2024
Tlr9 deficiency in B cells leads to obesity by promoting inflammation and gut dysbiosis
Wang P, Yang X, Zhang L, Sha S, Huang J, Peng J, Gu J, Pearson J, Hu Y, Zhao H, Wong F, Wang Q, Wen L. Tlr9 deficiency in B cells leads to obesity by promoting inflammation and gut dysbiosis. Nature Communications 2024, 15: 4232. PMID: 38762479, PMCID: PMC11102548, DOI: 10.1038/s41467-024-48611-8.Peer-Reviewed Original ResearchConceptsToll-like receptor 9Gut microbiotaGut microbial communityTransferred to germ-free miceB cellsGerm-free miceTLR9 deficiencyKO miceGene sequencesGerminal center B cellsMicrobial communitiesMarginal zone B cellsGut dysbiosisFollicular helper cellsSelf-DNAMetabolic homeostasisAssociated with increased frequencyPro-inflammatory stateFat tissue inflammationGutHigh-fat dietMicrobiotaHelper cellsT cellsControl mice
2022
IgM-associated gut bacteria in obesity and type 2 diabetes in C57BL/6 mice and humans
Pearson JA, Ding H, Hu C, Peng J, Galuppo B, Wong FS, Caprio S, Santoro N, Wen L. IgM-associated gut bacteria in obesity and type 2 diabetes in C57BL/6 mice and humans. Diabetologia 2022, 65: 1398-1411. PMID: 35587276, PMCID: PMC9283171, DOI: 10.1007/s00125-022-05711-8.Peer-Reviewed Original ResearchConceptsFecal microbiota transplantType 2 diabetesNormal glucose toleranceB6 miceWild-type miceGlucose toleranceIgM antibodiesObese youthGut microbiotaWeight gainGut bacteriaObese young individualsImpaired glucose toleranceDiet-induced obesityConclusions/interpretationOur resultsBody weight gainGreater weight gainMice fecal microbiotaHuman stool samplesGlucose intoleranceClinical featuresC57BL/6 miceMicrobiota transplantRecipient miceStool samplesObesity aggravates contact hypersensitivity reaction in mice
Majewska‐Szczepanik M, Kowalczyk P, Marcińska K, Strzępa A, Lis GJ, Wong FS, Szczepanik M, Wen L. Obesity aggravates contact hypersensitivity reaction in mice. Contact Dermatitis 2022, 87: 28-39. PMID: 35234303, PMCID: PMC9949724, DOI: 10.1111/cod.14088.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCD4-Positive T-LymphocytesDermatitis, Allergic ContactHumansInflammationInterleukin-17MiceMice, Inbred C57BLMice, KnockoutObesityConceptsContact hypersensitivityFecal microbiota transplantationQuantitative polymerase chain reactionIL-17AObese miceEnhanced contact hypersensitivityGut microbiota dysbiosisLow-grade inflammationContact hypersensitivity reactionInfluence of obesityInflammatory skin diseaseT helper 1Antigen-specific responsesHigh-fat dietSubcutaneous adipose tissueProinflammatory CD4Proinflammatory milieuCytokine profileMicrobiota dysbiosisDendritic cellsLymph nodesMicrobiota transplantationHelper 1Hypersensitivity reactionsImmune cells
2021
Toll-like receptor 7 deficiency suppresses type 1 diabetes development by modulating B-cell differentiation and function
Huang J, Peng J, Pearson JA, Efthimiou G, Hu Y, Tai N, Xing Y, Zhang L, Gu J, Jiang J, Zhao H, Zhou Z, Wong FS, Wen L. Toll-like receptor 7 deficiency suppresses type 1 diabetes development by modulating B-cell differentiation and function. Cellular & Molecular Immunology 2021, 18: 328-338. PMID: 33432061, PMCID: PMC8027372, DOI: 10.1038/s41423-020-00590-8.Peer-Reviewed Original ResearchConceptsType 1 diabetes developmentToll-like receptorsType 1 diabetesDiabetes developmentB cellsTLR7 deficiencyNOD miceB cell differentiationT cellsClassical MHC class I moleculesHuman type 1 diabetesImmunodeficient NOD miceNOD B cellsDiabetogenic T cellsAntigen-presenting functionNonobese diabetic (NOD) miceT cell responsesB cell functionMHC class I moleculesPattern recognition receptorsT cell activationPathogen molecular patternsClass I moleculesDiabetogenic CD4Cytotoxic CD8
