Featured Publications
“Deficiency in ELF4, X-Linked”: a Monogenic Disease Entity Resembling Behçet’s Syndrome and Inflammatory Bowel Disease
Olyha S, O’Connor S, Kribis M, Bucklin M, Uthaya Kumar D, Tyler P, Alam F, Jones K, Sheikha H, Konnikova L, Lakhani S, Montgomery R, Catanzaro J, Du H, DiGiacomo D, Rothermel H, Moran C, Fiedler K, Warner N, Hoppenreijs E, van der Made C, Hoischen A, Olbrich P, Neth O, Rodríguez-Martínez A, Lucena Soto J, van Rossum A, Dalm V, Muise A, Lucas C. “Deficiency in ELF4, X-Linked”: a Monogenic Disease Entity Resembling Behçet’s Syndrome and Inflammatory Bowel Disease. Journal Of Clinical Immunology 2024, 44: 44. PMID: 38231408, PMCID: PMC10929603, DOI: 10.1007/s10875-023-01610-8.Peer-Reviewed Original ResearchConceptsDEX patientsClass-switched memory B cellsInborn errors of immunityTreated with anti-inflammatory agentsLow natural killerX-linkedMemory B cellsErrors of immunityCohort of patientsIncreased inflammatory cytokinesLoss-of-function variantsHeterogeneous clinical phenotypesInflammatory bowel diseaseTargeted therapeutic interventionsNatural killerAnti-inflammatory agentsAphthous ulcersTherapeutic responseAutoinflammatory syndromeInflammatory markersClinical manifestationsB cellsBehcet's syndromeGastrointestinal symptomsMechanisms of diseaseHuman autoinflammatory disease reveals ELF4 as a transcriptional regulator of inflammation
Tyler PM, Bucklin ML, Zhao M, Maher TJ, Rice AJ, Ji W, Warner N, Pan J, Morotti R, McCarthy P, Griffiths A, van Rossum AMC, Hollink IHIM, Dalm VASH, Catanzaro J, Lakhani SA, Muise AM, Lucas CL. Human autoinflammatory disease reveals ELF4 as a transcriptional regulator of inflammation. Nature Immunology 2021, 22: 1118-1126. PMID: 34326534, PMCID: PMC8985851, DOI: 10.1038/s41590-021-00984-4.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCalgranulin ADNA-Binding ProteinsFemaleGene Expression RegulationHereditary Autoinflammatory DiseasesHumansInflammatory Bowel DiseasesInterleukin 1 Receptor Antagonist ProteinLipocalin-2LipopolysaccharidesMacrophagesMaleMiceMice, Inbred C57BLMice, KnockoutTh17 CellsTranscription FactorsTranscription, GeneticTriggering Receptor Expressed on Myeloid Cells-1ConceptsInterleukin-1Inflammatory bowel disease (IBD) characteristicsInflammatory immune cellsHuman inflammatory disordersAnti-inflammatory genesTumor necrosis factorHuman autoinflammatory diseasesInnate stimuliHyperinflammatory responseMale patientsNeutrophil chemoattractantDisease characteristicsInflammatory disordersMucosal diseaseImmune cellsInflammation amplifierNecrosis factorUnrelated male patientsAutoinflammatory diseasesMouse modelBroad translational relevanceTranslational relevanceInflammationFunction variantsMouse macrophagesHuman PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology
Takeda AJ, Maher TJ, Zhang Y, Lanahan SM, Bucklin ML, Compton SR, Tyler PM, Comrie WA, Matsuda M, Olivier KN, Pittaluga S, McElwee JJ, Long Priel DA, Kuhns DB, Williams RL, Mustillo PJ, Wymann MP, Koneti Rao V, Lucas CL. Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology. Nature Communications 2019, 10: 4364. PMID: 31554793, PMCID: PMC6761123, DOI: 10.1038/s41467-019-12311-5.Peer-Reviewed Original ResearchConceptsT cellsAppropriate adaptive immune responsePet store miceRegulatory T cellsCD4 T cellsAnti-inflammatory functionsAdaptive immune responsesLymphocytic pneumonitisPI3Kγ deficiencyTissue immunopathologyIL-23Memory CD8IL-12TLR stimulationImmune modulationImmune responseGSK3α/βMouse modelMemory BHuman patientsMiceDependent mannerP110γ catalytic subunitFunction mutationsDrug targetsNovel PIK3CD mutations affecting N-terminal residues of p110δ cause activated PI3Kδ syndrome (APDS) in humans
