{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T04:58:35Z","timestamp":1781240315937,"version":"3.54.1"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:00:00Z","timestamp":1781222400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Combined immunodeficiencies (CIDs) are a severe class of inborn errors of immunity characterized by defective T cell development and function, often accompanied by impaired humoral and natural killer (NK) cell responses. Despite their shared clinical classification, the immunological heterogeneity within CIDs remains incompletely understood. This study aims to characterize the immune cell landscape in CID patients caused by disease-causing mutations in different genes to identify immunophenotypic patterns.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We analyzed peripheral blood immune cells from four CID patients with disease-causing mutations in\n                      <jats:italic>ARPC1B, EZR, BCL10<\/jats:italic>\n                      , and\n                      <jats:italic>IRF4<\/jats:italic>\n                      using mass cytometry. Unbiased computational approaches were used to profile major immune populations and their subsets, and results were compared with healthy control samples to identify differences in immune cell frequencies and phenotypes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      All patients retained major immune populations, but their relative frequencies differed significantly from those of healthy controls. Patients with EZR and ARPC1B deficiency had markedly reduced CD4\n                      <jats:sup>+<\/jats:sup>\n                      and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell frequencies, whereas the BCL10-deficient patient had a near absence of NK cells, highlighting mutation-specific immune distributions. Detailed T cell subset analyses revealed increased na\u00efve and decreased memory T cells in patients with BCL10 and IRF4 deficiencies, indicative of impaired T cell activation and memory formation. In contrast, ARPC1B deficiency was associated with elevated memory T cells and reduced na\u00efve cells, suggesting thymic output defects. The Ezrin-deficient patient maintained a na\u00efve-to-memory T cell ratio similar to controls despite an overall reduction in T cells. B cell abnormalities were consistent across patients, characterized by increased na\u00efve B cells, decreased memory B cells, and severely diminished plasmablast frequencies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Our findings reveal pronounced immunological heterogeneity among CID patients caused by different genetic defects, challenging the notion that CIDs constitute a uniform entity. Disease-causing gene-specific alterations in immune cell composition and differentiation states underscore the complexity of CID pathophysiology. Comprehensive immunophenotypic profiling offers valuable insights into distinct mechanistic pathways and may guide the development of tailored therapeutic strategies to improve clinical outcomes for CID patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1830231","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T04:42:14Z","timestamp":1781239334000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Heterogeneous immune cell composition in patients with combined immunodeficiency"],"prefix":"10.3389","volume":"17","author":[{"given":"Jareb J.","family":"P\u00e9rez-Caraballo","sequence":"first","affiliation":[{"name":"Division of Genetic Medicine and Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center","place":["Nashville, TN, United States"]},{"name":"Division of Molecular Pathogenesis, Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center","place":["Nashville, TN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colleen M.","family":"Roark","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine and Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center","place":["Nashville, TN, United States"]},{"name":"Division of Molecular Pathogenesis, Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center","place":["Nashville, TN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan M.","family":"Dobrose","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine and Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center","place":["Nashville, TN, United States"]},{"name":"Division of Molecular Pathogenesis, Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center","place":["Nashville, TN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Van den Rym","sequence":"additional","affiliation":[{"name":"Laboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, La Paz University Hospital","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aid\u00e9 Tamara","family":"Staines-Boone","sequence":"additional","affiliation":[{"name":"Immunology Service, Hospital de Especialidades Unidad M\u00e9dica de Alta Especialidad (UMAE), 25 del Instituto Mexicano del Seguro Social (IMSS)","place":["Monterrey, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuridia","family":"Salazar-Galvez","sequence":"additional","affiliation":[{"name":"Immunology Service, Hospital de Especialidades Unidad M\u00e9dica de Alta Especialidad (UMAE), 25 del Instituto Mexicano del Seguro Social (IMSS)","place":["Monterrey, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noemi","family":"Gomez-Hernandez","sequence":"additional","affiliation":[{"name":"Allergy and Clinical Immunology Service, Unidad M\u00e9dica de Alta Especialidad, Centro M\u00e9dico Nacional de Occidente