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
2013
Protein array–based profiling of CSF identifies RBPJ as an autoantigen in multiple sclerosis
Querol L, Clark PL, Bailey MA, Cotsapas C, Cross AH, Hafler DA, Kleinstein SH, Lee JY, Yaari G, Willis SN, O'Connor KC. Protein array–based profiling of CSF identifies RBPJ as an autoantigen in multiple sclerosis. Neurology 2013, 81: 956-963. PMID: 23921886, PMCID: PMC3888197, DOI: 10.1212/wnl.0b013e3182a43b48.Peer-Reviewed Original ResearchConceptsCSF of patientsMultiple sclerosisNeurologic diseaseEpstein-Barr virus infectionImmunoglobulin GElevated immunoglobulin GInflammatory neurologic diseasesSubset of patientsLarger validation cohortRecombination signal binding proteinImmunoglobulin kappa J regionCSF autoantibodiesValidation cohortControl subjectsSerum reactivityAutoantigen candidatesHigh prevalenceVirus infectionPatientsAutoantibodiesCSFSclerosisArray-based profilingDiseaseELISA
2011
Increased Frequencies of Myelin Oligodendrocyte Glycoprotein/MHC Class II-Binding CD4 Cells in Patients with Multiple Sclerosis
Raddassi K, Kent SC, Yang J, Bourcier K, Bradshaw EM, Seyfert-Margolis V, Nepom GT, Kwok WW, Hafler DA. Increased Frequencies of Myelin Oligodendrocyte Glycoprotein/MHC Class II-Binding CD4 Cells in Patients with Multiple Sclerosis. The Journal Of Immunology 2011, 187: 1039-1046. PMID: 21653833, PMCID: PMC3131477, DOI: 10.4049/jimmunol.1001543.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAmino Acid SubstitutionCD4 Lymphocyte CountCD4-Positive T-LymphocytesCell CommunicationCell Line, TransformedCells, CulturedEpitopes, T-LymphocyteFemaleGene FrequencyHLA-DR AntigensHLA-DRB1 ChainsHumansImmunophenotypingMaleMiddle AgedMultiple SclerosisMyelin-Associated GlycoproteinMyelin-Oligodendrocyte GlycoproteinPeptide FragmentsProtein BindingProtein MultimerizationConceptsMyelin-reactive T cellsMultiple sclerosisT cell clonesT cellsHealthy controlsMOG-reactive T cellsAutoantigen-specific T cellsCell clonesStimulation of PMBCsClass II tetramersPathogenic immune cellsReactive T cellsSpecific T cellsMyelin oligodendrocyte glycoproteinHLA class IIBlood of subjectsT-cell cloning techniqueMOG peptidesShort-term cultureCD4 cellsMS subjectsAutoimmune diseasesPeripheral bloodControl subjectsOligodendrocyte glycoprotein
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 1The 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 mechanismsSclerosisSoluble IL-2RA Levels in Multiple Sclerosis Subjects and the Effect of Soluble IL-2RA on Immune Responses
Maier LM, Anderson DE, Severson CA, Baecher-Allan C, Healy B, Liu DV, Wittrup KD, De Jager PL, Hafler DA. Soluble IL-2RA Levels in Multiple Sclerosis Subjects and the Effect of Soluble IL-2RA on Immune Responses. The Journal Of Immunology 2009, 182: 1541-1547. PMID: 19155502, PMCID: PMC3992946, DOI: 10.4049/jimmunol.182.3.1541.Peer-Reviewed Original ResearchConceptsMultiple sclerosisIL-2 receptorMS subjectsHealthy controlsOrgan-specific autoimmune disordersChronic systemic inflammationType 1 diabetesT cell proliferationMultiple sclerosis subjectsStrong genetic factorIL-2 signalingSIL-2RaSystemic inflammationAutoimmune disordersImmunological perturbationsAutoimmune diseasesIL-2RAControl subjectsMS casesSerum concentrationsDisease onsetSpecific allelic variantsImmune responseAggressive formDisease riskIL2RA Genetic Heterogeneity in Multiple Sclerosis and Type 1 Diabetes Susceptibility and Soluble Interleukin-2 Receptor Production
Maier LM, Lowe CE, Cooper J, Downes K, Anderson DE, Severson C, Clark PM, Healy B, Walker N, Aubin C, Oksenberg JR, Hauser SL, Compston A, Sawcer S, , De Jager PL, Wicker LS, Todd JA, Hafler DA. IL2RA Genetic Heterogeneity in Multiple Sclerosis and Type 1 Diabetes Susceptibility and Soluble Interleukin-2 Receptor Production. PLOS Genetics 2009, 5: e1000322. PMID: 19119414, PMCID: PMC2602853, DOI: 10.1371/journal.pgen.1000322.Peer-Reviewed Original ResearchConceptsMultiple sclerosisT1D subjectsSoluble interleukin-2 receptor productionSoluble interleukin-2 receptorOrgan-specific autoimmune disordersHealthy control subjectsInterleukin-2 receptorType 1 diabetesHuman leukocyte antigen (HLA) complexMS risk genesAutoimmune disordersControl subjectsAutoimmunity riskHealthy controlsIL2RA regionType 1Autoimmune lociRisk allelesReceptor productionCandidate gene association studiesAntigen complexGene association studiesAssociation studiesT1D.Sclerosis
