Featured Publications
PI3Kγ in B cells promotes antibody responses and generation of antibody-secreting cells
Lanahan S, Yang L, Jones K, Qi Z, Cabrera E, Cominsky L, Ramaswamy A, Barmada A, Gabernet G, Uthaya Kumar D, Xu L, Shan P, Wymann M, Kleinstein S, Rao V, Mustillo P, Romberg N, Abraham R, Lucas C. PI3Kγ in B cells promotes antibody responses and generation of antibody-secreting cells. Nature Immunology 2024, 25: 1422-1431. PMID: 38961274, DOI: 10.1038/s41590-024-01890-1.Peer-Reviewed Original ResearchAntibody-secreting cellsMemory B cellsB cellsKinase activity-dependent mannerDifferentiation of antibody-secreting cellsAntibody responseGeneration of antibody-secreting cellsInborn errors of immunityActivity-dependent mannerMouse immunization modelFate choiceT cell-dependent antigensToll-like receptor activationTranscriptional programsB cell biologyPhosphoinositide 3-kinase-gammaErrors of immunityNaive B cellsTransduce signalsActivated B cellsB lineage cellsRobust antibody responsesHumoral defectsHumoral immunityReceptor activationHuman genetic errors of immunity illuminate an adaptive arsenal model of rapid defenses
Lucas C. Human genetic errors of immunity illuminate an adaptive arsenal model of rapid defenses. Trends In Immunology 2024, 45: 113-126. PMID: 38302340, DOI: 10.1016/j.it.2023.12.006.Peer-Reviewed Original Research“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 diseaseCytokinopathy with aberrant cytotoxic lymphocytes and profibrotic myeloid response in SARS-CoV-2 mRNA vaccine–associated myocarditis
Barmada A, Klein J, Ramaswamy A, Brodsky N, Jaycox J, Sheikha H, Jones K, Habet V, Campbell M, Sumida T, Kontorovich A, Bogunovic D, Oliveira C, Steele J, Hall E, Pena-Hernandez M, Monteiro V, Lucas C, Ring A, Omer S, Iwasaki A, Yildirim I, Lucas C. Cytokinopathy with aberrant cytotoxic lymphocytes and profibrotic myeloid response in SARS-CoV-2 mRNA vaccine–associated myocarditis. Science Immunology 2023, 8: eadh3455-eadh3455. PMID: 37146127, PMCID: PMC10468758, DOI: 10.1126/sciimmunol.adh3455.Peer-Reviewed Original ResearchConceptsMRNA vaccinesSARS-CoV-2 mRNA vaccinesSARS-CoV-2 mRNA vaccinationC-reactive protein levelsB-type natriuretic peptidePeripheral blood mononuclear cellsCardiac tissue inflammationDeep immune profilingSerum soluble CD163Vaccine-associated myocarditisCohort of patientsBlood mononuclear cellsCytotoxic T cellsLate gadolinium enhancementHypersensitivity myocarditisElevated troponinMRNA vaccinationImaging abnormalitiesNK cellsImmune profilingKiller cellsMyeloid responseNatriuretic peptideHumoral mechanismsInflammatory cytokinesThe role of PI3Kγ in the immune system: new insights and translational implications
Lanahan SM, Wymann MP, Lucas CL. The role of PI3Kγ in the immune system: new insights and translational implications. Nature Reviews Immunology 2022, 22: 687-700. PMID: 35322259, PMCID: PMC9922156, DOI: 10.1038/s41577-022-00701-8.Peer-Reviewed Original ResearchConceptsProtein structure determinationContext-dependent modulatorNew insightsImmune systemMonogenic immune disordersSpecific PI3Kγ inhibitorInflammatory cytokine releaseRole of PI3KγPI3Kγ deficiencyImmunomodulatory roleCytokine releaseClinical trialsImmune disordersPI3KγTherapeutic targetOncology indicationsTranslational implicationsDrug developmentStructure determinationPI3Kγ inhibitorsRecent advancesPhosphoinositideRoleHumansInsightsHuman 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 macrophagesImmune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children