IMSS","place":["Guadalajara, Jalisco, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Cui","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine and Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center","place":["Nashville, TN, United States"]},{"name":"Division of Molecular Pathogenesis, Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center","place":["Nashville, TN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren E.","family":"Brown","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine and Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center","place":["Nashville, TN, United States"]},{"name":"Division of Molecular Pathogenesis, Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center","place":["Nashville, TN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhen","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine and Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center","place":["Nashville, TN, United States"]},{"name":"Division of Molecular Pathogenesis, Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center","place":["Nashville, TN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saul O.","family":"Lugo Reyes","sequence":"additional","affiliation":[{"name":"Immune Deficiencies Laboratory, National Institute of Pediatrics, Health Secretariat","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lizbeth","family":"Blancas-Galicia","sequence":"additional","affiliation":[{"name":"Immune Deficiencies Laboratory, National Institute of Pediatrics, Health Secretariat","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d3scar","family":"de la Calle-Mart\u00edn","sequence":"additional","affiliation":[{"name":"Immunology Department, Hospital de la Santa Creu i Sant Pau","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reem","family":"Mohammed","sequence":"additional","affiliation":[{"name":"Section of Pediatric Allergy and Immunology, Department of Pediatrics, King Faisal Specialist Hospital and Research Centre","place":["Riyadh, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebeca","family":"P\u00e9rez de Diego","sequence":"additional","affiliation":[{"name":"Laboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, La Paz University Hospital","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rub\u00e9n","family":"Mart\u00ednez-Barricarte","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine and Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center","place":["Nashville, TN, United States"]},{"name":"Division of Molecular Pathogenesis, Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center","place":["Nashville, TN, United States"]},{"name":"Vanderbilt Institute of Infection, Immunology and Inflammation, Vanderbilt University Medical Center","place":["Nashville, TN, United States"]},{"name":"Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center","place":["Nashville, TN, United States"]},{"name":"Vanderbilt Genetics Institute, Vanderbilt University Medical Center","place":["Nashville, TN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e20250002","DOI":"10.70962\/JHI.20250002","article-title":"The 2024 update of IUIS phenotypic classification of human inborn errors of immunity","volume":"1","author":"Bousfiha","year":"2025","journal-title":"J Hum Immun"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.70962\/JHI.20250003","article-title":"Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee","volume":"1","author":"Poli","year":"2025","journal-title":"J Hum Immun"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMOA1413462","article-title":"Inherited DOCK2 deficiency in patients with early-onset invasive infections","volume":"372","author":"Dobbs","year":"2015","journal-title":"N Engl J Med"},{"key":"B4","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1146\/annurev-immunol-032712-095927","article-title":"Functional T cell immunodeficiencies (with T cells present)","volume":"57","author":"Notarangelo","year":"2026"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1302","DOI":"10.1016\/J.JACI.2016.07.040","article-title":"A prospective study on the natural history of patients with profound combined immunodeficiency: an interim analysis","volume":"139","author":"Speckmann","year":"2016","journal-title":"J Allergy Clin Immunol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"eabb1662","DOI":"10.1126\/sciimmunol.abb1662","article-title":"Human inborn errors of immunity: an expanding universe","volume":"5","author":"Notarangelo","year":"2020","journal-title":"Sci Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1172\/JCI77493","article-title":"Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunity","volume":"124","author":"Torres","year":"2014","journal-title":"J Clin Invest"},{"key":"B8","doi-asserted-by":"publisher","first-page":"15061","DOI":"10.1038\/nrdp.2015.61","article-title":"Severe combined immunodeficiencies and related disorders","volume":"1","author":"Fischer","year":"2015","journal-title":"Nat Rev Dis Primers"},{"key":"B9","doi-asserted-by":"publisher","first-page":"S39","DOI":"10.1016\/J.JPED.2020.10.014","article-title":"Combined immunodeficiencies","volume":"97","author":"Aranda","year":"2020","journal-title":"Jornal Pediatria"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1126\/SCIIMMUNOL.ADE7953","article-title":"A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency","volume":"8","author":"Fornes","year":"2023","journal-title":"Sci Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/s41435-025-00368-w","article-title":"Molecular analysis and immunological characterization of a founder mutation