Takeda AJ, Zhang Y, Dornan GL, Siempelkamp BD, Jenkins ML, Matthews HF, McElwee JJ, Bi W, Seeborg FO, Su HC, Burke JE, Lucas CL. Novel PIK3CD mutations affecting N-terminal residues of p110δ cause activated PI3Kδ syndrome (APDS) in humans. Journal Of Allergy And Clinical Immunology 2017, 140: 1152-1156.e10. PMID: 28414062, PMCID: PMC5632585, DOI: 10.1016/j.jaci.2017.03.026.Peer-Reviewed Original ResearchHeterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K
Lucas CL, Zhang Y, Venida A, Wang Y, Hughes J, McElwee J, Butrick M, Matthews H, Price S, Biancalana M, Wang X, Richards M, Pozos T, Barlan I, Ozen A, Rao VK, Su HC, Lenardo MJ. Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K. Journal Of Experimental Medicine 2014, 211: 2537-2547. PMID: 25488983, PMCID: PMC4267241, DOI: 10.1084/jem.20141759.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAlternative SplicingAntibody FormationBase SequenceCatalytic DomainCD8-Positive T-LymphocytesCell DifferentiationChild, PreschoolClass Ia Phosphatidylinositol 3-KinaseEnzyme ActivationExonsFemaleGenes, DominantHeterozygoteHumansImmunologic Deficiency SyndromesLymphoproliferative DisordersMaleMolecular Sequence DataMutationPedigreePhosphatidylinositol 3-KinasesProtein Structure, TertiarySequence DeletionSignal TransductionTelomereTOR Serine-Threonine KinasesConceptsT cellsPI3KPI3K subunitsSenescent T cellsRecurrent sinopulmonary infectionsHeterozygous splice site mutationSplice site mutationEffector cellsPeripheral bloodSinopulmonary infectionsHuman immunodeficiencyHeterozygous splice mutationsImmunodeficiency diseaseHealthy subjectsUnique disorderHeterozygous mutationsClass IaPatient cellsProminent expansionK subunitLymphoproliferationPatientsSimilar diseasesShort telomeresDiseaseDominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency
Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, Avery DT, Moens L, Cannons JL, Biancalana M, Stoddard J, Ouyang W, Frucht DM, Rao VK, Atkinson TP, Agharahimi A, Hussey AA, Folio LR, Olivier KN, Fleisher TA, Pittaluga S, Holland SM, Cohen JI, Oliveira JB, Tangye SG, Schwartzberg PL, Lenardo MJ, Uzel G. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nature Immunology 2013, 15: 88-97. PMID: 24165795, PMCID: PMC4209962, DOI: 10.1038/ni.2771.Peer-Reviewed Original ResearchMeSH KeywordsAntibiotics, AntineoplasticCell DifferentiationCells, CulturedCellular SenescenceClass I Phosphatidylinositol 3-KinasesCytomegalovirus InfectionsEpstein-Barr Virus InfectionsFemaleGenes, DominantGerm-Line MutationHumansImmunoblottingImmunologic Deficiency SyndromesMalePedigreePhosphatidylinositol 3-KinasesPhosphorylationProto-Oncogene Proteins c-aktSirolimusT-LymphocytesTOR Serine-Threonine KinasesViremia
2021
Hematopoietic Cell Transplantation Cures Adenosine Deaminase 2 Deficiency: Report on 30 Patients
Hashem H, Bucciol G, Ozen S, Unal S, Bozkaya IO, Akarsu N, Taskinen M, Koskenvuo M, Saarela J, Dimitrova D, Hickstein DD, Hsu AP, Holland SM, Krance R, Sasa G, Kumar AR, Müller I, de Sousa MA, Delafontaine S, Moens L, Babor F, Barzaghi F, Cicalese MP, Bredius R, van Montfrans J, Baretta V, Cesaro S, Stepensky P, Benedicte N, Moshous D, Le Guenno G, Boutboul D, Dalal J, Brooks JP, Dokmeci E, Dara J, Lucas CL, Hambleton S, Wilson K, Jolles S, Koc Y, Güngör T, Schnider C, Candotti F, Steinmann S, Schulz A, Chambers C, Hershfield M, Ombrello A, Kanakry JA, Meyts I. Hematopoietic Cell Transplantation Cures Adenosine Deaminase 2 Deficiency: Report on 30 Patients. Journal Of Clinical Immunology 2021, 41: 1633-1647. PMID: 34324127, PMCID: PMC8452581, DOI: 10.1007/s10875-021-01098-0.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine DeaminaseAdolescentAdultAgammaglobulinemiaBone Marrow Failure DisordersChildChild, PreschoolFemaleGraft vs Host DiseaseHematopoietic Stem Cell TransplantationHumansIntercellular Signaling Peptides and ProteinsKaplan-Meier EstimateMaleRetrospective StudiesSevere Combined ImmunodeficiencyTreatment OutcomeYoung AdultConceptsHematopoietic cell transplantationBone marrow failureImmune cytopeniasOverall survivalRefractory cytopeniaGVHD-free relapse-free survivalOutcomes of HCTNecrosis factor blockadeNew vascular eventsRelapse-free survivalTreatment of choiceAdenosine deaminase 2ADA2 enzyme activityInherited inborn errorFinal transplantVascular eventsMedian agePrimary outcomeDADA2 patientsRetrospective studyCell transplantationImmunological phenotypeDefinitive cureEffective treatmentCytopenias