Ramaswamy A, Brodsky NN, Sumida TS, Comi M, Asashima H, Hoehn KB, Li N, Liu Y, Shah A, Ravindra NG, Bishai J, Khan A, Lau W, Sellers B, Bansal N, Guerrerio P, Unterman A, Habet V, Rice AJ, Catanzaro J, Chandnani H, Lopez M, Kaminski N, Dela Cruz CS, Tsang JS, Wang Z, Yan X, Kleinstein SH, van Dijk D, Pierce RW, Hafler DA, Lucas CL. Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children. Immunity 2021, 54: 1083-1095.e7. PMID: 33891889, PMCID: PMC8043654, DOI: 10.1016/j.immuni.2021.04.003.Peer-Reviewed Original ResearchConceptsMIS-C patientsDisease severityInflammatory syndromeTCR repertoireSARS-CoV-2-associated multisystem inflammatory syndromeAsymptomatic SARS-CoV-2 infectionSARS-CoV-2 infectionAdult COVID-19Post-infectious complicationsMultisystem inflammatory syndromeCytotoxicity genesHealthy pediatricImmune dysregulationMemory TActive infectionMyeloid dysfunctionPatientsSingle-cell RNA sequencingFlow cytometrySerum proteomicsRepertoire analysisElevated expressionSeverityAlarminsCOVID-19Human 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 targetsUncontrolled Epstein-Barr Virus as an Atypical Presentation of Deficiency in ADA2 (DADA2)
Brooks JP, Rice AJ, Ji W, Lanahan SM, Konstantino M, Dara J, Hershfield MS, Cruickshank A, Dokmeci E, Lakhani S, Lucas CL. Uncontrolled Epstein-Barr Virus as an Atypical Presentation of Deficiency in ADA2 (DADA2). Journal Of Clinical Immunology 2021, 41: 680-683. PMID: 33394316, DOI: 10.1007/s10875-020-00940-1.Peer-Reviewed Original ResearchAdenosine DeaminaseAntiviral AgentsBiomarkersBiopsyChildDisease ManagementDisease SusceptibilityDNA Mutational AnalysisEpstein-Barr Virus InfectionsExome SequencingFemaleHematopoietic Stem Cell TransplantationHumansIntercellular Signaling Peptides and ProteinsSevere Combined ImmunodeficiencySiblingsSymptom AssessmentTomography, X-Ray ComputedTreatment OutcomeNovel 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
2023
Biallelic CRELD1 variants cause a multisystem syndrome, including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections
Jeffries L, Mis E, McWalter K, Donkervoort S, Brodsky N, Carpier J, Ji W, Ionita C, Roy B, Morrow J, Darbinyan A, Iyer K, Aul R, Banka S, Chao K, Cobbold L, Cohen S, Custodio H, Drummond-Borg M, Elmslie F, Finanger E, Hainline B, Helbig I, Hewson S, Hu Y, Jackson A, Josifova D, Konstantino M, Leach M, Mak B, McCormick D, McGee E, Nelson S, Nguyen J, Nugent K, Ortega L, Goodkin H, Roeder E, Roy S, Sapp K, Saade D, Sisodiya S, Stals K, Towner S, Wilson W, Disorders D, Borras S, Clark C, Dean J, Miedzybrodzka Z, Ross A, Tennant S, Dabir T, Donnelly D, Humphreys M, Magee A, McConnell V, McKee S, McNerlan S, Morrison P, Rea G, Stewart F, Cole T, Cooper N, Cooper-Charles L, Cox H, Islam L, Jarvis J, Keelagher