2023
Immune sensing of food allergens promotes avoidance behaviour
Florsheim E, Bachtel N, Cullen J, Lima B, Godazgar M, Carvalho F, Chatain C, Zimmer M, Zhang C, Gautier G, Launay P, Wang A, Dietrich M, Medzhitov R. Immune sensing of food allergens promotes avoidance behaviour. Nature 2023, 620: 643-650. PMID: 37437602, PMCID: PMC10432274, DOI: 10.1038/s41586-023-06362-4.Peer-Reviewed Original ResearchConceptsMast cellsImmune systemBALB/c miceAllergen-specific IgEDifferentiation factor 15Behavioral modificationAllergen avoidanceAllergic sensitizationAllergic inflammationFood allergyTractus solitariusC miceCysteinyl leukotrienesParabrachial nucleusAllergen ingestionE antibodiesCentral amygdalaFactor 15Mouse modelFood allergensBrain areasImmune sensingAvoidance behaviorAversive stimuliGenetic backgroundAn autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis
Wang S, Li K, Pickholz E, Dobie R, Matchett K, Henderson N, Carrico C, Driver I, Borch Jensen M, Chen L, Petitjean M, Bhattacharya D, Fiel M, Liu X, Kisseleva T, Alon U, Adler M, Medzhitov R, Friedman S. An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis. Science Translational Medicine 2023, 15: eadd3949. PMID: 36599008, PMCID: PMC10686705, DOI: 10.1126/scitranslmed.add3949.Peer-Reviewed Original ResearchConceptsHepatic stellate cellsAdvanced hepatic fibrosisNonalcoholic steatohepatitisAdvanced fibrosisHepatic fibrosisHSC activationStellate cellsMurine nonalcoholic steatohepatitisStage-specific therapyHuman nonalcoholic steatohepatitisHuman HSC activationNeurotrophic receptor tyrosine kinaseDrug targetsSingle-nucleus RNA sequencingAdvanced diseaseAntifibrotic efficacyAntifibrotic therapyFibrosisTherapeutic paradigmAutocrine interactionsPharmacological inhibitionReceptor tyrosine kinasesSteatohepatitisStrongest predictorTherapy
2003
Toll-like receptors and their role in experimental models of microbial infection
Qureshi S, Medzhitov R. Toll-like receptors and their role in experimental models of microbial infection. Genes & Immunity 2003, 4: 87-94. PMID: 12618855, DOI: 10.1038/sj.gene.6363937.Peer-Reviewed Original ResearchConceptsImmune systemHost defenseToll-like receptor (TLR) familyExperimental modelTLR-deficient miceMicrobial infectionsAdaptive immune responsesToll-like receptorsEffective host defenseLimited human studiesInnate immune systemAdaptive immune systemPrompt recognitionImmune responseHuman studiesInnate immunityInfectious threatsInfectionReceptor familyAntimicrobial effectorsContainment measuresPathogen recognitionConstant surveillancePathogensActivation
2001
Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3
Alexopoulou L, Holt A, Medzhitov R, Flavell R. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 2001, 413: 732-738. PMID: 11607032, DOI: 10.1038/35099560.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAmino Acid SequenceAnimalsAntigens, DifferentiationB-LymphocytesCell LineCells, CulturedCytokinesDrosophila ProteinsGalactosamineHumansInterferon Type ILymphocyte ActivationMacrophagesMembrane GlycoproteinsMiceMitogen-Activated Protein KinasesMolecular Sequence DataMyeloid Differentiation Factor 88NF-kappa BPoly I-CReceptors, Cell SurfaceReceptors, ImmunologicRNA, Double-StrandedSequence Homology, Amino AcidSignal TransductionToll-Like Receptor 3Toll-Like ReceptorsVirus DiseasesConceptsToll-like receptorsNF-κBI interferonInnate immune recognition receptorsToll-like receptor 3TLR3-deficient miceMolecular patternsPolyinosine-polycytidylic acidMitogen-activated proteinType I interferonMammalian TLR3Dendritic cellsInflammatory cytokinesImmune recognition receptorsViral infectionD-galactosamineReceptor 3MyD88Reduced productionReceptorsActivationMicrobial pathogensLethal effectsMost virusesAdaptor proteinTIRAP: an adapter molecule in the Toll signaling pathway
