2013
PhIP-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
2009
Evaluating the Intrinsic Cysteine Redox-Dependent States of the A-Chain of Human Insulin Using NMR Spectroscopy, Quantum Chemical Calculations, and Mass Spectrometry
Sharma AK, Ling Y, Greer AB, Hafler DA, Kent SC, Zhang Y, Rigby AC. Evaluating the Intrinsic Cysteine Redox-Dependent States of the A-Chain of Human Insulin Using NMR Spectroscopy, Quantum Chemical Calculations, and Mass Spectrometry. The Journal Of Physical Chemistry B 2009, 114: 585-591. PMID: 19954153, PMCID: PMC2829747, DOI: 10.1021/jp908729h.Peer-Reviewed Original ResearchConceptsQuantum chemical calculationsChemical calculationsFree thiol moietyNMR spectroscopy dataA-chain peptideRedox chemistryNMR spectroscopyThiol moietyCell surface class II moleculesMass spectrometry analysisOxidized stateFunctional studiesA-chain analogueIntrinsic cysteine residuesMass spectrometryPeptide interactionsConformational equilibriumSpectroscopy dataRedox-dependent mechanismDisulfide conformationSpectrometry analysisDependent conformational equilibriumPrevious functional studiesConformationProtein systems
2008
Lysosomal Cysteine and Aspartic Proteases Are Heterogeneously Expressed and Act Redundantly to Initiate Human Invariant Chain Degradation
Costantino CM, Hang HC, Kent SC, Hafler DA, Ploegh HL. Lysosomal Cysteine and Aspartic Proteases Are Heterogeneously Expressed and Act Redundantly to Initiate Human Invariant Chain Degradation. The Journal Of Immunology 2008, 180: 2876-2885. PMID: 18292509, DOI: 10.4049/jimmunol.180.5.2876.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAntigen PresentationAntigens, Differentiation, B-LymphocyteAspartic Acid EndopeptidasesB-LymphocytesCD4-Positive T-LymphocytesCell Line, TransformedClone CellsCoculture TechniquesCysteine EndopeptidasesGene Expression Regulation, EnzymologicGenetic HeterogeneityHistocompatibility Antigens Class IIHLA-D AntigensHumansLysosomesMolecular Sequence DataProtease InhibitorsProtein Processing, Post-TranslationalConceptsAsparagine endopeptidasePeptide AgClass II MHC productsMyelin basic protein epitopeClass II MHCClass II invariant chainInvariant chain cleavageInvariant chain degradationPresentation of AgInvariant chain processingAEP inhibitionB cell linesDistinct allelic variantsII MHCMHC productsDifferent EBVMHC dimersAllelic variantsHuman AgInvariant chainAltered regulation
2007
A Local Antigen-Driven Humoral Response Is Present in the Inflammatory Myopathies
Bradshaw EM, Orihuela A, McArdel SL, Salajegheh M, Amato AA, Hafler DA, Greenberg SA, O’Connor K. A Local Antigen-Driven Humoral Response Is Present in the Inflammatory Myopathies. The Journal Of Immunology 2007, 178: 547-556. PMID: 17182595, DOI: 10.4049/jimmunol.178.1.547.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAmino Acid SequenceAntibody FormationAutoantigensB-Lymphocyte SubsetsFemaleGenes, Immunoglobulin Heavy ChainHumansImmunoglobulin Switch RegionImmunoglobulin Variable RegionMaleMicrodissectionMiddle AgedMolecular Sequence DataMutationMyocardiumMyositisReceptors, Antigen, B-CellSyndecan-1Transcription, GeneticConceptsInclusion body myositisLaser capture microdissectionBody myositisCapture microdissectionInflammatory myopathiesMuscle tissueInsertions/deletionsT cell-mediated diseaseGene sequencesCell-mediated diseaseGene transcriptsInflamed muscle tissueAg-specific responsesAg receptorB cell maturationPlasma cell populationPutative autoimmune disordersControl muscle tissueSignificant somatic mutationsIndividual cellsVariable region gene sequencesOligoclonal expansionInflammatory infiltrateSomatic mutationsMuscle weakness
