2019
Autoantibodies 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 toleranceTIGIT 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 pathway
2015
Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cells
Hernandez AL, Kitz A, Wu C, Lowther DE, Rodriguez DM, Vudattu N, Deng S, Herold KC, Kuchroo VK, Kleinewietfeld M, Hafler DA. Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cells. Journal Of Clinical Investigation 2015, 125: 4212-4222. PMID: 26524592, PMCID: PMC4639983, DOI: 10.1172/jci81151.Peer-Reviewed Original ResearchMeSH KeywordsAdoptive TransferAnimalsAntibodies, NeutralizingAutoimmunityCD4-Positive T-LymphocytesCells, CulturedCoculture TechniquesColitisCytokinesForkhead Transcription FactorsGene Expression ProfilingGenes, ReporterGraft vs Host DiseaseHeterograftsHumansImmediate-Early ProteinsInflammationInterferon-gammaLeukocytes, MononuclearMaleMiceProtein Serine-Threonine KinasesRNA InterferenceRNA, Small InterferingSodium ChlorideSodium Chloride, DietaryT-Lymphocytes, RegulatoryConceptsHigh-salt dietTreg functionIFNγ secretionCD4 effector cellsHuman Treg functionRegulatory T cellsAdoptive transfer modelAnti-IFNγ antibodyHost disease modelType 1 diabetesInduction of proinflammatoryTreg pathwayExperimental colitisXenogeneic graftEffector cellsMultiple sclerosisProinflammatory responseT cellsTregsMurine modelSuppressive activitySuppressive functionSerum/glucocorticoid-regulated kinaseAutoimmunityGlucocorticoid-regulated kinase
2013
Specific peripheral B cell tolerance defects in patients with multiple sclerosis
Kinnunen T, Chamberlain N, Morbach H, Cantaert T, Lynch M, Preston-Hurlburt P, Herold KC, Hafler DA, O’Connor K, Meffre E. Specific peripheral B cell tolerance defects in patients with multiple sclerosis. Journal Of Clinical Investigation 2013, 123: 2737-2741. PMID: 23676463, PMCID: PMC3668812, DOI: 10.1172/jci68775.Peer-Reviewed Original ResearchConceptsB cell tolerance checkpointsB cell tolerance defectsMultiple sclerosisRheumatoid arthritisTolerance checkpointsB cellsPeripheral B cell tolerance checkpointsTolerance defectsAutoreactive B cell clonesMature naive B cellsType 1 diabetesAutoreactive B cellsB cell toleranceCentral nervous systemNaive B cellsB cell clonesB cell selectionEarly B cell developmentIPEX patientsMost patientsTreg functionHomeostatic proliferationAutoimmune diseasesPatientsHealthy individualsPhIP-Seq characterization of autoantibodies from patients with multiple sclerosis, type 1 diabetes and rheumatoid arthritis
Larman HB, Laserson U, Querol L, Verhaeghen K, Solimini NL, Xu GJ, Klarenbeek PL, Church GM, Hafler DA, Plenge RM, Nigrovic PA, De Jager PL, Weets I, Martens GA, O'Connor KC, Elledge SJ. PhIP-Seq characterization of autoantibodies from patients with multiple sclerosis, type 1 diabetes and rheumatoid arthritis. Journal Of Autoimmunity 2013, 43: 1-9. PMID: 23497938, PMCID: PMC3677742, DOI: 10.1016/j.jaut.2013.01.013.Peer-Reviewed Original ResearchConceptsType 1 diabetes patientsRheumatoid arthritis patientsMultiple sclerosis patientsLoss of tolerancePhage immunoprecipitation sequencingType 1 diabetesNeurological autoimmunitySeropositivity statusArthritis patientsRheumatoid arthritisSclerosis patientsMultiple sclerosisAutoimmune diseasesDiabetes patientsCerebrospinal fluidGeneral populationSynovial fluidHealthy seraPatientsSusceptible individualsAntibody specificityDiseaseReceptor specificitySerumHuman peptidome
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
On-Chip Activation and Subsequent Detection of Individual Antigen-Specific T Cells
Song Q, Han Q, Bradshaw EM, Kent SC, Raddassi K, Nilsson B, Nepom GT, Hafler DA, Love JC. On-Chip Activation and Subsequent Detection of Individual Antigen-Specific T Cells. Analytical Chemistry 2009, 82: 473-477. PMID: 20000848, PMCID: PMC2828941, DOI: 10.1021/ac9024363.Peer-Reviewed Original ResearchConceptsAntigen-specific T cellsAntigen-specific CD4T cellsAntigen-specific mannerType 1 diabetesMajor histocompatibility complex receptorIndividual CD4Multiple sclerosisAutoimmune diseasesPrimary T cellsCD4Subnanoliter wellsClinical samplesNumber of cellsComplex receptorSubsequent assessmentHuman tissuesCellsChip activationVivoActivationSclerosisDiabetesCytokinesDiseaseMonocytes 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 1Soluble 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
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 roleInsulin auto-antigenicity in type 1 diabetes (Reply)
Hafler D, Kent S, Chen Y, Bregoli L, Clemmings S, Hering B, Kenyon N, Ricordi C. Insulin auto-antigenicity in type 1 diabetes (Reply). Nature 2005, 438: e5-e6. DOI: 10.1038/nature04424.Peer-Reviewed Original ResearchExpanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope
