cellsMultiple sclerosisT cellsB7-1Myelin basic proteinPathogenesis of MSMyelin-reactive T cellsPeripheral blood T cellsB7-2 engagementAutoreactive T cellsBlood T cellsAbsence of costimulationCentral nervous systemAntigen-specific signalT cell activationMS patientsB7 costimulationInflammatory diseasesTetanus toxoidB7-2Normal controlsNormal subjectsCostimulatory signalsNervous systemCell activation
1997
Increased interleukin 12 production in progressive multiple sclerosis: Induction by activated CD4+ T cells via CD40 ligand
Balashov K, Smith D, Khoury S, Hafler D, Weiner H. Increased interleukin 12 production in progressive multiple sclerosis: Induction by activated CD4+ T cells via CD40 ligand. Proceedings Of The National Academy Of Sciences Of The United States Of America 1997, 94: 599-603. PMID: 9012830, PMCID: PMC19559, DOI: 10.1073/pnas.94.2.599.Peer-Reviewed Original ResearchConceptsIL-12 secretionIFN-gamma secretionMS patientsMultiple sclerosisT cellsIL-12Anti-CD40 ligand antibodyTh1-type immune activationCell-mediated autoimmune diseaseProgressive MS patientsProgressive multiple sclerosisIFN-gamma administrationRelapsing-remitting patientsExacerbation of diseaseInterleukin-12 productionChronic inflammatory diseaseCD40 ligand expressionCentral nervous systemActivated T cellsImmune interventionImmune activationAutoimmune diseasesInterleukin-12Inflammatory diseasesCD40 ligand
1992
Autoreactive T Cells in Multiple Sclerosis
Zhang J, Weiner H, Hafler D. Autoreactive T Cells in Multiple Sclerosis. International Reviews Of Immunology 1992, 9: 183-201. PMID: 1285060, DOI: 10.3109/08830189209061790.Peer-Reviewed Original ResearchConceptsCentral nervous systemMultiple sclerosisInflammatory processT cellsCerebrospinal fluidNervous systemAcute MS plaquesActive inflammatory processAutoreactive T cellsChronic inflammatory diseaseCNS inflammatory processesIL-2 receptorPeripheral nervous systemActivated T cellsNeurologic disabilityNeurological functionMS plaquesSensory deficitsInflammatory diseasesOligoclonal immunoglobulinsPositive macrophagesT lymphocytesWhite matterVisual problemsDemyelinationTreatment of Multiple Sclerosis with Cyclophosphamide
Mackin G, Dawson D, Hafler D, Weiner H. Treatment of Multiple Sclerosis with Cyclophosphamide. Clinical Medicine And The Nervous System 1992, 199-216. DOI: 10.1007/978-1-4471-3184-7_9.Peer-Reviewed Original Research