Human carmil2 deficiency underlies a broader immunological and clinical phenotype than cd28 deficiency

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dc.contributor.authorLévy, R.
dc.contributor.authorGothe, F.
dc.contributor.authorMomenilandi, M.
dc.contributor.authorMagg, T.
dc.contributor.authorMaterna, M.
dc.contributor.authorPeters, P.
dc.contributor.authorRaedler J.
dc.date.accessioned2024-05-19T14:34:34Z
dc.date.available2024-05-19T14:34:34Z
dc.date.issued2023
dc.departmentİstinye Üniversitesien_US
dc.description.abstractPatients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-?B but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4+ T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28. © 2022 Lévy et al.en_US
dc.description.sponsorshipANR-10-LABX-62-IBEID; S10OD018521; National Institutes of Health, NIH: R01AI088364, R01AI163029; National Institutes of Health, NIH; Howard Hughes Medical Institute, HHMI; National Human Genome Research Institute, NHGRI: U24HG008956, UM1HG006504; National Human Genome Research Institute, NHGRI; Fisher Center for Alzheimer's Research Foundation; Glenn Foundation for Medical Research, GFMR: ANR-21-CE15-0034, EQU201903007798; Glenn Foundation for Medical Research, GFMR; St. Giles Foundation; National Center for Advancing Translational Sciences, NCATS: UL1 TR001866; National Center for Advancing Translational Sciences, NCATS; Leona M. and Harry B. Helmsley Charitable Trust; JPB Foundation, JPBF; Deutsches Zentrum für Infektionsforschung, DZIF: TTU 07.909; Deutsches Zentrum für Infektionsforschung, DZIF; Care-for-Rare Foundation: 160073; Care-for-Rare Foundation; Rockefeller University; Center for Mendelian Genomics, University of Washington, UWCMG; Fonds de Recherche du Québec - Santé, FRQS; Deutsche Forschungsgemeinschaft, DFG: GO2955/1-1; Deutsche Forschungsgemeinschaft, DFG; Agence Nationale de la Recherche, ANR: ANR-10-IAHU-01; Agence Nationale de la Recherche, ANR; Institut National de la Santé et de la Recherche Médicale, Inserm; Bundesministerium für Bildung und Forschung, BMBF: 01GM1910C; Bundesministerium für Bildung und Forschung, BMBF; Else Kröner-Fresenius-Stiftung, EKFS: 2017_A110; Else Kröner-Fresenius-Stiftung, EKFS; Agence Nationale de Recherches sur le Sida et les Hépatites Virales, ANRS; Türkiye Bilimsel ve Teknolojik Araştırma Kurumu, TÜBİTAK; Ludwig-Maximilians-Universität München, LMU; Société Française de Dermatologie et de Pathologie Sexuellement Transmissible, SFD; Institut National Du Cancer, INCa; Université Paris-Saclay; Fondation Meyer pour le Développement Culturel et Artistiqueen_US
dc.description.sponsorshipDisclosures: J. Raedler reported grants from Foerderprogramm fuer Forschung und Lehre (FöFoLe), Medical Faculty, LMU Munich, Germany outside the submitted work. A. Fasth reported personal fees from Lipum AB (rheumatology, advisory board) outside the submitted work. S. Baris reported grants from TUBITAK outside the submitted work. A. Kumar reported personal fees from SOBI and SpringWorks Therapeutics outside the submitted work. No other disclosures were reported.en_US
dc.description.sponsorship2021–2030 Cancer Control Strategy (on funds administered by Institut National de la Santé et de la Recherche Médicale), the Square Foundation, Grandir–Fonds de solidarité pour l’Enfance, Institut National de la Santé et de la Recherche Médicale, the French Society of Dermatology, and the University of Paris. Open Access funding provided by Rockefeller University.en_US
dc.description.sponsorshipR. Lévy was supported by the Institut National de la Santé et de la Recherche Médicale PhD program, a Fulbright grant, and the INSERM-Bettencourt program. M. Momenilandi was supported by the Agence Nationale de Recherches sur le Sida et les Hépatites Virales. F. Gothe was supported by the Deutsche Forschungsgemeinschaft (GO2955/1-1), the Care-For-Rare Foundation, and the Munich Clinician Scientist Program (Foe-FoLeplus). F. Hauck received funding from the Care-for-Rare Foundation (160073), the German Center for Infection Research (TTU 07.909), the Else Kröner-Fresenius Stiftung (2017_A110), and the German Federal Ministry of Education and Research (01GM1910C). D. Langlais was supported by a Fonds de la Recherche Québec-Santé Chercheur-Boursier Junior 1 Award. D.S. Shouval is supported by the Leona M. and Harry B. Helmsley Charitable Trust. The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (R01AI088364 and R01AI163029), the National Center for Advancing Translational Sciences, National Institutes of Health Clinical and Translational Science Awards program (UL1 TR001866), a Fast Grant from Emergent Ventures, Mercatus Center at George Mason University, the Yale Center for Mendelian Genomics and the Genome Sequencing Program Coordinating Center funded by the National Human Genome Research Institute (UM1HG006504 and U24HG008956), the Yale High-Performance Computing Center (S10OD018521), the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the JPB Foundation, the French National Research Agency (ANR) under the “Investments for the Future” program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (EQU201903007798), ANR CARMIL2 (ANR-21-CE15-0034), ITMO Cancer of Aviesan and INCa within the framework of theen_US
dc.identifier.doi10.1084/jem.20220275
dc.identifier.issn0022-1007
dc.identifier.issue2en_US
dc.identifier.scopus2-s2.0-85152482775en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://doi.org/10.1084/jem.20220275
dc.identifier.urihttps://hdl.handle.net/20.500.12713/4512
dc.identifier.volume220en_US
dc.indekslendigikaynakScopusen_US
dc.language.isoenen_US
dc.publisherRockefeller University Pressen_US
dc.relation.ispartofJournal of Experimental Medicineen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.snmz20240519_kaen_US
dc.subjectCapping Protein Regulator And Myosin 1 Linker 2en_US
dc.subjectTropomodulinen_US
dc.subjectUnclassified Drugen_US
dc.subjectAdolescenten_US
dc.subjectAdulten_US
dc.subjectAntibody Responseen_US
dc.subjectArticleen_US
dc.subjectBlood Cell Counten_US
dc.subjectCd4+ T Lymphocyteen_US
dc.subjectControlled Studyen_US
dc.subjectEpstein Barr Virus İnfectionen_US
dc.subjectHumanen_US
dc.subjectİnflammatory Bowel Diseaseen_US
dc.subjectMajor Clinical Studyen_US
dc.subjectMemory B Lymphocyteen_US
dc.subjectMemory T Lymphocyteen_US
dc.subjectNatural Killer Cellen_US
dc.subjectPhenotypeen_US
dc.subjectProtein Deficiencyen_US
dc.subjectRegulatory T Lymphocyteen_US
dc.subjectRevertanten_US
dc.subjectSignal Transductionen_US
dc.subjectSmooth Muscle Tumoren_US
dc.subjectT Cell Dysfunctionen_US
dc.subjectT Lymphocyteen_US
dc.titleHuman carmil2 deficiency underlies a broader immunological and clinical phenotype than cd28 deficiencyen_US
dc.typeArticleen_US

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