R, Lim D, McMullan D, Morton J, Naik S, O’Driscoll M, Ong K, Osio D, Ragge N, Turton S, Vogt J, Williams D, Bodek S, Donaldson A, Hills A, Low K, Newbury-Ecob R, Norman A, Roberts E, Scurr I, Smithson S, Tooley M, Abbs S, Armstrong R, Dunn C, Holden S, Park S, Paterson J, Raymond L, Reid E, Sandford R, Simonic I, Tischkowitz M, Woods G, Bradley L, Comerford J, Green A, Lynch S, McQuaid S, Mullaney B, Berg J, Goudie D, Mavrak E, McLean J, McWilliam C, Reavey E, Azam T, Cleary E, Jackson A, Lam W, Lampe A, Moore D, Porteous M, Baple E, Baptista J, Brewer C, Castle B, Kivuva E, Owens M, Rankin J, Shaw-Smith C, Turner C, Turnpenny P, Tysoe C, Bradley T, Davidson R, Gardiner C, Joss S, Kinning E, Longman C, McGowan R, Murday V, Pilz D, Tobias E, Whiteford M, Williams N, Barnicoat A, Clement E, Faravelli F, Hurst J, Jenkins L, Jones W, Kumar V, Lees M, Loughlin S, Male A, Morrogh D, Rosser E, Scott R, Wilson L, Beleza A, Deshpande C, Flinter F, Holder M, Irving M, Izatt L, Josifova D, Mohammed S, Molenda A, Robert L, Roworth W, Ruddy D, Ryten M, Yau S, Bennett C, Blyth M, Campbell J, Coates A, Dobbie A, Hewitt S, Hobson E, Jackson E, Jewell R, Kraus A, Prescott K, Sheridan E, Thomson J, Bradshaw K, Dixit A, Eason J, Haines R, Harrison R, Mutch S, Sarkar A, Searle C, Shannon N, Sharif A, Suri M, Vasudevan P, Canham N, Ellis I, Greenhalgh L, Howard E, Stinton V, Swale A, Weber A, Banka S, Breen C, Briggs T, Burkitt-Wright E, Chandler K, Clayton-Smith J, Donnai D, Douzgou S, Gaunt L, Jones E, Kerr B, Langley C, Metcalfe K, Smith A, Wright R, Bourn D, Burn J, Fisher R, Hellens S, Henderson A, Montgomery T, Splitt M, Straub V, Wright M, Zwolinski S, Allen Z, Bernhard B, Brady A, Brooks C, Busby L, Clowes V, Ghali N, Holder S, Ibitoye R, Wakeling E, Blair E, Carmichael J, Cilliers D, Clasper S, Gibbons R, Kini U, Lester T, Nemeth A, Poulton J, Price S, Shears D, Stewart H, Wilkie A, Albaba S, Baker D, Balasubramanian M, Johnson D, Parker M, Quarrell O, Stewart A, Willoughby J, Crosby C, Elmslie F, Homfray T, Jin H, Lahiri N, Mansour S, Marks K, McEntagart M, Saggar A, Tatton-Brown K, Butler R, Clarke A, Corrin S, Fry A, Kamath A, McCann E, Mugalaasi H, Pottinger C, Procter A, Sampson J, Sansbury F, Varghese V, Baralle D, Callaway A, Cassidy E, Daniels S, Douglas A, Foulds N, Hunt D, Kharbanda M, Lachlan K, Mercer C, Side L, Temple I, Wellesley D, Consortium G, Ambrose J, Arumugam P, Baple E, Bleda M, Boardman-Pretty F, Boissiere J, Boustred C, Caulfield M, Chan G, Craig C, Daugherty L, de Burca A, Devereau A, Elgar G, Foulger R, Fowler T, FurióTarí P, Hackett J, Halai D, Hamblin A, Henderson S, Holman J, Hubbard T, Ibáñez K, Jackson R, Jones L, Kasperaviciute D, Kayikci M, Lahnstein L, Lawson K, Leigh S, Leong I, Lopez F, MaleadyCrowe F, Mason J, McDonagh E, Moutsianas L, Mueller M, Murugaesu N, Need A, Odhams C, Patch C, Perez-Gil D, Polychronopoulos D, Pullinger J, Rahim T, Rendon A, Riesgo-Ferreiro P, Rogers T, Ryten M, Savage K, Sawant K, Scott R, Siddiq A, Sieghart A, Smedley D, Smith K, Sosinsky A, Spooner W, Stevens H, Stuckey A, Sultana R, Thomas E, Thompson S, Tucci A, Walsh E, Watters S, Welland