causing ARPC1B deficiency","volume":"27","author":"Dobrose","year":"2026","journal-title":"Genes Immun"},{"key":"B12","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1016\/J.IAC.2008.01.002","article-title":"Genetic defects of apoptosis and primary immunodeficiency","volume":"28","author":"Su","year":"2008","journal-title":"Immunol Allergy Clinics North America"},{"key":"B13","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1016\/J.JACI.2019.10.004","article-title":"Combined immunodeficiency due to a loss of function mutation in DNA polymerase delta 1","volume":"145","author":"Cui","year":"2019","journal-title":"J Allergy Clin Immunol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1016\/J.JAIP.2022.12.045","article-title":"Is your kid actin out? A series of six patients with inherited actin-related protein 2\/3 complex subunit 1B deficiency and review of the literature","volume":"11","author":"V\u00e1squez-Echeverri","year":"2023","journal-title":"J Allergy Clin Immunol In Pract"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/NRM2026","article-title":"The ARP2\/3 complex: an actin nucleator comes of age","volume":"7","author":"Goley","year":"2006","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1622928","article-title":"Regulation of actin cytoskeletal dynamics in T cell development and function","volume":"16","author":"Lam","year":"2025","journal-title":"Front Immunol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1016\/J.JACI.2023.05.022","article-title":"Inherited human ezrin deficiency impairs adaptive immunity","volume":"152","author":"Garc\u00eda-Sol\u00eds","year":"2023","journal-title":"J Allergy Clin Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.2741\/1940","article-title":"Role of ERM (ezrin-radixin-moesin) proteins in T lymphocyte polarization, immune synapse formation and in T cell receptor-mediated signaling","volume":"11","author":"Charrin","year":"2006","journal-title":"Front Bioscience: A J Virtual Library"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.4049\/JIMMUNOL.182.2.1021","article-title":"Ezrin and moesin function together to promote T cell activation","volume":"182","author":"Shaffer","year":"2009","journal-title":"J Immunol (Baltimore Md: 1950)"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2866","article-title":"Organizing the cell cortex: the role of ERM proteins","volume":"11","author":"Fehon","year":"2010","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.786572","article-title":"Clinical and immunological features of human BCL10 deficiency","volume":"12","author":"Garcia-Solis","year":"2021","journal-title":"Front Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/J.JACI.2015.06.031","article-title":"Genetic errors of the human caspase recruitment domain-B-cell lymphoma 10-mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (CBM) complex: molecular, immunologic, and clinical heterogeneity","volume":"136","author":"P\u00e9rez de Diego","year":"2015","journal-title":"J Allergy Clin Immunol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1016\/J.IT.2008.07.006","article-title":"Interferon regulatory factor 4 and 8 in B cell development","volume":"29","author":"Lu","year":"2008","journal-title":"Trends Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1002\/EJI.201344279","article-title":"IRF4 at the crossroads of effector T-cell fate decision","volume":"44","author":"Huber","year":"2014","journal-title":"Eur J Immunol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"e71","DOI":"10.1186\/S13046-022-02526-8","article-title":"ARPC1B promotes mesenchymal phenotype maintenance and radiotherapy resistance by blocking TRIM21-mediated degradation of IFI16 and HuR in glioma stem cells","volume":"93","author":"Gao","year":"2022","journal-title":"J Exp Clin Cancer Research: CR"},{"key":"B26","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1002\/CPCY.71","article-title":"Training novices in generation and analysis of high-dimensional human cell phospho-flow cytometry data","volume":"6","author":"Roe","year":"2020","journal-title":"Curr Protoc Cytometry"},{"key":"B27","doi-asserted-by":"publisher","first-page":"748","DOI":"10.12688\/f1000research.11622.3","article-title":"CyTOF workflow: differential discovery in high-throughput high-dimensional cytometry datasets","volume":"6","author":"Nowicka","year":"2019","journal-title":"F1000Research"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.00415","article-title":"Validation of CyTOF against flow cytometry for immunological studies and monitoring of human cancer clinical trials","volume":"9","author":"Gadalla","year":"2019","journal-title":"Front Oncol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.815828","article-title":"Panel Design and Optimization for High-Dimensional Immunophenotyping Assays Using Spectral Flow Cytometry","volume":"92","author":"Ferrer-Font","year":"2020","journal-title":"Curr Protoc Cytom"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.815828","article-title":"CyTOF\u00ae for the masses","volume":"13","author":"Iyer","year":"2022","journal-title":"Front Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1830231\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T04:42:22Z","timestamp":1781239342000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1830231\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,12]]},"references-count":30,"alternative-id":["10.3389\/fimmu.2026.1830231"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1830231","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,12]]},"article-number":"1830231"}}