Horng T, Barton G, Medzhitov R. TIRAP: an adapter molecule in the Toll signaling pathway. Nature Immunology 2001, 2: 835-841. PMID: 11526399, DOI: 10.1038/ni0901-835.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAmino Acid SequenceAnimalsAntigens, DifferentiationCell DifferentiationCell LineCloning, MolecularCpG IslandsDendritic CellsDrosophila ProteinsEIF-2 KinaseHSP40 Heat-Shock ProteinsHumansLipopolysaccharidesMembrane GlycoproteinsMiceMolecular Sequence DataMutationMyeloid Differentiation Factor 88Receptors, Cell SurfaceReceptors, ImmunologicReceptors, Interleukin-1Sequence Homology, Amino AcidSignal TransductionToll-Like Receptor 4Toll-Like Receptor 9Toll-Like ReceptorsConceptsMammalian Toll-like receptorsProtein kinase PKRMitogen-activated protein kinaseToll-like receptorsKinase PKRAdapter proteinProtein kinaseMyD88-independent signalingPathways downstreamAdapter moleculeNF-κBSignaling pathwaysCellular responsesMicrobial metabolismAdapter protein MyD88MyD88-dependent signaling pathwaysProtein MyD88Absence of MyD88MyD88-deficient miceDendritic cell maturationCell maturationPathwayTLR4 ligationKinasePKR
2000
Structural basis for signal transduction by the Toll/interleukin-1 receptor domains
Xu Y, Tao X, Shen B, Horng T, Medzhitov R, Manley J, Tong L. Structural basis for signal transduction by the Toll/interleukin-1 receptor domains. Nature 2000, 408: 111-115. PMID: 11081518, DOI: 10.1038/35040600.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsCloning, MolecularCrystallography, X-RayDrosophilaDrosophila ProteinsHumansMembrane GlycoproteinsMiceModels, MolecularMolecular Sequence DataPoint MutationProtein BindingProtein ConformationProtein Structure, TertiaryReceptors, Cell SurfaceReceptors, Interleukin-1Recombinant Fusion ProteinsStructure-Activity RelationshipToll-Like Receptor 1Toll-Like Receptor 2Toll-Like Receptor 4Toll-Like ReceptorsConceptsTIR domainSignal transductionFunctional studiesToll/interleukinSingle point mutationToll-like receptorsEquivalent residuesStructural basisReceptor domainInterleukin-1 receptorHuman TLR1Receptor signalingMutationsMyD88 adapterTransductionMurine TLR4Host immune responseAdaptive immunitySurface patchesResiduesReceptorsDomainMutantsMutagenesisYeastThe Toll receptor family and microbial recognition
Medzhitov R, Janeway C. The Toll receptor family and microbial recognition. Trends In Microbiology 2000, 8: 452-456. PMID: 11044679, DOI: 10.1016/s0966-842x(00)01845-x.Peer-Reviewed Original ResearchRecognition of CpG DNA is mediated by signaling pathways dependent on the adaptor protein MyD88
Schnare M, Holt†A, Takeda K, Akira S, Medzhitov R. Recognition of CpG DNA is mediated by signaling pathways dependent on the adaptor protein MyD88. Current Biology 2000, 10: 1139-1142. PMID: 10996797, DOI: 10.1016/s0960-9822(00)00700-4.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAnimalsAntigens, DifferentiationB-LymphocytesCpG IslandsDendritic CellsDNADrosophila ProteinsEnzyme-Linked Immunosorbent AssayInterleukin-6Macrophages, PeritonealMembrane GlycoproteinsMiceMice, KnockoutMyeloid Differentiation Factor 88Receptors, Cell SurfaceReceptors, ImmunologicSignal TransductionToll-Like Receptor 2Toll-Like Receptor 4Toll-Like ReceptorsConceptsPathogen-associated molecular patternsPattern recognition receptorsInnate immune systemBacterial DNAFungal cell wallParticular sequence motifsParticular sequence contextCpG DNAToll-like receptorsAdaptor proteinSequence motifsAdaptor protein MyD88Signal transductionInnate immune recognitionToll familyCell wallSequence contextMolecular patternsDNAUnmethylated CpGRecognition receptorsProtein MyD88Immune systemPeptidoglycanDiverse group
1999
Alpha(1,3)-fucosyltransferase VII and alpha(2,3)-sialyltransferase IV are up-regulated in activated CD4 T cells and maintained after their differentiation into Th1 and migration into inflammatory sites.