2015
NLRP3 deficiency protects from type 1 diabetes through the regulation of chemotaxis into the pancreatic islets
Hu C, Ding H, Li Y, Pearson JA, Zhang X, Flavell RA, Wong FS, Wen L. NLRP3 deficiency protects from type 1 diabetes through the regulation of chemotaxis into the pancreatic islets. Proceedings Of The National Academy Of Sciences Of The United States Of America 2015, 112: 11318-11323. PMID: 26305961, PMCID: PMC4568693, DOI: 10.1073/pnas.1513509112.Peer-Reviewed Original ResearchMeSH KeywordsAdoptive TransferAnimalsCarrier ProteinsCell MovementChemokine CCL5Chemokine CXCL10ChemotaxisDiabetes Mellitus, Type 1Gene ExpressionHumansInflammasomesInterferon Regulatory Factor-1Interleukin-1betaIslets of LangerhansMice, Inbred C57BLMice, Inbred NODMice, KnockoutMice, SCIDNLR Family, Pyrin Domain-Containing 3 ProteinReceptors, CCR5Receptors, CXCR3Reverse Transcriptase Polymerase Chain ReactionSignal TransductionTime FactorsT-LymphocytesConceptsType 1 diabetesLeucine-rich repeatsNonobese diabetic (NOD) mouse modelPancreatic isletsRegulation of chemotaxisTreatment of T1D.Role of TLRsDevelopment of T1DChemokine receptor CCR5Diabetic mouse modelT cell migrationT cell activationPresence of NLRP3Pancreatic islet cellsNLRP3 ablationOligomerization domainNLRP3 inflammasomeReceptor CCR5T cellsTh1 differentiationInflammasome pathwayAdaptive immunityMouse modelAnimal modelsIslet cells
2014
Interleukin-10+ Regulatory B Cells Arise Within Antigen-Experienced CD40+ B Cells to Maintain Tolerance to Islet Autoantigens
Kleffel S, Vergani A, Tezza S, Nasr M, Niewczas MA, Wong S, Bassi R, D’Addio F, Schatton T, Abdi R, Atkinson M, Sayegh MH, Wen L, Wasserfall CH, O’Connor K, Fiorina P. Interleukin-10+ Regulatory B Cells Arise Within Antigen-Experienced CD40+ B Cells to Maintain Tolerance to Islet Autoantigens. Diabetes 2014, 64: 158-171. PMID: 25187361, PMCID: PMC4274804, DOI: 10.2337/db13-1639.Peer-Reviewed Original ResearchConceptsIslet autoantigensB cellsT1D patientsInterleukin-10IL-10-producing B cellsHyperglycemic nonobese diabetic miceRegulatory B-cell responsesAutoreactive T cell responsesT cell-mediated responsesRole of BregsB-cell depletionRegulatory B cellsNonobese diabetic (NOD) miceNOD mouse modelT cell responsesB cell responsesType 1 diabetesB cell receptorAdoptive transferDiabetic miceAutoimmune diseasesHuman ILHyperglycemic miceMouse modelBregsEpicutaneous Immunization with TNP-Ig and Zymosan Induces TCRαβ+ CD4+ Contrasuppressor Cells That Reverse Skin-Induced Suppression via IL-17A
Majewska-Szczepanik M, Strzepa A, Marcińska K, Wen L, Szczepanik M. Epicutaneous Immunization with TNP-Ig and Zymosan Induces TCRαβ+ CD4+ Contrasuppressor Cells That Reverse Skin-Induced Suppression via IL-17A. International Archives Of Allergy And Immunology 2014, 164: 122-136. PMID: 24993442, PMCID: PMC4141016, DOI: 10.1159/000363446.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, CutaneousAnimalsAntigensCD4-Positive T-LymphocytesDermatitis, ContactHaptensImmunity, InnateImmunizationImmunoglobulinsImmunosuppression TherapyInterleukin-17Lymph NodesMiceMice, Inbred C57BLMice, Inbred CBAMyeloid Differentiation Factor 88Receptors, Antigen, T-Cell, alpha-betaSkinToll-Like Receptor 2Transforming Growth Factor betaTrinitrobenzenesVaccinationZymosanConceptsSkin-induced suppressionSuppression of CHSContact hypersensitivityEC immunizationEpicutaneous immunizationTNP-IgAdoptive cell transfer experimentsProtein antigensT contrasuppressor cellsT suppressor cellsLymph node cellsCell transfer experimentsCHS responseContrasuppressor cellsIL-17ASuppressor cellsCytokine productionNode cellsImmunogenic antigensPresence of zymosanAntigen E.ImmunizationInnate immunityCD4Gauze patches