2005
Antibodies from Inflamed Central Nervous System Tissue Recognize Myelin Oligodendrocyte Glycoprotein
O’Connor K, Appel H, Bregoli L, Call ME, Catz I, Chan JA, Moore NH, Warren KG, Wong SJ, Hafler DA, Wucherpfennig KW. Antibodies from Inflamed Central Nervous System Tissue Recognize Myelin Oligodendrocyte Glycoprotein. The Journal Of Immunology 2005, 175: 1974-1982. PMID: 16034142, PMCID: PMC4515951, DOI: 10.4049/jimmunol.175.3.1974.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAutoantibodiesBinding Sites, AntibodyCentral Nervous SystemDemyelinating Autoimmune Diseases, CNSFemaleFluoroimmunoassayHumansMaleMolecular Sequence DataMultiple SclerosisMyelin ProteinsMyelin-Associated GlycoproteinMyelin-Oligodendrocyte GlycoproteinRadioimmunoassaySolutionsConceptsMyelin oligodendrocyte glycoproteinMultiple sclerosisCNS diseaseOligodendrocyte glycoproteinCNS tissueChronic inflammatory CNS diseasesAutoantibody-mediated pathologyInflammatory CNS diseasesCentral nervous system tissueInflammatory CNS diseaseCases of encephalitisHigh-affinity autoantibodiesCases of subacuteNervous system tissueCNS parenchymaMOG autoantibodiesMS patientsOligodendrocyte lossMOG-AbCNS diseasesAutoantibodiesCerebrospinal fluidMOG proteinPostmortem casesControl tissuesCharacterization of in vivo expanded OspA-specific human T-cell clones
Ausubel LJ, O'Connor KC, Baecher-Allen C, Trollmo C, Kessler B, Hekking B, Merritt D, Meyer AL, Kwok B, Ploegh H, Huber BT, Hafler DA. Characterization of in vivo expanded OspA-specific human T-cell clones. Clinical Immunology 2005, 115: 313-322. PMID: 15893699, DOI: 10.1016/j.clim.2005.02.015.Peer-Reviewed Original ResearchConceptsT cell clonesMajor histocompatibility complex class II tetramersTreatment-resistant Lyme arthritisCD4 T-cell clonesDistinct T-cell clonesT cell receptor repertoireHuman T cell clonesClass II tetramersBeta chainT cell recognitionTCR contact residuesTCR beta chainT cell receptorCell flow cytometryTCR usageImmune compartmentLyme arthritisAutoimmune diseasesMicrobial antigensT cellsOspA epitopeImmunodominant epitopesSynovial fluidReceptor repertoireReactive clonesExpanded 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
Cross-Reactive TCR Responses to Self Antigens Presented by Different MHC Class II Molecules
Mycko MP, Waldner H, Anderson DE, Bourcier KD, Wucherpfennig KW, Kuchroo VK, Hafler DA. Cross-Reactive TCR Responses to Self Antigens Presented by Different MHC Class II Molecules. The Journal Of Immunology 2004, 173: 1689-1698. PMID: 15265898, DOI: 10.4049/jimmunol.173.3.1689.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAmino Acid SubstitutionAnimalsAntigen PresentationAutoantigensCD4 AntigensCross ReactionsEncephalomyelitis, Autoimmune, ExperimentalHLA-DR alpha-ChainsHLA-DR AntigensHLA-DRB1 ChainsHumansHybridomasL CellsLymphocyte ActivationMembrane ProteinsMiceMolecular Sequence DataMultiple Sclerosis, Relapsing-RemittingMyelin Basic ProteinPeptide FragmentsPhosphorylationProtein Processing, Post-TranslationalReceptors, Antigen, T-CellReceptors, Antigen, T-Cell, alpha-betaT-Lymphocyte SubsetsTransfectionConceptsAutoreactive T cellsMHC class II moleculesClass II moleculesT cellsSpontaneous experimental autoimmune encephalomyelitisRelapsing-remitting multiple sclerosisDifferent MHC class II moleculesExperimental autoimmune encephalomyelitisAltered peptide ligandTh cell clonesT cell hybridomasMyelin basic proteinAutoimmune encephalomyelitisMultiple sclerosisSelf antigensCD4 coreceptorRestriction elementsHealthy individualsDiseased patientsHuman TCRPatientsTCR responsesCell clonesCell hybridomasPeptide ligandsAn Autoimmune Disease-Associated CTLA-4 Splice Variant Lacking the B7 Binding Domain Signals Negatively in T Cells