Blander J, Visintin I, Janeway C, Medzhitov R. Alpha(1,3)-fucosyltransferase VII and alpha(2,3)-sialyltransferase IV are up-regulated in activated CD4 T cells and maintained after their differentiation into Th1 and migration into inflammatory sites. The Journal Of Immunology 1999, 163: 3746-52. PMID: 10490970, DOI: 10.4049/jimmunol.163.7.3746.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBeta-Galactoside alpha-2,3-SialyltransferaseCD4-Positive T-LymphocytesCell DifferentiationCell MovementDown-RegulationEpitopes, T-LymphocyteFucosyltransferasesGangliosidesHistocompatibility Antigens Class IIHypersensitivity, DelayedInterleukin-12Interleukin-4InterphaseLewis Blood Group AntigensLymph NodesLymphocyte ActivationMiceMice, Inbred BALB CMice, Inbred C3HMice, Inbred C57BLMice, TransgenicPeptide FragmentsRNA, MessengerSialyl Lewis X AntigenSialyltransferasesTh1 CellsTh2 CellsUp-RegulationECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway
Kopp E, Medzhitov R, Carothers J, Xiao C, Douglas I, Janeway C, Ghosh S. ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway. Genes & Development 1999, 13: 2059-2071. PMID: 10465784, PMCID: PMC316957, DOI: 10.1101/gad.13.16.2059.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAmino Acid SequenceAnimalsBiological EvolutionCell Line, TransformedCloning, MolecularDrosophilaDrosophila ProteinsEnzyme ActivationHumansInsect ProteinsMAP Kinase Kinase Kinase 1Membrane GlycoproteinsMiceMolecular Sequence DataNF-kappa BProtein Processing, Post-TranslationalProtein Serine-Threonine KinasesProteinsReceptors, Cell SurfaceReceptors, ImmunologicReceptors, Interleukin-1Saccharomyces cerevisiaeSignal TransductionTNF Receptor-Associated Factor 6Toll-Like ReceptorsToll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium
Frantz S, Kobzik L, Kim Y, Fukazawa R, Medzhitov R, Lee R, Kelly R. Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium. Journal Of Clinical Investigation 1999, 104: 271-280. PMID: 10430608, PMCID: PMC408420, DOI: 10.1172/jci6709.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsCD4 AntigensCells, CulturedCloning, MolecularCoronary VesselsDNA, ComplementaryDrosophila ProteinsGene Expression RegulationHeart FailureHeart VentriclesHumansImmunohistochemistryInterferon-gammaInterleukin-1LipopolysaccharidesMaleMembrane GlycoproteinsMiceMice, Inbred C57BLMolecular Sequence DataMyocardial InfarctionMyocardiumNF-kappa BNitric Oxide SynthaseNitric Oxide Synthase Type IIOrgan SpecificityRatsRats, Sprague-DawleyReceptors, Cell SurfaceRNA, MessengerToll-Like Receptor 4Toll-Like ReceptorsTranscription Factor AP-1ConceptsHuman Toll-like receptor 4Cardiac myocytesIL-1betaHuman myocardiumToll-like receptor 4Coronary microvascular endothelial cellsInnate immune response proteinsCytokine-inducible isoformTLR4 expression levelsNitric oxide synthaseMicrovascular endothelial cellsHearts of humansTLR4 stainingTLR4 expressionHeart failureTLR4 mRNAIschemic injuryReceptor 4Oxide synthaseImmune response proteinsControl myocardiumInnate immunityToll homologuesExperimental animalsMyocardium
1998
Subtle conformational changes induced in major histocompatibility complex class II molecules by binding peptides
Chervonsky A, Medzhitov R, Denzin L, Barlow A, Rudensky A, Janeway C. Subtle conformational changes induced in major histocompatibility complex class II molecules by binding peptides. Proceedings Of The National Academy Of Sciences Of The United States Of America 1998, 95: 10094-10099. PMID: 9707606, PMCID: PMC21467, DOI: 10.1073/pnas.95.17.10094.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsAntibodies, MonoclonalAntigens, Differentiation, B-LymphocyteB-LymphocytesCarrier ProteinsCell MembraneDimerizationHistocompatibility Antigens Class IIMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicMolecular Sequence DataProtein BindingProtein ConformationT-Lymphocytes
1997
The orientation of a T cell receptor to its MHC class II:peptide ligands.