Kent SC, Chen Y, Bregoli L, Clemmings SM, Kenyon NS, Ricordi C, Hering BJ, Hafler DA. Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope. Nature 2005, 435: 224-228. PMID: 15889096, DOI: 10.1038/nature03625.Peer-Reviewed Original ResearchConceptsWhite blood cellsAutoimmune diabetesLymph nodesType 1 diabetic subjectsPancreatic lymph nodesAntigen-specific therapyExpanded T cellsIslet cell transplantationType 1 diabetesPossible clinical relevanceStandard animal modelPrimary autoantigenNOD miceDiabetic subjectsImmune therapyMultiple sclerosisChildhood diabetesInsulin-producing cellsSpecific therapyImmune cellsT cellsT lymphocytesInsulin epitopesAnimal modelsClinical relevance
2004
Regulatory T cells in type 1 diabetes mellitus
Viglietta V, Baecher-Allan C, Hafler A, Gottlieb P. Regulatory T cells in type 1 diabetes mellitus. Current Opinion In Endocrinology Diabetes And Obesity 2004, 11: 85-90. DOI: 10.1097/01.med.0000129641.34639.2e.Peer-Reviewed Original ResearchRegulatory T cellsType 1 diabetes mellitusType 1 diabetesT cellsDiabetes mellitusT lymphocytesHuman type 1 diabetesΒ-cell antigensNK T cellsTh2-type responseMost healthy subjectsReactive T lymphocytesOnset of diseaseInsulin-producing β-cellsAutoimmune conditionsPeripheral toleranceRegulatory cellsPeripheral deletionSpecific immunizationTh2 cytokinesAutoimmune diseasesHealthy subjectsAntigen reactivityHealthy individualsAnergy induction
2002
GAD65-reactive T cells are activated in patients with autoimmune type 1a diabetes
Viglietta V, Kent SC, Orban T, Hafler DA. GAD65-reactive T cells are activated in patients with autoimmune type 1a diabetes. Journal Of Clinical Investigation 2002, 109: 895-903. PMID: 11927616, PMCID: PMC150925, DOI: 10.1172/jci14114.Peer-Reviewed Original ResearchMeSH KeywordsAbataceptAdultAntigens, CDAntigens, DifferentiationAutoimmunityB7-1 AntigenB7-2 AntigenCD28 AntigensCell DivisionCTLA-4 AntigenDiabetes Mellitus, Type 1FemaleGlutamate DecarboxylaseHumansImmunoconjugatesInterferon-gammaInterleukin-13IsoenzymesMaleMembrane GlycoproteinsSignal TransductionT-LymphocytesConceptsGAD65-reactive T cellsType 1 diabetesAutoreactive T cellsT cellsB7-1New-onset type 1 diabetesPancreatic islet cell antigensInsulin-dependent type 1 diabetesGlutamic acid decarboxylase 65B7-2 engagementType 1A diabetesMemory T cellsStimulation ex vivoIslet cell antigensB7-2 moleculesT cell proliferationB7-1 costimulationAutoimmune diseasesCTLA-4Healthy controlsPathogenic roleSelective blockadeCytokine secretionHuman diabetesT lymphocytes
2001
Heterophile Antibodies Indicate Progression of Autoimmunity in Human Type 1 Diabetes Mellitus Before Clinical Onset
Orban T, Kent SC, Malik P, Milner JD, Schuster K, Jackson RA, Hafler DA. Heterophile Antibodies Indicate Progression of Autoimmunity in Human Type 1 Diabetes Mellitus Before Clinical Onset. Autoimmunity 2001, 34: 247-264. PMID: 11905851, DOI: 10.3109/08916930109014694.Peer-Reviewed Original ResearchConceptsHeterophile antibodiesType 1 diabetes autoimmunityType 1 diabetes mellitus patientsDiabetes mellitus patientsProgression of autoimmunityAntibody-positive seraType 1 diabetesFirst-degree relativesHuman type 1T cell growthAnti-human immunoglobulinDiabetes autoimmunitySerum cytokinesMellitus patientsClinical onsetAntibody presenceIL-4Degree relativesDisease progressionLower incidenceHigh riskHigh incidenceHeterophilic antibodiesAntibody activityAntibody reactivity
2000
Multiple differences in gene expression in regulatory Vα24JαQ T cells from identical twins discordant for type I diabetes
Wilson S, Kent S, Horton H, Hill A, Bollyky P, Hafler D, Strominger J, Byrne M. Multiple differences in gene expression in regulatory Vα24JαQ T cells from identical twins discordant for type I diabetes. Proceedings Of The National Academy Of Sciences Of The United States Of America 2000, 97: 7411-7416. PMID: 10840051, PMCID: PMC16559, DOI: 10.1073/pnas.120161297.Peer-Reviewed Original ResearchConceptsT cell receptor activationCell receptor activationT cellsTranscriptional consequencesDNA microarraysGene expressionActivation of cellsMyeloid lineageClonesMurine autoimmune diseaseInvariant T (MAIT) cellsIL-4 secretionType 1 diabetesAnti-CD3 stimulationT cell clonesIdentical twinsMRNA levelsReceptor activationCellsCell clonesAutoimmune diseasesActivationSecreting clonesQualitative defectsMultiple differences
1999
Heterophile antibodies segregate in families and are associated with protection from type 1 diabetes
She J, Ellis T, Wilson S, Wasserfall C, Marron M, Reimsneider S, Kent S, Hafler D, Neuberg D, Muir A, Strominger J, Atkinson M. Heterophile antibodies segregate in families and are associated with protection from type 1 diabetes. Proceedings Of The National Academy Of Sciences Of The United States Of America 1999, 96: 8116-8119. PMID: 10393957, PMCID: PMC22197, DOI: 10.1073/pnas.96.14.8116.Peer-Reviewed Original ResearchErratum: 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. Erratum: Extreme Th1 bias of invariant Vα24JαQ T cells in type 1 diabetes. Nature 1999, 399: 84-84. DOI: 10.1038/20007.Peer-Reviewed Original Research
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