{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:56:46Z","timestamp":1790704606880,"version":"4.1.0"},"reference-count":46,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"69","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sci. Immunol."],"published-print":{"date-parts":[[2022,3,25]]},"abstract":"<jats:p>\n                    IKZF1\/IKAROS is a key transcription factor of lymphocyte development expressed throughout hematopoiesis. Heterozygous germline\n                    <jats:italic>IKZF1<\/jats:italic>\n                    haploinsufficient (\n                    <jats:italic>IKZF1<\/jats:italic>\n                    <jats:sup>HI<\/jats:sup>\n                    ) and dominant-negative (\n                    <jats:italic>IKZF1<\/jats:italic>\n                    <jats:sup>DN<\/jats:sup>\n                    ) variants in humans cause B cell immune deficiency and combined immunodeficiency. Here, we identified previously unidentified heterozygous\n                    <jats:italic>IKZF1<\/jats:italic>\n                    variants (R183C\/H) located in the DNA binding domain in eight individuals with inflammatory, autoimmune, allergic symptoms, and abnormal plasma cell (PC) proliferation. Leukocytes of patients exhibited specific defects including impaired IL-2 production by T cells, T helper (T\n                    <jats:sub>H<\/jats:sub>\n                    ) skewing toward T\n                    <jats:sub>H<\/jats:sub>\n                    2, low numbers of regulatory T cells (T\n                    <jats:sub>reg<\/jats:sub>\n                    ), eosinophilia, and abnormal PC proliferation. In contrast to IKZF1\n                    <jats:sup>HI<\/jats:sup>\n                    and IKZF1\n                    <jats:sup>DN<\/jats:sup>\n                    , IKZF1\n                    <jats:sup>R183H\/C<\/jats:sup>\n                    proteins showed increased DNA binding associated with increased gene expression of T\n                    <jats:sub>H<\/jats:sub>\n                    2 and PC differentiation, thus demonstrating that\n                    <jats:italic>IKZF1<\/jats:italic>\n                    <jats:sup>R183H\/C<\/jats:sup>\n                    behave as gain-of-function (GOF) alleles. In vitro treatment with lenalidomide, known to degrade IKZF1, corrected T\n                    <jats:sub>H<\/jats:sub>\n                    2 and PC abnormalities caused by IKZF1\n                    <jats:sup>R183H\/C<\/jats:sup>\n                    . These data extend the spectrum of pathological mechanisms associated with\n                    <jats:italic>IKZF1<\/jats:italic>\n                    deficiencies and highlight the role of IKZF1 in late lymphoid differentiation stages.\n                  <\/jats:p>","DOI":"10.1126\/sciimmunol.abi7160","type":"journal-article","created":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T13:58:04Z","timestamp":1648216684000},"source":"Crossref","is-referenced-by-count":81,"title":["Gain-of-function\n                    <i>IKZF1<\/i>\n                    variants in humans cause immune dysregulation associated with abnormal T\/B cell late differentiation"],"prefix":"10.1126","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4392-0988","authenticated-orcid":true,"given":"Akihiro","family":"Hoshino","sequence":"first","affiliation":[{"name":"Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, INSERM UMR 1163, Imagine Institute, Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5006-8279","authenticated-orcid":true,"given":"David","family":"Boutboul","sequence":"additional","affiliation":[{"name":"Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, INSERM UMR 1163, Imagine Institute, Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Irving Medical Center, Columbia University, New York, NY, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye Sun","family":"Kuehn","sequence":"additional","affiliation":[{"name":"Immunology Service, Department of Laboratory Medicine, National Institutes of Health Clinical Center, NIH, Bethesda, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jer\u00f4me","family":"Hadjadj","sequence":"additional","affiliation":[{"name":"Laboratory of Immunogenetics of Pediatric Autoimmunity, INSERM UMR 1163, Imagine Institute, Paris, France."},{"name":"Universit\u00e9 de Paris, Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3204-4353","authenticated-orcid":true,"given":"Nihal","family":"\u00d6zdemir","sequence":"additional","affiliation":[{"name":"Kanuni Sultan S\u00fcleyman Training and Research Hospital, Pediatric Hematology Oncology Department, Istanbul, Turkey."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiraje","family":"Celkan","sequence":"additional","affiliation":[{"name":"Cerrahpasa Medical University, Pediatric Hematology Oncology Department, Istanbul, Turkey."