M, Williams E, Witkowska K, Network U, Acosta M, Adam M, Adams D, Agrawal P, Alejandro M, Alvey J, Amendola L, Andrews A, Ashley E, Azamian M, Bacino C, Bademci G, Baker E, Balasubramanyam A, Baldridge D, Bale J, Bamshad M, Barbouth D, Bayrak-Toydemir P, Beck A, Beggs A, Behrens E, Bejerano G, Bennet J, Berg-Rood B, Bernstein J, Berry G, Bican A, Bivona S, Blue E, Bohnsack J, Bonnenmann C, Bonner D, Botto L, Boyd B, Briere L, Brokamp E, Brown G, Burke E, Burrage L, Butte M, Byers P, Byrd W, Carey J, Carrasquillo O, Chang T, Chanprasert S, Chao H, Clark G, Coakley T, Cobban L, Cogan J, Coggins M, Cole F, Colley H, Cooper C, Craigen W, Crouse A, Cunningham M, D'Souza P, Dai H, Dasari S, Davids M, Dayal J, Deardorff M, Dell'Angelica E, Dhar S, Dipple K, Doherty D, Dorrani N, Douine E, Draper D, Duncan L, Earl D, Eckstein D, Emrick L, Eng C, Esteves C, Estwick T, Falk M, Fernandez L, Ferreira C, Fieg E, Findley L, Fisher P, Fogel B, Forghani I, Fresard L, Gahl W, Glass I, Godfrey R, Golden-Grant K, Goldman A, Goldstein D, Grajewski A, Groden C, Gropman A, Gutierrez I, Hahn S, Hamid R, Hanchard N, Hassey K, Hayes N, High F, Hing A, Hisama F, Holm I, Hom J, Horike-Pyne M, Huang A, Huang Y, Isasi R, Jamal F, Jarvik G, Jarvik J, Jayadev S, Johnston J, Karaviti L, Kelley E, Kennedy J, Kiley D, Kohane I, Kohler J, Krakow D, Krasnewich D, Kravets E, Korrick S, Koziura M, Krier J, Lalani S, Lam B, Lam C, Lanpher B, Lanza I, Lau C, LeBlanc K, Lee B, Lee H, Levitt R, Lewis R, Lincoln S, Liu P, Liu X, Longo N, Loo S, Loscalzo J, Maas R, Macnamara E, MacRae C, Maduro V, Majcherska M, Mak B, Malicdan M, Mamounas L, Manolio T, Mao R, Maravilla K, Markello T, Marom R, Marth G, Martin B, Martin M, Martínez-Agosto J, Marwaha S, McCauley J, McCormack C, McCray A, McGee E, Mefford H, Merritt J, Might M, Mirzaa G, Morava E, Moretti P, Morimoto M, Mulvihill J, Murdock D, Nakano-Okuno M, Nath A, Nelson S, Newman J, Nicholas S, Nickerson D, Nieves-Rodriguez S, Novacic D, Oglesbee D, Orengo J, Pace L, Pak S, Pallais J, Papp J, Parker N, Phillips J, Posey J, Potocki L, Pusey B, Quinlan A, Raskind W, Raja A, Rao D, Renteria G, Reuter C, Rives L, Robertson A, Rodan L, Rosenfeld J, Rosenwasser N, Ruzhnikov M, Sacco R, Sampson J, Samson S, Saporta M, Scott C, Schaechter J, Schedl T, Scott D, Sharma P, Shin J, Signer R, Sillari C, Silverman E, Sinsheimer J, Sisco K, Smith E, Smith K, Solem E, Solnica-Krezel L, Stoler J, Stong N, Sullivan J, Sun A, Sutton S, Sweetser D, Sybert V, Tabor H, Tamburro C, Tekin M, Telischi F, Thorson W, Tifft C, Toro C, Tran A, Tucker B, Urv T, Vanderver A, Velinder M, Viskochil D, Vogel T, Wahl C, Wallace S, Walley N, Walsh C, Walker M, Wambach J, Wan J, Wang L, Wangler M, Ward P, Wegner D, Wener M, Wenger T, Perry K, Westerfield M, Wheeler M, Whitlock J, Wolfe L, Woods J, Yamamoto S, Yang J, Yu G, Zastrow D, Zhao C, Zuchner S, Khokha M, Bönnemann C, Lucas C, Lakhani S. Biallelic CRELD1 variants cause a multisystem syndrome, including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections. Genetics In Medicine 2023, 26: 101023. PMID: 37947183, PMCID: PMC10932913, DOI: 10.1016/j.gim.2023.101023.Peer-Reviewed