Vijayakrishnan L, Slavik JM, Illés Z, Greenwald RJ, Rainbow D, Greve B, Peterson LB, Hafler DA, Freeman GJ, Sharpe AH, Wicker LS, Kuchroo VK. An Autoimmune Disease-Associated CTLA-4 Splice Variant Lacking the B7 Binding Domain Signals Negatively in T Cells. Immunity 2004, 20: 563-575. PMID: 15142525, DOI: 10.1016/s1074-7613(04)00110-4.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsAntigens, CDAntigens, DifferentiationAutoimmune DiseasesB7-1 AntigenBlotting, WesternCloning, MolecularCTLA-4 AntigenFemaleFlow CytometryHumansMembrane ProteinsMiceMice, Inbred NODMolecular Sequence DataReceptors, Antigen, T-CellReverse Transcriptase Polymerase Chain ReactionRNA, MessengerSignal TransductionT-LymphocytesConceptsCytotoxic T-lymphocyte-associated antigen 4T cell responsesT cellsNOD miceAutoimmune diseasesT cell-mediated autoimmune diseaseT-lymphocyte-associated antigen 4Cell responsesCell-mediated autoimmune diseaseSusceptible NOD miceRegulatory T cellsNOD congenic miceCTLA-4 locusAntigen-4B7-1B7-2Primary T cellsCongenic miceSplice variantsMiceNegative signalingMYPPPY motifDiseaseType IGenetic linkage
2001
Conserved CDR3 Regions in T-Cell Receptor (TCR) CD8+T Cells That Recognize the Tax11-19/HLA-A*0201 Complex in a Subject Infected with Human T-Cell Leukemia Virus Type 1: Relationship of T-Cell Fine Specificity and Major Histocompatibility Complex/Peptide/TCR Crystal Structure
Bourcier K, Lim D, Ding Y, Smith K, Wucherpfennig K, Hafler D. Conserved CDR3 Regions in T-Cell Receptor (TCR) CD8+T Cells That Recognize the Tax11-19/HLA-A*0201 Complex in a Subject Infected with Human T-Cell Leukemia Virus Type 1: Relationship of T-Cell Fine Specificity and Major Histocompatibility Complex/Peptide/TCR Crystal Structure. Journal Of Virology 2001, 75: 9836-9843. PMID: 11559817, PMCID: PMC114556, DOI: 10.1128/jvi.75.20.9836-9843.2001.Peer-Reviewed Original ResearchConceptsT cell clonesT cell receptorCDR3 regionTCR alphaHTLV-1-associated myelopathyTax11-19Beta chainHTLV-1-infected individualsT cell receptor repertoirePeripheral blood lymphocytesHuman T-cell leukemia virusHuman T-cell leukemia virus type 1T-cell leukemia virusVirus type 1TCR usageT cell fine specificityBlood lymphocytesT cellsImmunodominant epitopesReceptor repertoireType 1Fine specificitySimilar recognition patternTCR structureLeukemia virusHeterophile 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
Glatiramer acetate (Copaxone®) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis
Duda PW, Schmied MC, Cook SL, Krieger JI, Hafler DA. Glatiramer acetate (Copaxone®) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis. Journal Of Clinical Investigation 2000, 105: 967-976. PMID: 10749576, PMCID: PMC377485, DOI: 10.1172/jci8970.Peer-Reviewed Original ResearchMeSH KeywordsAdultAmino Acid SequenceCell DivisionCells, CulturedCross ReactionsEpitopes, T-LymphocyteFemaleGlatiramer AcetateHumansImmunodominant EpitopesImmunosuppressive AgentsInterferon-gammaInterleukin-5Leukocytes, MononuclearLigandsMaleMiddle AgedMolecular Sequence DataMultiple SclerosisMyelin Basic ProteinMyelin SheathPeptide FragmentsPeptidesTetanus ToxoidTh2 CellsConceptsT cell responsesMultiple sclerosisGlatiramer acetateT cellsAntigen-specific T cell responsesTh2-polarized immune responseCross-reactive T cellsAlters immune functionHuman autoimmune diseasesAcetate inducesCross-reactive responsesT cell receptorT cell linesImmune deviationMost patientsTh2 typeAutoimmune disordersTh2 cytokinesAutoimmune diseasesDaily injectionsIL-13IL-5Th2 cellsHealthy subjectsImmune response
