{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:36:53Z","timestamp":1787027813114,"version":"build-2736575974"},"reference-count":72,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,28]],"date-time":"2022-01-28T00:00:00Z","timestamp":1643328000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["TRR130 TP07, TP08, TP25, WA 1597\/4-2, CRC 850 subprojects C9 and Z1, CRC1479 (Project ID: 441891347- S1), CRC 1160 (Project Z02), CRC1453 (Project ID 431984000 - S1) and TRR167 (Project Z01), GR1617\/14-1\/iPAD; SFB1160\/2_B5; RESIST\u2013EXC 2155\u2013Project ID 3908"],"award-info":[{"award-number":["TRR130 TP07, TP08, TP25, WA 1597\/4-2, CRC 850 subprojects C9 and Z1, CRC1479 (Project ID: 441891347- S1), CRC 1160 (Project Z02), CRC1453 (Project ID 431984000 - S1) and TRR167 (Project Z01), GR1617\/14-1\/iPAD; SFB1160\/2_B5; RESIST\u2013EXC 2155\u2013Project ID 3908"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Federal Ministry of Education and Research","doi-asserted-by":"publisher","award":["BMBF 01EO1303, MIRACUM within the Medical Informatics Funding Scheme (FKZ 01ZZ1801B), GAIN 01GM1910A"],"award-info":[{"award-number":["BMBF 01EO1303, MIRACUM within the Medical Informatics Funding Scheme (FKZ 01ZZ1801B), GAIN 01GM1910A"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The altered wiring of signaling pathways downstream of antigen receptors of T and B cells contributes to the dysregulation of the adaptive immune system, potentially causing immunodeficiency and autoimmunity. In humans, the investigation of such complex systems benefits from nature\u2019s experiments in patients with genetically defined primary immunodeficiencies. Disturbed B-cell receptor (BCR) signaling in a subgroup of common variable immunodeficiency (CVID) patients with immune dysregulation and expanded T-bethighCD21low B cells in peripheral blood has been previously reported. Here, we investigate PI3K signaling and its targets as crucial regulators of survival, proliferation and metabolism by intracellular flow cytometry, imaging flow cytometry and RNAseq. We observed increased basal but disturbed BCR-induced PI3K signaling, especially in T-bethighCD21low B cells from CVID patients, translating into impaired activation of crucial downstream molecules and affecting proliferation, survival and the metabolic profile. In contrast to CVID, increased basal activity of PI3K in patients with a gain-of-function mutation in PIK3CD and activated PI3K delta syndrome (APDS) did not result in impaired BCR-induced AKT-mTOR-S6 phosphorylation, highlighting that signaling defects in B cells in CVID and APDS patients are fundamentally different and that assessing responses to BCR stimulation is an appropriate confirmative diagnostic test for APDS. The active PI3K signaling in vivo may render autoreactive T-bethighCD21low B cells in CVID at the same time to be more sensitive to mTOR or PI3K inhibition.<\/jats:p>","DOI":"10.3390\/cells11030464","type":"journal-article","created":{"date-parts":[[2022,1,29]],"date-time":"2022-01-29T01:41:59Z","timestamp":1643420519000},"page":"464","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Dysregulated PI3K Signaling in B Cells of CVID Patients"],"prefix":"10.3390","volume":"11","author":[{"given":"Ina","family":"Harder","sequence":"first","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, Medical Center\u2014University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"},{"name":"Center for Chronic Immunodeficiency (CCI), Medical Center\u2014University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9240-9342","authenticated-orcid":false,"given":"Matthias","family":"M\u00fcnchhalfen","sequence":"additional","affiliation":[{"name":"Institute of Cellular and Molecular Immunology, University Medical Center G\u00f6ttingen, G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5389-9481","authenticated-orcid":false,"given":"Geoffroy","family":"Andrieux","sequence":"additional","affiliation":[{"name":"Institute of Medical Bioinformatics and Systems Medicine, Medical Center\u2014University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Boerries","sequence":"additional","affiliation":[{"name":"Institute of Medical Bioinformatics and Systems Medicine, Medical Center\u2014University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"},{"name":"German Cancer Consortium (DKTK), Partner site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bodo","family":"Grimbacher","sequence":"additional","affiliation":[{"name":"Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg, Germany"},{"name":"Clinic of Rheumatology and Clinical Immunology, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg, Germany"},{"name":"DZIF\u2014German Center for Infection Research, Satellite Center Freiburg, Freiburg, Germany"},{"name":"CIBSS\u2014Centre for Integrative Biological Signalling Studies, Albert-Ludwigs University, Freiburg, Germany"},{"name":"RESIST\u2014Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hermann","family":"Eibel","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, Medical Center\u2014University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"},{"name":"Center for Chronic Immunodeficiency (CCI), Medical Center\u2014University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6488-7622","authenticated-orcid":false,"given":"Maria Elena","family":"Maccari","sequence":"additional","affiliation":[{"name":"Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg, Germany"},{"name":"Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center\u2013University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9265-2721","authenticated-orcid":false,"given":"Stephan","family":"Ehl","sequence":"additional","affiliation":[{"name":"Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8278-7668","authenticated-orcid":false,"given":"J\u00fcrgen","family":"Wienands","sequence":"additional","affiliation":[{"name":"Institute of Cellular and Molecular Immunology, University Medical Center G\u00f6ttingen, G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Jellusova","sequence":"additional","affiliation":[{"name":"Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, 81675 Munich, Germany"},{"name":"TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Warnatz","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, Medical Center\u2014University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"},{"name":"Center for Chronic Immunodeficiency (CCI), Medical Center\u2014University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baerbel","family":"Keller","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, Medical Center\u2014University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"},{"name":"Center for Chronic Immunodeficiency (CCI), Medical Center\u2014University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1016\/j.jaip.2019.02.004","article-title":"The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity","volume":"7","author":"Seidel","year":"2019","journal-title":"J. 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