2012
TLR4 regulates cardiac lipid accumulation and diabetic heart disease in the nonobese diabetic mouse model of type 1 diabetes
Dong B, Qi D, Yang L, Huang Y, Xiao X, Tai N, Wen L, Wong F. TLR4 regulates cardiac lipid accumulation and diabetic heart disease in the nonobese diabetic mouse model of type 1 diabetes. AJP Heart And Circulatory Physiology 2012, 303: h732-h742. PMID: 22842069, PMCID: PMC3468457, DOI: 10.1152/ajpheart.00948.2011.Peer-Reviewed Original ResearchMeSH KeywordsAMP-Activated Protein KinasesAnimalsBlood GlucoseCell LineDiabetes Mellitus, Type 1Diabetic CardiomyopathiesDisease Models, AnimalFatty Acids, NonesterifiedJNK Mitogen-Activated Protein KinasesLipid MetabolismLipoprotein LipaseMiceMice, Inbred C57BLMice, Inbred NODMice, KnockoutMyeloid Differentiation Factor 88MyocardiumMyocytes, CardiacOleic AcidP38 Mitogen-Activated Protein KinasesPhosphorylationRatsRNA InterferenceTime FactorsToll-Like Receptor 4TriglyceridesConceptsDiabetic heart diseaseType 1 diabetesHeart diseaseNOD animalsLipoprotein lipaseLipid accumulationNonobese diabetic (NOD) mouse modelLeft ventricular developed pressureCardiac fatty acid metabolismMyeloid differentiation primary response geneCardiac lipid accumulationControl nondiabetic miceGreater ejection fractionRole of TLR4Nonobese diabetic (NOD) miceOnset of diabetesVentricular developed pressureDevelopment of diabetesToll-like receptorsGreater fractional shorteningDiabetic mouse modelPlasma triglyceride levelsWild-type NODLower triglyceride accumulationCellular lipid accumulation
2010
Importance of TLR2 in the direct response of T lymphocytes to Schistosoma mansoni antigens
Burton O, Gibbs S, Miller N, Jones F, Wen L, Dunne D, Cooke A, Zaccone P. Importance of TLR2 in the direct response of T lymphocytes to Schistosoma mansoni antigens. European Journal Of Immunology 2010, 40: 2221-2229. PMID: 20480503, DOI: 10.1002/eji.200939998.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, CDAntigens, HelminthCD4-Positive T-LymphocytesCells, CulturedFemaleForkhead Transcription FactorsGalectin 3Helminth ProteinsHost-Pathogen InteractionsImmunomodulationLectins, C-TypeMiceMice, Inbred C57BLMice, Inbred NODMice, KnockoutMinor Histocompatibility AntigensReceptors, Cell SurfaceSchistosoma mansoniToll-Like Receptor 2Transforming Growth Factor betaConceptsS. mansoni soluble egg antigenSchistosoma mansoni antigensT cellsFoxp3 expressionImportance of TLR2S. mansoni antigensSurface-bound TGFTLR2 ligand stimulationT cell secretionAccessory cell interactionsNOD miceTh2 responsesEgg antigenImmunomodulatory effectsT lymphocytesAbsence of APCC-type lectinBioactive TGFGalectin-3AntigenTGFTLR2Cell interactionsCellsLigand stimulation
2008
IFN‐α Can Both Protect against and Promote the Development of Type 1 Diabetes
Wong F, Wen L. IFN‐α Can Both Protect against and Promote the Development of Type 1 Diabetes. Annals Of The New York Academy Of Sciences 2008, 1150: 187-189. PMID: 19120292, DOI: 10.1196/annals.1447.031.Peer-Reviewed Original Research
2005
The Influence of the Major Histocompatibility Complex on Development of Autoimmune Diabetes in RIP-B7.1 Mice
