2021
The E3 ubiquitin ligase RNF186 and RNF186 risk variants regulate innate receptor-induced outcomes
Ranjan K, Hedl M, Abraham C. The E3 ubiquitin ligase RNF186 and RNF186 risk variants regulate innate receptor-induced outcomes. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2013500118. PMID: 34353900, PMCID: PMC8364215, DOI: 10.1073/pnas.2013500118.Peer-Reviewed Original ResearchMeSH KeywordsCytokinesHumansImmunity, InnateInflammatory Bowel DiseasesIntestinesMacrophagesMyeloid CellsNF-kappa BNod2 Signaling Adaptor ProteinPolymorphism, Single NucleotideReceptor-Interacting Protein Serine-Threonine Kinase 2Receptors, Pattern RecognitionToll-Like Receptor 2Toll-Like Receptor 4UbiquitinationUbiquitin-Protein LigasesConceptsPattern recognition receptorsE3 ubiquitin ligase activityStimulation of PRRsAntimicrobial reactive oxygen speciesMultiple pattern recognition receptorsLoss of functionLigase activityReactive nitrogen speciesComplex assemblyIntestinal myeloid cellsReactive oxygen speciesAutophagy pathwayDownstream signalingRNF186Bacterial clearanceRisk variantsRecognition receptorsHuman macrophagesOxygen speciesInnate immunityInflammatory bowel diseaseNitrogen speciesMicrobial clearanceSpeciesMyeloid cells
2019
IL23 induces IL23R recycling and amplifies innate receptor-induced signalling and cytokines in human macrophages, and the IBD-protective IL23R R381Q variant modulates these outcomes
Sun R, Hedl M, Abraham C. IL23 induces IL23R recycling and amplifies innate receptor-induced signalling and cytokines in human macrophages, and the IBD-protective IL23R R381Q variant modulates these outcomes. Gut 2019, 69: 264. PMID: 31097538, PMCID: PMC6858485, DOI: 10.1136/gutjnl-2018-316830.Peer-Reviewed Original ResearchConceptsMonocyte-derived macrophagesHuman monocyte-derived macrophagesJanus kinase/signal transducerKinase/signal transducerDynamin-mediated endocytosisReceptor-induced signalingCell surface regulationR381Q variantIBD pathogenesisIntestinal myeloid cellsLate endosomesPattern recognition receptorsSignal transducerPathway membersDefines mechanismsReal-time PCRCell typesHeLa cellsSignalingKey playersRNA expressionHuman macrophagesPathwayWestern blotMyeloid cells
2017
An inflammatory bowel disease–risk variant in INAVA decreases pattern recognition receptor–induced outcomes
Yan J, Hedl M, Abraham C. An inflammatory bowel disease–risk variant in INAVA decreases pattern recognition receptor–induced outcomes. Journal Of Clinical Investigation 2017, 127: 2192-2205. PMID: 28436939, PMCID: PMC5451247, DOI: 10.1172/jci86282.Peer-Reviewed Original ResearchMeSH KeywordsActive Transport, Cell NucleusCarrier ProteinsCase-Control StudiesCytokinesEnterococcus faecalisGene ExpressionGenetic Association StudiesGenetic Predisposition to DiseaseHEK293 CellsHeterozygoteHumansInflammatory Bowel DiseasesMacrophagesMAP Kinase Signaling SystemMyeloid CellsPolymorphism, Single NucleotidePrimary Cell CultureReceptors, Pattern RecognitionRisk FactorsStaphylococcus aureusConceptsInflammatory bowel diseasePattern recognition receptor signalingDisease risk variantsIntestinal immune homeostasisActivation of MAPKIBD risk lociINAVAPrimary human cellsBacterial clearanceIntestinal myeloid cellsRisk lociAutophagy pathwayProper regulationIntronic regionsHuman cellsImmune homeostasisReceptor signalingDownstream signalsPRR stimulationReactive oxygenIntestinal microbesNF-κB activationGenesNF-κB pathwayMAPK
2016
Lessons Learned From Trials Targeting Cytokine Pathways in Patients With Inflammatory Bowel Diseases
Abraham C, Dulai PS, Vermeire S, Sandborn WJ. Lessons Learned From Trials Targeting Cytokine Pathways in Patients With Inflammatory Bowel Diseases. Gastroenterology 2016, 152: 374-388.e4. PMID: 27780712, PMCID: PMC5287922, DOI: 10.1053/j.gastro.2016.10.018.Peer-Reviewed Original ResearchMeSH KeywordsAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedCytokinesHumansInflammatory Bowel DiseasesInterleukin-23Janus KinasesLysophospholipidsMolecular Targeted TherapyOligonucleotidesPiperidinesProtein Kinase InhibitorsPyrimidinesPyrrolesSignal TransductionSmad7 ProteinSphingosineTh17 CellsTransforming Growth Factor betaUstekinumabConceptsInflammatory bowel diseaseTreatment of IBDBowel diseaseAnti-inflammatory mechanismsSeverity of colitisInflamed intestinal tissueCell pathwaysBiomarkers of responseImmune system pathwaysIBD pathogenesisInterleukin-23Proinflammatory cytokinesFuture trialsEffects of agentsClinical trialsCytokine pathwaysPatient featuresIntestinal tissueDevelopment of therapeuticsIL23System pathwaysPathway moleculesFunction variantsSelection of therapeuticsTrials