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 diseases
2007
Risk Alleles for Multiple Sclerosis Identified by a Genomewide Study
Hafler D, Compston A, Sawcer S, Lander E, Daly M, De Jager P, de Bakker P, Gabriel S, Mirel D, Ivinson A, Pericak-Vance M, Gregory S, Rioux J, McCauley J, Haines J, Barcellos L, Cree B, Oksenberg J, Hauser S. Risk Alleles for Multiple Sclerosis Identified by a Genomewide Study. New England Journal Of Medicine 2007, 357: 851-862. PMID: 17660530, DOI: 10.1056/nejmoa073493.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAgedAllelesFemaleGenetic Predisposition to DiseaseGenome, HumanHLA-DR alpha-ChainsHLA-DR AntigensHumansInterleukin-2 Receptor alpha SubunitInterleukin-7 Receptor alpha SubunitLinkage DisequilibriumMaleMiddle AgedMultiple SclerosisMutationOligonucleotide Array Sequence AnalysisPolymorphism, Single NucleotideRisk FactorsConceptsMultiple sclerosisReceptor alpha geneSingle nucleotide polymorphismsControl subjectsCase subjectsInterleukin-7 receptor alpha geneHeritable risk factorsAlpha geneRisk factorsFamily triosSclerosisRisk allelesHLA lociHLA-DRA locusTransmission disequilibrium testStringent P valueP-valueEffect sizeSignificant heritable componentInterleukin-2 receptor alpha geneNonsynonymous single nucleotide polymorphismsGenomewide association studiesMultiple single nucleotide polymorphismsSubjectsAssociationA second major histocompatibility complex susceptibility locus for multiple sclerosis
Yeo TW, De Jager PL, Gregory SG, Barcellos LF, Walton A, Goris A, Fenoglio C, Ban M, Taylor CJ, Goodman RS, Walsh E, Wolfish CS, Horton R, Traherne J, Beck S, Trowsdale J, Caillier SJ, Ivinson AJ, Green T, Pobywajlo S, Lander ES, Pericak-Vance MA, Haines JL, Daly MJ, Oksenberg JR, Hauser SL, Compston A, Hafler DA, Rioux JD, Sawcer S, . A second major histocompatibility complex susceptibility locus for multiple sclerosis. Annals Of Neurology 2007, 61: 228-236. PMID: 17252545, PMCID: PMC2737610, DOI: 10.1002/ana.21063.Peer-Reviewed Original ResearchConceptsMajor histocompatibility complexMultiple sclerosisHLA-C geneHLA-DRB1 geneHuman leukocyte antigen (HLA) typingResidual associationHLA-DRB1 locusComplex susceptibility lociTight linkage disequilibriumControl subjectsAntigen typingProtective effectSclerosisClass II regionHistocompatibility complexHLA lociRisk haplotypeClassical HLA lociSingle nucleotide polymorphismsIndependent effectsChromosome 6p21AssociationNucleotide polymorphismsTrio familiesSusceptibility loci
2006
Dysregulated T cell expression of TIM3 in multiple sclerosis
Koguchi K, Anderson DE, Yang L, O'Connor KC, Kuchroo VK, Hafler DA. Dysregulated T cell expression of TIM3 in multiple sclerosis. Journal Of Experimental Medicine 2006, 203: 1413-1418. PMID: 16754722, PMCID: PMC2118310, DOI: 10.1084/jem.20060210.Peer-Reviewed Original ResearchConceptsIFN-gamma secretionCSF clonesT cell expressionMultiple sclerosisT cellsHuman T cellsTIM3 expressionControl subjectsCerebrospinal fluidCell expressionMucin-domain-containing moleculesPathogenesis of MSEx vivo CD4Human autoimmune diseasesT helper cellsT-cell immunoglobulinT cell clonesVivo CD4Costimulatory blockadeTh1 responseCytokine profileCell surface moleculesAutoimmune diseasesHelper cellsInterleukin-12
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 role
1999
T cell Autoreactivity to Proinsulin Epitopes in Diabetic Patients and Healthy Subjects
Semana G, Gausling R, Jackson R, Hafler D. T cell Autoreactivity to Proinsulin Epitopes in Diabetic Patients and Healthy Subjects. Journal Of Autoimmunity 1999, 12: 259-267. PMID: 10330297, DOI: 10.1006/jaut.1999.0282.Peer-Reviewed Original ResearchConceptsProinsulin epitopesImmune responseProliferative responseReactive cellsPeptide-specific T cellsShort-term cell linesSpecific T cell clonesHigher 3H-thymidine incorporationPredominant immune responseT cell autoreactivitySpecific T cellsLow proliferative responseTissue-specific autoantigensT cell clonesCD3-CD28IDDM groupIDDM patientsDiabetic patientsControl subjectsDisease onsetPotential autoantigensStrong TCR signalsC-peptideT cellsHealthy subjects
1995
T cell recognition of immunodominant and cryptic proteolipid protein epitopes in humans.