2020
Novel compound heterozygous variants in NHLRC2 in a patient with FINCA syndrome
Brodsky NN, Boyarchuk O, Kovalchuk T, Hariyan T, Rice A, Ji W, Khokha M, Lakhani S, Lucas CL. Novel compound heterozygous variants in NHLRC2 in a patient with FINCA syndrome. Journal Of Human Genetics 2020, 65: 911-915. PMID: 32435055, DOI: 10.1038/s10038-020-0776-0.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAngiomatosisBrain NeoplasmsCardiomegalyChild, PreschoolExome SequencingFibrosisHeterozygoteHumansIntracellular Signaling Peptides and ProteinsLung DiseasesMaleModels, MolecularNeurodegenerative DiseasesPedigreePoint MutationProtein ConformationProtein DomainsSequence AlignmentSequence Homology, Amino AcidSyndromeConceptsWhole-exome sequencingNovel compound heterozygous variantsCompound heterozygous variantsUkrainian patientsClinical featuresNovel variantsNew patientsHealthy humansCompound heterozygous combinationPatientsHeterozygous variantsSyndromeFinnish childrenNHLRC2Sanger sequencingFibrosisDiseaseGnomAD databaseN-terminal thioredoxinCentral regulatorVariantsNeurodegeneration
2017
Effective “activated PI3Kδ syndrome”–targeted therapy with the PI3Kδ inhibitor leniolisib
Rao VK, Webster S, Dalm VASH, Šedivá A, van Hagen PM, Holland S, Rosenzweig SD, Christ AD, Sloth B, Cabanski M, Joshi AD, de Buck S, Doucet J, Guerini D, Kalis C, Pylvaenaeinen I, Soldermann N, Kashyap A, Uzel G, Lenardo MJ, Patel DD, Lucas CL, Burkhart C. Effective “activated PI3Kδ syndrome”–targeted therapy with the PI3Kδ inhibitor leniolisib. Blood 2017, 130: 2307-2316. PMID: 28972011, PMCID: PMC5701526, DOI: 10.1182/blood-2017-08-801191.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsChemokinesChildChild, PreschoolClass I Phosphatidylinositol 3-KinasesDemographyDose-Response Relationship, DrugFemaleHumansImmunoglobulin MImmunologic Deficiency SyndromesInfantLymph NodesLymphocyte ActivationMaleMolecular Targeted TherapyMutationOrgan SizePhenotypePrimary Immunodeficiency DiseasesProtein Kinase InhibitorsPyridinesPyrimidinesRatsSpleenT-LymphocytesTOR Serine-Threonine KinasesTransfectionConceptsImmune dysregulationT cellsB cellsElevated serum immunoglobulin MPI3K/Akt pathway activityDose-escalation studyLymph node sizeSenescent T cellsWeeks of treatmentDose-dependent suppressionTransitional B cellsTumor necrosis factorDose-dependent reductionPrecision medicine therapiesSerum immunoglobulin MNaive B cellsT cell blastsAkt pathway activityAPDS patientsPI3Kδ pathwayInflammatory markersPD-1Clinical parametersSpleen volumeImmune deficiency
2015
Genomics of Immune Diseases and New Therapies
Lenardo M, Lo B, Lucas CL. Genomics of Immune Diseases and New Therapies. Annual Review Of Immunology 2015, 34: 1-29. PMID: 26735698, PMCID: PMC5736009, DOI: 10.1146/annurev-immunol-041015-055620.Peer-Reviewed Original ResearchConceptsDNA sequencing technologiesMagnesium transportersSequencing technologiesNew genetic diseasesGenomicsGenetic lossGenetic diseasesMolecular definitionGenetic pathogenesisPatient phenotypesBiochemical investigationsImmune regulationImmune diseasesPrecision medicine treatmentImmunological diseasesNew therapiesGenetic counselingTransportersAdditional examplesPhenotypeRegulationGreat advancesImproved diagnosis