Wong FS, Du W, Thomas IJ, Wen L. The Influence of the Major Histocompatibility Complex on Development of Autoimmune Diabetes in RIP-B7.1 Mice. Diabetes 2005, 54: 2032-2040. PMID: 15983204, DOI: 10.2337/diabetes.54.7.2032.Peer-Reviewed Original ResearchMeSH KeywordsAdoptive TransferAnimalsB7-1 AntigenCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesDiabetes Mellitus, Type 1Histocompatibility Antigens Class IHistocompatibility Antigens Class IIIslets of LangerhansLymphocyte DepletionMajor Histocompatibility ComplexMiceMice, Inbred C57BLMice, Inbred NODMice, SCIDConceptsT cell repertoireMajor histocompatibility complexI-Ag7Autoimmune T cell repertoireImportant genetic susceptibility factorAutoreactive T cell repertoireBALB/c miceHistocompatibility complexNonobese-resistant miceRIP-B7.1 miceCD8 T cellsNonobese diabetic (NOD) miceMHC class II moleculesDiabetes-resistant miceType 1 diabetesIslet beta cellsClass II moleculesCostimulatory molecule B7.1MHC class IC57BL/6 genetic backgroundGenetic susceptibility factorsLocal costimulationAutoimmune diabetesNOD miceSpontaneous diabetes
2004
What can the HLA transgenic mouse tell us about autoimmune diabetes?
Wong F, Wen L. What can the HLA transgenic mouse tell us about autoimmune diabetes? Diabetologia 2004, 47: 1476-1487. PMID: 15349728, DOI: 10.1007/s00125-004-1505-5.Peer-Reviewed Original ResearchConceptsHLA transgenic miceType 1 diabetes mellitusTransgenic miceDiabetes mellitusHLA class II allelesCD4 T lymphocytesAntigen-presenting moleculesClass II allelesPeptide-MHC complexesStudies of micePutative autoantigenParticular HLAT lymphocytesHLA moleculesPeptide antigensMHC complexesMiceDiseasePolygenic diseaseMellitusVivo roleInsultIntracellular processingImmunotherapyDiabetes
2003
Autoimmune diabetes in HLA‐DR3/DQ8 transgenic mice expressing the co‐stimulatory molecule B7‐1 in the β cells of islets of Langerhans
Rajagopalan G, Kudva YC, Chen L, Wen L, David CS. Autoimmune diabetes in HLA‐DR3/DQ8 transgenic mice expressing the co‐stimulatory molecule B7‐1 in the β cells of islets of Langerhans. International Immunology 2003, 15: 1035-1044. PMID: 12917255, DOI: 10.1093/intimm/dxg103.Peer-Reviewed Original ResearchConceptsCo-stimulatory molecules B7-1Incidence of diabetesTransgenic miceB7-1Autoimmune diabetesHLA-DQ8HLA-DR3T cellsBeta cellsBeta-cell toxin streptozotocinHLA class II associationsDQ8 transgenic micePresence of DR3HLA transgenic miceAntibody-mediated depletionPathogenesis of T1D.Class II associationsHLA class IIWhole-body irradiationPancreatic beta cellsNon-specific activationSpontaneous diabetesToxin streptozotocinDiabetogenic potentialSTZ treatment
2002
Induction and acceleration of insulitis/diabetes in mice with a viral mimic (polyinosinic-polycytidylic acid) and an insulin self-peptide
Moriyama H, Wen L, Abiru N, Liu E, Yu L, Miao D, Gianani R, Wong F, Eisenbarth G. Induction and acceleration of insulitis/diabetes in mice with a viral mimic (polyinosinic-polycytidylic acid) and an insulin self-peptide. Proceedings Of The National Academy Of Sciences Of The United States Of America 2002, 99: 5539-5544. PMID: 11943868, PMCID: PMC122805, DOI: 10.1073/pnas.082120099.Peer-Reviewed Original ResearchConceptsT lymphocytesB7-1 transgenic miceBALB/c miceAnti-islet autoimmunityExperimental autoimmune diabetesAutoreactive T lymphocytesB7-1 moleculeCD4 T lymphocytesType 1 diabetesPolyinosinic-polycytidylic acidAutoimmune diabetesInsulin autoantibodiesC micePeptide immunizationSimultaneous administrationDisease inductionMurine modelMouse modelDiabetesTransgenic miceInsulin peptidesMiceImmunizationPolyICViral mimic
2001
The regulatory role of DR4 in a spontaneous diabetes DQ8 transgenic model