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Walz","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, Munich, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8788-5056","authenticated-orcid":true,"given":"Capucine","family":"Picard","sequence":"additional","affiliation":[{"name":"Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, INSERM UMR 1163, Imagine Institute, Paris, France."},{"name":"Universit\u00e9 de Paris, Paris, France."},{"name":"Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital, Assistance Publique H\u00f4pitaux de Paris (APHP), Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christelle","family":"Lenoir","sequence":"additional","affiliation":[{"name":"Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, INSERM UMR 1163, Imagine Institute, Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0030-8094","authenticated-orcid":true,"given":"Nizar","family":"Mahlaoui","sequence":"additional","affiliation":[{"name":"Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, APHP, Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0956-0445","authenticated-orcid":true,"given":"Christoph","family":"Klein","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Dr. von Hauner Children\u2019s Hospital, University Hospital, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, Munich, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7738-1150","authenticated-orcid":true,"given":"Xiao","family":"Peng","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Immunology and Microbiology and the Immune Deficiency Genetics Section, NIH, Bethesda, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoine","family":"Azar","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Immunology and Microbiology and the Immune Deficiency Genetics Section, NIH, Bethesda, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin","family":"Reigh","sequence":"additional","affiliation":[{"name":"Dartmouth-Hitchcock Medical Center, Boston, MA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgane","family":"Cheminant","sequence":"additional","affiliation":[{"name":"Department of Adult Hematology, Necker-Enfants Malades Hospital, APHP, Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain","family":"Fischer","sequence":"additional","affiliation":[{"name":"Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, APHP, Paris, France."},{"name":"Imagine Institute, Paris, France."},{"name":"Coll\u00e8ge de France, Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7858-7866","authenticated-orcid":true,"given":"Fr\u00e9d\u00e9ric","family":"Rieux-Laucat","sequence":"additional","affiliation":[{"name":"Laboratory of Immunogenetics of Pediatric Autoimmunity, INSERM UMR 1163, Imagine Institute, Paris, France."},{"name":"Universit\u00e9 de Paris, Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3124-887X","authenticated-orcid":true,"given":"Isabelle","family":"Callebaut","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Mus\u00e9um National d\u2019Histoire Naturelle, UMR CNRS 7590, Institut de Min\u00e9ralogie, de Physique des Mat\u00e9riaux et de Cosmochimie, IMPMC, Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9644-2003","authenticated-orcid":true,"given":"Fabian","family":"Hauck","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Dr. von Hauner Children\u2019s Hospital, University Hospital, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, Munich, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Milner","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Irving Medical Center, Columbia University, New York, NY, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5550-9678","authenticated-orcid":true,"given":"Sergio D.","family":"Rosenzweig","sequence":"additional","affiliation":[{"name":"Immunology Service, Department of Laboratory Medicine, National Institutes of Health Clinical Center, NIH, Bethesda, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8238-4391","authenticated-orcid":true,"given":"Sylvain","family":"Latour","sequence":"additional","affiliation":[{"name":"Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, INSERM UMR 1163, Imagine Institute, Paris, France."},{"name":"Universit\u00e9 de Paris, Paris, 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Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciimmunol.abi7160","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T05:43:20Z","timestamp":1705383800000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciimmunol.abi7160"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,25]]},"references-count":46,"journal-issue":{"issue":"69","published-print":{"date-parts":[[2022,3,25]]}},"alternative-id":["10.1126\/sciimmunol.abi7160"],"URL":"https:\/\/doi.org\/10.1126\/sciimmunol.abi7160","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.741857026.793592862","asserted-by":"object"}]},"ISSN":["2470-9468"],"issn-type":[{"value":"2470-9468","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,25]]},"article-number":"eabi7160"}}