Original ResearchPeripheral blood mononuclear cellsPatient's immune cellsBlood mononuclear cellsImmune cell subtypesEarly-onset epilepsyAffected individualsInduced seizuresCardiac dysrhythmiasRecurrent infectionsClinical syndromeFrequent infectionsMononuclear cellsPatient cohortImmune cellsMultisystem syndromeHealthy donorsMultisystem disorderCardiac arrhythmiasBiallelic variantsCell subtypesDevelopmental delayGene variantsProtein overexpressionRecessive variantsMissense variantsPI3Kδ Pathway Dysregulation and Unique Features of Its Inhibition by Leniolisib in Activated PI3Kδ Syndrome and Beyond
Cant A, Chandra A, Munro E, Rao V, Lucas C. PI3Kδ Pathway Dysregulation and Unique Features of Its Inhibition by Leniolisib in Activated PI3Kδ Syndrome and Beyond. The Journal Of Allergy And Clinical Immunology In Practice 2023, 12: 69-78. PMID: 37777067, PMCID: PMC10872751, DOI: 10.1016/j.jaip.2023.09.016.Peer-Reviewed Original ResearchConceptsPI3Kδ inhibitorsActivated PI3Kδ SyndromeImmune cell developmentPI3Kδ syndromeSpecific inhibitory propertiesAdverse eventsTreatment optionsPI3Kδ activityHematological malignanciesPathway dysregulationInborn errorsDrug mechanismsGenetic hyperactivationLeniolisibSyndromeΔ isoformsCell developmentInhibitorsInhibitory propertiesΓ isoformsColitisNeutropeniaTolerabilityMalignancyHepatotoxicityVariable CD18 expression in a 22‐year‐old female with leukocyte adhesion deficiency I: Clinical case and literature review
Bondarenko A, Boyarchuk O, Sakovich I, Polyakova E, Migas A, Kupchinskaya A, Opalinska A, Reich A, Volianska L, Hilfanova A, Lapiy F, Chernyshova L, Volokha A, Zabara D, Belevtsev M, Shman T, Kukharenko L, Goltsev M, Dubouskaya T, Hancharou A, Ji W, Lakhani S, Lucas C, Aleinikova O, Sharapova S. Variable CD18 expression in a 22‐year‐old female with leukocyte adhesion deficiency I: Clinical case and literature review. Clinical Case Reports 2023, 11: e7791. PMID: 37601427, PMCID: PMC10432584, DOI: 10.1002/ccr3.7791.Peer-Reviewed Original ResearchCD18 expressionLAD-1Effector cytotoxic T cellsPyoderma gangrenosum-like lesionsHematopoietic stem cell transplantationGangrenosum-like lesionsRespiratory tract infectionsStem cell transplantationInflammatory skin diseaseCytotoxic T cellsImmune system imbalanceType 1 deficiencyYears of ageLeukocyte adhesion deficiency (LAD) IWhole-exome sequencingAutosomal recessive disorderAutoinflammatory complicationsInfectious manifestationsTract infectionsCell transplantationRare conditionT cellsOral cavitySkin diseasesClinical casesSARS-CoV-2 mRNA vaccines decouple anti-viral immunity from humoral autoimmunity
Jaycox J, Lucas C, Yildirim I, Dai Y, Wang E, Monteiro V, Lord S, Carlin J, Kita M, Buckner J, Ma S, Campbell M, Ko A, Omer S, Lucas C, Speake C, Iwasaki A, Ring A. SARS-CoV-2 mRNA vaccines decouple anti-viral immunity from humoral autoimmunity. Nature Communications 2023, 14: 1299. PMID: 36894554, PMCID: PMC9996559, DOI: 10.1038/s41467-023-36686-8.Peer-Reviewed Original ResearchConceptsVaccine-associated myocarditisAutoimmune patientsAutoantibody reactivitySARS-CoV-2 mRNA vaccinationVaccine-related adverse effectsSARS-CoV-2 immunitySARS-CoV-2 infectionAcute COVID-19Development of autoantibodiesCOVID-19 patientsAnti-viral immunityVirus-specific antibodiesCOVID-19 vaccineCOVID-19Humoral autoimmunityMRNA vaccinationAutoantibody responsePost vaccinationAutoantibody developmentAutoimmune diseasesHumoral responseHealthy individualsPatientsAntigen profilingAdverse effects