Hong S, Sant'Angelo D, Dittel B, Medzhitov R, Yoon S, Waterbury P, Janeway C. The orientation of a T cell receptor to its MHC class II:peptide ligands. The Journal Of Immunology 1997, 159: 4395-402. PMID: 9379037, DOI: 10.4049/jimmunol.159.9.4395.Peer-Reviewed Original ResearchConceptsMHC class II moleculesClass II moleculesComplementarity-determining region 1Self MHC class II moleculesCD4 T cellsMHC class IIT cell clonesMHC class II ligandsMHC class I.T cell receptorT cell linesCD4(-) TCRClass II ligandsD10 T cell cloneT cellsClass IICell receptorI-AkCell clonesClass I.ReceptorsCell linesTCRPresent studyA human homologue of the Drosophila Toll protein signals activation of adaptive immunity
Medzhitov R, Preston-Hurlburt P, Janeway C. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 1997, 388: 394-397. PMID: 9237759, DOI: 10.1038/41131.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsB7-1 AntigenCell LineCloning, MolecularDrosophilaDrosophila ProteinsHumansImmunityInsect ProteinsInterleukinsJurkat CellsMembrane GlycoproteinsMembrane ProteinsMiceMolecular Sequence DataMutationNF-kappa BReceptors, Cell SurfaceReceptors, ImmunologicRecombinant Fusion ProteinsSequence Homology, Amino AcidSignal TransductionT-LymphocytesToll-Like ReceptorsTransfectionConceptsDrosophila Toll proteinToll proteinCytoplasmic domainDrosophila TollHuman homologueLeucine-rich repeat domainNF-κB-controlled genesHuman cell linesRepeat domainActive mutantExtracellular domainNF-κBImmune responseInnate immune responseCo-stimulatory molecules B7.1Adaptive immune systemComponents of immunityInflammatory cytokines IL-1ProteinCell linesCo-stimulatory moleculesAntigen-presenting cellsAdaptive immune responsesNaive T cellsHomologues
1996
Immunological tolerance: Danger – pathogen on the premises!
Janeway C, Goodnow C, Medzhitov R. Immunological tolerance: Danger – pathogen on the premises! Current Biology 1996, 6: 519-522. PMID: 8805259, DOI: 10.1016/s0960-9822(02)00531-6.Peer-Reviewed Original ResearchThe Specificity and Orientation of a TCR to its Peptide–MHC Class II Ligands
Sant'Angelo D, Waterbury G, Preston-Hurlburt P, Yoon S, Medzhitov R, Hong S, Janeway C. The Specificity and Orientation of a TCR to its Peptide–MHC Class II Ligands. Immunity 1996, 4: 367-376. PMID: 8612131, DOI: 10.1016/s1074-7613(00)80250-2.Peer-Reviewed Original Research