Wen L, Chen N, Tang J, Sherwin R, Wong F. The regulatory role of DR4 in a spontaneous diabetes DQ8 transgenic model. Journal Of Clinical Investigation 2001, 107: 871-880. PMID: 11285306, PMCID: PMC199575, DOI: 10.1172/jci11708.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBone Marrow CellsCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCell DifferentiationDiabetes Mellitus, Type 1Disease Models, AnimalFemaleGene ExpressionHistocompatibility Antigens Class IIHLA-DQ AntigensHLA-DR4 AntigenIncidenceInsulinMaleMiceMice, Inbred C57BLMice, TransgenicMicrosatellite RepeatsPancreasSialadenitisSpleenTh2 CellsTransgenesConceptsMHC class II moleculesSpontaneous diabetesClass II moleculesTransgenic miceT cellsHLA-DQ8Diabetogenic effectMouse MHC class II moleculesHLA-DR transgenic miceTh2-like immune responsesHuman type 1 diabetesAutoreactive T cellsDouble transgenic miceType 1 diabetesC57BL/6 transgenic miceTh2-like phenotypePancreatic beta cellsExpression of DR4DQ8 allelesDiabetes developmentCostimulatory moleculesHLA-DQImmune responseBeta cellsDiabetesType 1 Diabetes-Predisposing MHC Alleles Influence the Selection of Glutamic Acid Decarboxylase (GAD) 65-Specific T Cells in a Transgenic Model
Abraham R, Wen L, Marietta E, David C. Type 1 Diabetes-Predisposing MHC Alleles Influence the Selection of Glutamic Acid Decarboxylase (GAD) 65-Specific T Cells in a Transgenic Model. The Journal Of Immunology 2001, 166: 1370-1379. PMID: 11145722, DOI: 10.4049/jimmunol.166.2.1370.Peer-Reviewed Original ResearchMeSH KeywordsAllelesAmino Acid SequenceAnimalsAntibody SpecificityCells, CulturedCytokinesDiabetes Mellitus, Type 1Disease Models, AnimalEpitopes, T-LymphocyteGenes, MHC Class IIGenetic Predisposition to DiseaseGlutamate DecarboxylaseHLA-DQ AntigensHLA-DR3 AntigenHumansImmunophenotypingIslets of LangerhansIsoenzymesLymphocyte ActivationMiceMice, Inbred C57BLMice, TransgenicMolecular Sequence DataRatsT-Lymphocyte SubsetsConceptsGlutamic acid decarboxylaseGAD 65T cellsDQ8 miceMixed Th1/Th2 cytokine profileEndogenous MHC class IISpontaneous T-cell reactivityTh1/Th2 cytokine profileGlutamic acid decarboxylase 65Self-reactive responsesT cell reactivityTh2 cytokine profileAutoantigen glutamic acid decarboxylase 65Type 1 diabetesMHC class IIDiabetes-associated genesCytokine profileIslet autoantigensHLA-DR3Immune toleranceHLA-DQ6Cell reactivitySelf-AgImmune responseHLA alleles
2000
In Vivo Evidence for the Contribution of Human Histocompatibility Leukocyte Antigen (Hla)-Dq Molecules to the Development of Diabetes
Wen L, Wong F, Tang J, Chen N, Altieri M, David C, Flavell R, Sherwin R. In Vivo Evidence for the Contribution of Human Histocompatibility Leukocyte Antigen (Hla)-Dq Molecules to the Development of Diabetes. Journal Of Experimental Medicine 2000, 191: 97-104. PMID: 10620608, PMCID: PMC2195792, DOI: 10.1084/jem.191.1.97.Peer-Reviewed Original ResearchConceptsClass II moleculesMHC class II moleculesGlutamic acid decarboxylaseRat insulin promoterSpontaneous diabetesB7-1T cellsBeta cellsMouse MHC class II moleculesTransgenic miceHuman histocompatibility leukocyte antigenHuman type 1 diabetesMajor histocompatibility complex (MHC) class II moleculesCostimulatory molecules B7-1Human MHC class II moleculesVivo evidenceHistocompatibility leukocyte antigenDevelopment of diabetesType 1 diabetesMHC class IIC57BL/6 transgenic miceMurine MHC class IIPancreatic beta cellsVivo experimental evidenceDiabetogenic role
1996
T-cell alpha beta + and gamma delta + deficient mice display abnormal but distinct phenotypes toward a natural, widespread infection of the intestinal epithelium.