2015
MTMR3 risk allele enhances innate receptor-induced signaling and cytokines by decreasing autophagy and increasing caspase-1 activation
Lahiri A, Hedl M, Abraham C. MTMR3 risk allele enhances innate receptor-induced signaling and cytokines by decreasing autophagy and increasing caspase-1 activation. Proceedings Of The National Academy Of Sciences Of The United States Of America 2015, 112: 10461-10466. PMID: 26240347, PMCID: PMC4547281, DOI: 10.1073/pnas.1501752112.Peer-Reviewed Original ResearchMeSH KeywordsAllelesAutophagyCaspase 1CytokinesEnzyme ActivationGene Expression RegulationGenetic Predisposition to DiseaseGenotypeHomeostasisHumansInflammationInflammatory Bowel DiseasesLeukocytes, MononuclearLigandsMacrophagesMonocytesProtein Structure, TertiaryProtein Tyrosine Phosphatases, Non-ReceptorRisk FactorsRNA, Small InterferingSignal TransductionToll-Like ReceptorsConceptsPattern recognition receptorsCaspase-1 activationInflammatory bowel diseaseMTMR3 expressionReceptor-induced signalingHost pattern recognition receptorsCytokine secretionMultiple genetic lociPhosphatase domainMicrobial interactionsGenetic lociMTMR3Undefined roleAutophagyIL-1β secretionRecognition receptorsHuman macrophagesAutophagy levelEnhanced autophagyProtein 3Bowel diseaseCytokine productionRisk polymorphismsRisk allelesAltered function
2012
Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease
Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, Lee JC, Philip Schumm L, Sharma Y, Anderson CA, Essers J, Mitrovic M, Ning K, Cleynen I, Theatre E, Spain SL, Raychaudhuri S, Goyette P, Wei Z, Abraham C, Achkar JP, Ahmad T, Amininejad L, Ananthakrishnan AN, Andersen V, Andrews JM, Baidoo L, Balschun T, Bampton PA, Bitton A, Boucher G, Brand S, Büning C, Cohain A, Cichon S, D’Amato M, De Jong D, Devaney KL, Dubinsky M, Edwards C, Ellinghaus D, Ferguson LR, Franchimont D, Fransen K, Gearry R, Georges M, Gieger C, Glas J, Haritunians T, Hart A, Hawkey C, Hedl M, Hu X, Karlsen TH, Kupcinskas L, Kugathasan S, Latiano A, Laukens D, Lawrance IC, Lees CW, Louis E, Mahy G, Mansfield J, Morgan AR, Mowat C, Newman W, Palmieri O, Ponsioen CY, Potocnik U, Prescott NJ, Regueiro M, Rotter JI, Russell RK, Sanderson JD, Sans M, Satsangi J, Schreiber S, Simms LA, Sventoraityte J, Targan SR, Taylor KD, Tremelling M, Verspaget HW, De Vos M, Wijmenga C, Wilson DC, Winkelmann J, Xavier RJ, Zeissig S, Zhang B, Zhang CK, Zhao H, Silverberg M, Annese V, Hakonarson H, Brant S, Radford-Smith G, Mathew C, Rioux J, Schadt E, Daly M, Franke A, Parkes M, Vermeire S, Barrett J, Cho J. Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 2012, 491: 119-124. PMID: 23128233, PMCID: PMC3491803, DOI: 10.1038/nature11582.Peer-Reviewed Original ResearchMeSH KeywordsColitis, UlcerativeCrohn DiseaseGenetic Predisposition to DiseaseGenome, HumanGenome-Wide Association StudyHaplotypesHost-Pathogen InteractionsHumansInflammatory Bowel DiseasesMycobacteriumMycobacterium InfectionsMycobacterium tuberculosisPhenotypePolymorphism, Single NucleotideReproducibility of Results
2011
Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses
Sarin R, Wu X, Abraham C. Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses. Proceedings Of The National Academy Of Sciences Of The United States Of America 2011, 108: 9560-9565. PMID: 21606346, PMCID: PMC3111257, DOI: 10.1073/pnas.1017854108.Peer-Reviewed Original ResearchMeSH KeywordsCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCell ProliferationCells, CulturedFlow CytometryHEK293 CellsHeLa CellsHumansImmunoblottingInflammatory Bowel DiseasesInterferon-gammaInterleukin-17Interleukin-23InterleukinsLuciferasesPolymorphism, Single NucleotideReceptors, InterleukinSignal TransductionSTAT3 Transcription FactorTh17 CellsConceptsT cellsIL-22 productionIL-23 receptorT cell functional responsesMultiple inflammatory diseasesPrimary human CD4WT CD8Tc17 cellsIL-17Arginine alleleInflammatory diseasesReceptor polymorphismsPrimary CD4Transcription 3 (STAT3) activationCD8Human CD4Function alterationsSignificant protectionHuman genetic polymorphismsGenetic polymorphismsR381QCD4AutoimmunityFunctional consequencesSignal transducer
2009
Inflammatory Bowel Disease
Abraham C, Cho JH. Inflammatory Bowel Disease. New England Journal Of Medicine 2009, 361: 2066-2078. PMID: 19923578, PMCID: PMC3491806, DOI: 10.1056/nejmra0804647.Peer-Reviewed Original Research