1999
Noncanonical Vα24JαQ T cells with conservative α chain CDR3 region amino acid substitutions are restricted by CD1d
Kent S, Hafler D, Strominger J, Wilson S. Noncanonical Vα24JαQ T cells with conservative α chain CDR3 region amino acid substitutions are restricted by CD1d. Human Immunology 1999, 60: 1080-1089. PMID: 10600006, DOI: 10.1016/s0198-8859(99)00109-3.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAntigens, CD1Antigens, CD1dBase SequenceClone CellsComplementarity Determining RegionsConserved SequenceDNAGene Rearrangement, alpha-Chain T-Cell Antigen ReceptorHumansImmunoglobulin Variable RegionImmunophenotypingKiller Cells, NaturalReceptors, Antigen, T-Cell, alpha-betaT-Lymphocyte SubsetsConceptsT cell receptorT cellsCD1d restrictionPeripheral blood mononuclear cellsBlood mononuclear cellsAmino acid substitutionsAlpha chainSingle amino acid substitutionHuman CD161Total CD4Mononuclear cellsInterleukin-4Surface phenotypeRestriction elementsCD4Acid substitutionsCD1dCDR3 residuesJ rearrangementsJ junctionsVariant clonesChain transcriptsCellsJalpha18Valpha24T 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 subjectsCross-Reactivity of T-Cell Clones Specific for Altered Peptide Ligands of Myelin Basic Protein
Ausubel L, Bieganowska K, Hafler D. Cross-Reactivity of T-Cell Clones Specific for Altered Peptide Ligands of Myelin Basic Protein. Cellular Immunology 1999, 193: 99-107. PMID: 10202117, DOI: 10.1006/cimm.1998.1447.Peer-Reviewed Original ResearchConceptsT cell clonesT cellsSpecific T cell repertoireAutoreactive T cellsTh1-type cytokinesTh2-type cytokinesMultiple sclerosis patientsT cell repertoireAltered peptide ligandT cell receptor alphaPotential beneficial effectsTCR contact residuesMyelin basic proteinDownregulatory cytokinesSclerosis patientsIL-4IL-5Individual patientsReceptor alphaBeneficial effectsClonal expansionCytokinesPeptide ligandsSubstantial proliferationCross reactivity
1998
Differential Display Cloning of a Novel Human Histone Deacetylase (HDAC3) cDNA from PHA-Activated Immune Cells
Dangond F, Hafler D, Tong J, Randall J, Kojima R, Utku N, Gullans S. Differential Display Cloning of a Novel Human Histone Deacetylase (HDAC3) cDNA from PHA-Activated Immune Cells. Biochemical And Biophysical Research Communications 1998, 242: 648-652. PMID: 9464271, DOI: 10.1006/bbrc.1997.8033.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceBlotting, NorthernCD3 ComplexCell CycleCloning, MolecularDNAFlow CytometryGene Expression Regulation, EnzymologicGranulocyte-Macrophage Colony-Stimulating FactorHistone DeacetylasesHumansMolecular Sequence DataPhylogenyPhytohemagglutininsRNA, MessengerSequence AlignmentSequence Analysis, DNAT-LymphocytesTransfectionTumor Cells, CulturedConceptsPeripheral blood mononuclear cellsBlock T cell proliferationEffects of HDACsBlood mononuclear cellsT cell proliferationT cell clonesG2/M cell accumulationNon-immune tissuesTHP-1 cellsHDAC mRNAsPBMC levelsDifferential display cloningMononuclear cellsIL-4Immune cellsIFN-gammaAlpha CD3Histone acetyltransferasesCell accumulationHDAC3 mRNAHDAC inhibitorsHistone deacetylase assayCell clonesCell cycle progressionFunctional activity
1997
Weak peptide agonists reveal functional differences in B7-1 and B7-2 costimulation of human T cell clones.