Markovic-Plese S, Fukaura H, Zhang J, al-Sabbagh A, Southwood S, Sette A, Kuchroo VK, Hafler DA. T cell recognition of immunodominant and cryptic proteolipid protein epitopes in humans. The Journal Of Immunology 1995, 155: 982-92. PMID: 7541828, DOI: 10.4049/jimmunol.155.2.982.Peer-Reviewed Original ResearchConceptsMultiple sclerosisT cellsPLP epitopesMHC class II isotypesPLP-reactive T cellsShort-term T cell linesCryptic epitopesProteolipid proteinT cell responsesT cell recognitionClass II isotypesT cell linesIndividual synthetic peptidesControl subjectsMHC restrictionImmune responseDR2 moleculesProliferative responseImmunodominant epitopesPLP peptidesProtein AgCell responsesCentral nervous system myelin proteinsMyelin proteinsEpitopesIncreased frequency of gamma delta T cells in cerebrospinal fluid and peripheral blood of patients with multiple sclerosis. Reactivity, cytotoxicity, and T cell receptor V gene rearrangements.
Stinissen P, Vandevyver C, Medaer R, Vandegaer L, Nies J, Tuyls L, Hafler DA, Raus J, Zhang J. Increased frequency of gamma delta T cells in cerebrospinal fluid and peripheral blood of patients with multiple sclerosis. Reactivity, cytotoxicity, and T cell receptor V gene rearrangements. The Journal Of Immunology 1995, 154: 4883-94. PMID: 7722338, DOI: 10.4049/jimmunol.154.9.4883.Peer-Reviewed Original ResearchConceptsGamma delta T cell clonesGamma delta T cellsDelta T cellsT cell clonesGamma delta clonesMultiple sclerosisPeripheral bloodT cellsCerebrospinal fluidMS patientsOND patientsCell clonesControl subjectsNormal individualsBacterial superantigen staphylococcal enterotoxin BCentral nervous system demyelinationCSF of patientsSuperantigen staphylococcal enterotoxin BToxic shock syndrome toxin-1Nervous system demyelinationClonal originSecondary inflammatory processesV gene usageSyndrome toxin-1Staphylococcal enterotoxin B
1991
Common T‐cell receptor Vβ usage in oligoclonal T lymphocytes derived from cerebrospinal fluid and blood of patients with multiple sclerosis
Lee S, Wucherpfennig K, Brod S, Benjamin D, Weiner H, Hafler D. Common T‐cell receptor Vβ usage in oligoclonal T lymphocytes derived from cerebrospinal fluid and blood of patients with multiple sclerosis. Annals Of Neurology 1991, 29: 33-40. PMID: 1847614, DOI: 10.1002/ana.410290109.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAgedBase SequenceBlotting, SouthernChild, PreschoolClone CellsDNA ProbesFemaleGene Rearrangement, beta-Chain T-Cell Antigen ReceptorGene Rearrangement, gamma-Chain T-Cell Antigen ReceptorHumansMaleMiddle AgedMolecular Sequence DataMultiple SclerosisPhenotypePolymerase Chain ReactionT-LymphocytesConceptsT cell populationsT cell clonesCerebrospinal fluidMultiple sclerosisT cellsT cell receptor Vβ usageNeurological diseasesOligoclonal T-cell populationsT cell receptor V beta genesOligoclonal T lymphocytesOligoclonal T cellsSame T cell receptorBlood of patientsNormal control subjectsT cell receptor beta chainProgenitor T cellsT cell receptorIndividual T cellsGamma chain geneImmune compartmentVβ usageControl subjectsReceptor beta chainT lymphocytesPatients
1986
Cell-mediated immunity to myelin-associated glycoprotein, proteolipid protein, and myelin basic protein in multiple sclerosis
Johnson D, Hafler D, Fallis R, Lees M, Brady R, Quarles R, Weiner H. Cell-mediated immunity to myelin-associated glycoprotein, proteolipid protein, and myelin basic protein in multiple sclerosis. Journal Of Neuroimmunology 1986, 13: 99-108. PMID: 2428837, DOI: 10.1016/0165-5728(86)90053-6.Peer-Reviewed Original ResearchConceptsActive MS patientsMyelin basic proteinPeripheral blood lymphocytesMyelin antigensMS patientsControl subjectsActive MSMultiple sclerosisNeurologic diseaseProteolipid proteinStable multiple sclerosis patientsMean proliferative responseCell-mediated immunityMultiple sclerosis patientsBasic proteinStable MSOND groupSclerosis patientsT8 subsetsBlood lymphocytesLymphocyte stimulationProliferative responseProportion of individualsPatientsAntigen