2022
A multiple sclerosis–protective coding variant reveals an essential role for HDAC7 in regulatory T cells
Axisa P, Yoshida T, Lucca L, Kasler H, Lincoln M, Pham G, Del Priore D, Carpier J, Lucas C, Verdin E, Sumida T, Hafler D. A multiple sclerosis–protective coding variant reveals an essential role for HDAC7 in regulatory T cells. Science Translational Medicine 2022, 14: eabl3651. PMID: 36516268, DOI: 10.1126/scitranslmed.abl3651.Peer-Reviewed Original ResearchConceptsExperimental autoimmune encephalitisRegulatory T cellsHistone deacetylase 7Multiple sclerosisT cellsMouse modelFunction of Foxp3CD4 T cellsHigher suppressive capacityVivo modelingAutoimmune encephalitisEAE severityImmunosuppressive subsetAutoimmune diseasesImmunomodulatory roleSuppressive capacityImmune cellsDisease onsetDistinct molecular classesSusceptibility lociGenetic susceptibility lociSingle-cell RNA sequencingDisease riskPatient samplesProtective variantsA retrospective cohort analysis of the Yale pediatric genomics discovery program
Al‐Ali S, Jeffries L, Faustino EVS, Ji W, Mis E, Konstantino M, Zerillo C, Jiang Y, Spencer‐Manzon M, Bale A, Zhang H, McGlynn J, McGrath JM, Tremblay T, Brodsky NN, Lucas CL, Pierce R, Deniz E, Khokha MK, Lakhani SA. A retrospective cohort analysis of the Yale pediatric genomics discovery program. American Journal Of Medical Genetics Part A 2022, 188: 2869-2878. PMID: 35899841, PMCID: PMC9474639, DOI: 10.1002/ajmg.a.62918.Peer-Reviewed Original ResearchConceptsRetrospective cohort analysisNext-generation sequencingCohort analysisSystem abnormalitiesImmune system abnormalitiesCardiovascular system abnormalitiesFunctional molecular analysesNovel genesPrecise molecular diagnosisClinical characteristicsFurther genetic evaluationDiscovery programsComplex patientsMultisystem diseaseDisease genesPediatric providersRare genetic diseaseNew diagnosisPhenotype relationshipsPatientsGenetic diseasesMolecular analysisDiagnosisParticipant demographicsNGS results
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 treatmentCytopeniasInfections in activated PI3K delta syndrome (APDS)
Brodsky NN, Lucas CL. Infections in activated PI3K delta syndrome (APDS). Current Opinion In Immunology 2021, 72: 146-157. PMID: 34052541, DOI: 10.1016/j.coi.2021.04.010.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsPI3K delta syndromeHematopoietic stem cell transplantAnti-microbial prophylaxisPI3K-delta syndromeStem cell transplantSenescent T cellsSpectrum of infectionsAdaptive immune functionAutosomal dominant disorderCell transplantImmune defectsImmunoglobulin replacementRecurrent infectionsImmunomodulatory agentsTherapy optionsT cellsImmune functionInfection susceptibilityInborn errorsDominant disorderInfectionLymphadenopathyPatientsFunction mutationsImmunodeficiency