Roberts S, Smith A, West A, Wen L, Findly R, Owen M, Hayday A. T-cell alpha beta + and gamma delta + deficient mice display abnormal but distinct phenotypes toward a natural, widespread infection of the intestinal epithelium. Proceedings Of The National Academy Of Sciences Of The United States Of America 1996, 93: 11774-11779. PMID: 8876213, PMCID: PMC38134, DOI: 10.1073/pnas.93.21.11774.Peer-Reviewed Original ResearchMeSH KeywordsAdoptive TransferAnimalsCD4-Positive T-LymphocytesCoccidiosisEimeriaGastrointestinal HemorrhageIntestinal DiseasesIntestinal MucosaIntestine, SmallLymph NodesLymphocyte TransfusionMiceMice, Inbred C57BLMice, Inbred StrainsMice, KnockoutPhenotypeReceptors, Antigen, T-Cell, alpha-betaReceptors, Antigen, T-Cell, gamma-deltaT-LymphocytesConceptsAlpha beta T cellsBeta T cellsT cellsGamma deltaT cell antigen receptorAlpha beta T-cell responsesT cell effector functionGamma delta T-cell antigen receptorsAlpha betaT cell responsesIntestinal damageProtective immunityAutoimmune diseasesEpithelial infectionDeficient miceEffector functionsEimeria vermiformisImmune systemCell responsesIntestinal epitheliumIntracellular protozoanWidespread infectionAntigen receptorInfectionMiceCD8 T cell clones from young nonobese diabetic (NOD) islets can transfer rapid onset of diabetes in NOD mice in the absence of CD4 cells.
Wong FS, Visintin I, Wen L, Flavell RA, Janeway CA. CD8 T cell clones from young nonobese diabetic (NOD) islets can transfer rapid onset of diabetes in NOD mice in the absence of CD4 cells. Journal Of Experimental Medicine 1996, 183: 67-76. PMID: 8551245, PMCID: PMC2192404, DOI: 10.1084/jem.183.1.67.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsB7-1 AntigenBase SequenceCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesClone CellsCytokinesDiabetes Mellitus, Type 2FemaleImmunohistochemistryImmunotherapy, AdoptiveInsulinIslets of LangerhansLymphocyte ActivationMembrane GlycoproteinsMiceMice, Inbred BALB CMice, Inbred C57BLMice, Inbred NODMice, SCIDMolecular Sequence DataPancreasPerforinPore Forming Cytotoxic ProteinsPromoter Regions, GeneticConceptsT cell linesNOD miceT cellsCD8 T cell linesCD8 T cell clonesNonobese diabetic (NOD) miceCB17 SCID miceCD4 T cellsPathogenesis of diabetesT cell clonesCell linesIslets of LangerhansT cell antigen receptorNOD isletsCD4 cellsLymphocytic infiltrateNOD-SCIDDiabetic miceDiabetic isletsFemale NODRapid onsetCell antigen receptorH-2KdAntigen receptorMice