{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T03:23:11Z","timestamp":1793330591299,"version":"4.5.0"},"reference-count":43,"publisher":"American Society of Hematology","issue":"16","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,10,16]]},"abstract":"<jats:sec>\n                  <jats:title>Abstract<\/jats:title>\n                  <jats:p>VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is an autoinflammatory disorder caused by acquired somatic ubiquitin like modifier activating enzyme 1 (UBA1) mutations in hematopoietic stem cells, affecting peripheral myeloid and natural killer (NK) cells. Given the high rate of severe infections in patients with VEXAS, we hypothesized that NK-cell dysfunction contributes to this susceptibility. We conducted a comprehensive immune characterization of peripheral NK cells in patients with VEXAS (n = 40), patients with autoinflammatory diseases without UBA1 mutations (n = 22), and older sex-matched healthy controls (n = 16). Multiparameter phenotyping used cytometry by time-of-flight, single-cell RNA sequencing (scRNA-seq), whole-blood stimulation assays, and in vitro NK-cell cytotoxic assay. Peripheral NK cells in VEXAS were quantitatively and qualitatively impaired. Mass cytometry revealed reduced frequencies of mature cytotoxic CD56dim NK cells and expansion of the CD56high CD16dim subset. NK cells exhibited exhaustion features, including increased programmed cell death protein 1 expression, and reduced cytotoxic markers such as NKp46 and CD8\u03b1. scRNA-seq analysis showed decreased signatures of cytotoxicity and interleukin-2 (IL-2) and interferon gamma (IFN-\u03b3) production, alongside increased inflammatory signatures. Whole-blood stimulation assays confirmed impaired IL-2, IFN-\u03b3, and granzyme B production following Toll-like receptor 3 (TLR3), TLR4, and TLR7\/TLR8 agonist stimulation. Extended NK phenotyping by flow cytometry confirmed reduced activating receptors\u2019 expression and impaired IFN-\u03b3 production in VEXAS syndrome. Moreover, in vitro UBA1 inhibitors impaired NK-cell cytotoxic capacity and promote cell death. Finally, reduced NK-cell frequencies were independently associated with an increased risk of severe infections. These findings suggest that NK-cell dysfunction in VEXAS syndrome contributes to increased susceptibility to severe infections.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/blood.2024028216","type":"journal-article","created":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T20:32:52Z","timestamp":1753821172000},"page":"1950-1963","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":15,"title":["Impaired cytotoxic function and exhausted phenotype of natural killer cells in VEXAS syndrome"],"prefix":"10.1182","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0475-1218","authenticated-orcid":false,"given":"Paul","family":"Breillat","sequence":"first","affiliation":[{"name":"1Universit\u00e9 de Paris Cit\u00e9, INSERM, U970, Paris-Centre de Recherche Cardiovasculaire, Paris, France"},{"name":"2Department of Internal Medicine, National Reference Center for Rare Systemic Autoimmune Diseases, Assistance Publique-H\u00f4pitaux de Paris, H\u00f4pital Cochin, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0819-4471","authenticated-orcid":false,"given":"Francesco","family":"Carbone","sequence":"additional","affiliation":[{"name":"3Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, Imagine Institute, Universit\u00e9 de Paris Cit\u00e9, INSERM Unit\u00e9 Mixte de Recherche 1163, Paris, France"},{"name":"4Labtech Single-Cell@Imagine, Imagine Institute, INSERM Unit\u00e9 Mixte de Recherche 1163, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6128-9088","authenticated-orcid":false,"given":"Emilie","family":"Lereclus","sequence":"additional","affiliation":[{"name":"5Universit\u00e9 Paris Cit\u00e9, Institut de Recherche Saint Louis, INSERM Unit\u00e9 Mixte de Recherche 1342, Paris, France"},{"name":"6Leukemia Institute Paris Saint-Louis, Paris, France"},{"name":"7Institut Carnot, Organization for Partnerships in Leukemia, Institut de Recherche Saint Louis, H\u00f4pital Saint-Louis, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3323-0235","authenticated-orcid":false,"given":"Quentin","family":"Riller","sequence":"additional","affiliation":[{"name":"8Universit\u00e9 Paris Cit\u00e9, Paris, France"},{"name":"9Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM Unit\u00e9 Mixte de Recherche 1163, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6084-5836","authenticated-orcid":false,"given":"Thibaut","family":"d'Izarny-Gargas","sequence":"additional","affiliation":[{"name":"1Universit\u00e9 de Paris Cit\u00e9, INSERM, U970, Paris-Centre de Recherche Cardiovasculaire, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4182-6442","authenticated-orcid":false,"given":"C\u00e9line","family":"Posseme","sequence":"additional","affiliation":[{"name":"10Translational Immunology Unit, Institut Pasteur, Universit\u00e9 de Paris Cit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5247-8976","authenticated-orcid":false,"given":"Marie","family":"Templ\u00e9","sequence":"additional","affiliation":[{"name":"11Universit\u00e9 de Paris Cit\u00e9, Institut Cochin, Centre National de la Recherche Scientifique Unit\u00e9 Mixte de Recherche 8104, INSERM U1016, Paris, France"},{"name":"12Hematology Laboratory, Assistance Publique-H\u00f4pitaux de Paris, Centre-Universit\u00e9 de Paris Cit\u00e9, Cochin Hospital, Paris, 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Recherche 1163, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estibaliz","family":"Lazaro","sequence":"additional","affiliation":[{"name":"13Department of Internal Medicine, Bordeaux University Hospital-Haut-L\u00e9v\u00eaque, Pessac, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6411-884X","authenticated-orcid":false,"given":"Rod\u00e9rau","family":"Outh","sequence":"additional","affiliation":[{"name":"14Department of Internal Medicine, Centre Hospitalier de Perpignan, Perpignan, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7724-4607","authenticated-orcid":false,"given":"Guillaume","family":"Le Guenno","sequence":"additional","affiliation":[{"name":"15Department of Internal Medicine, Clermont-Ferrand University Hospital, Clermont-Ferrand, 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