Anderson DE, Ausubel LJ, Krieger J, Höllsberg P, Freeman GJ, Hafler DA. Weak peptide agonists reveal functional differences in B7-1 and B7-2 costimulation of human T cell clones. The Journal Of Immunology 1997, 159: 1669-75. PMID: 9257827, DOI: 10.4049/jimmunol.159.4.1669.Peer-Reviewed Original Research
1996
Complementary mutations in an antigenic peptide allow for crossreactivity of autoreactive T-cell clones
Ausubel L, Kwan C, Sette A, Kuchroo V, Hafler D. Complementary mutations in an antigenic peptide allow for crossreactivity of autoreactive T-cell clones. Proceedings Of The National Academy Of Sciences Of The United States Of America 1996, 93: 15317-15322. PMID: 8986809, PMCID: PMC26402, DOI: 10.1073/pnas.93.26.15317.Peer-Reviewed Original ResearchConceptsT cell clonesT cell receptorAutoreactive T cell clonesSpecific T cell clonesAntigenic peptidesMajor histocompatibility complex moleculesSpecific peptide antigenContext of MHCT cell recognitionTCR contact residuesMHC-antigen complexesHistocompatibility complex moleculesMHC-peptide complexesSingle conservative amino acid substitutionTCR-MHCT cellsReceptor plasticityPeptide antigensFunctional pocketStimulating peptideCrossreactivityAntigenTrimolecular complexAmino acid substitutionsConservative amino acid substitutions
1995
Structure of human T-cell receptors specific for an immunodominant myelin basic protein peptide: positioning of T-cell receptors on HLA-DR2/peptide complexes.
Wucherpfennig KW, Hafler DA, Strominger JL. Structure of human T-cell receptors specific for an immunodominant myelin basic protein peptide: positioning of T-cell receptors on HLA-DR2/peptide complexes. Proceedings Of The National Academy Of Sciences Of The United States Of America 1995, 92: 8896-8900. PMID: 7568039, PMCID: PMC41074, DOI: 10.1073/pnas.92.19.8896.Peer-Reviewed Original ResearchA Review of T‐Cell Receptors in Multiple Sclerosis: Clonal Expansion and Persistence of Human T‐Cells Specific for an Immunodominant Myelin Basic Protein Peptidea
WUCHERPFENNIG K, HAFLER D. A Review of T‐Cell Receptors in Multiple Sclerosis: Clonal Expansion and Persistence of Human T‐Cells Specific for an Immunodominant Myelin Basic Protein Peptidea. Annals Of The New York Academy Of Sciences 1995, 756: 241-258. PMID: 7544075, DOI: 10.1111/j.1749-6632.1995.tb44522.x.Peer-Reviewed Original ResearchConceptsImmunodominant MBP peptidesT cell clonesMBP peptidesImmune responseNormal subjectsMBP-specific T cell clonesIndividual multiple sclerosis patientsTCR beta-chain usageMBP-specific T cellsTCR V beta chainsDR2 haplotypeSpecific T cell clonesBeta-chain usageT cell responsesAntigen-specific therapyMultiple sclerosis patientsSpecific T cellsDifferent T-cell linesT Cells SpecificIdentical TCR sequencesT cell receptorT cell linesAlpha-chain rearrangementMyelin antigensMS patients