{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T06:12:24Z","timestamp":1778825544526,"version":"3.51.4"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"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>Humoral immunodeficiency is frequently observed in patients affected by chronic lymphocytic leukemia (CLL). The reasons for the compromised B-cell responses are only partly understood. We hypothesized that the normal residual B cells in CLL patients are negatively influenced in their functionality by soluble factors produced by CLL cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed functional B-cell assays to analyze the influence of serum from CLL patients or conditioned medium from CLL cells cultivated with stromal cells on B cells from healthy donors. Serum from healthy individuals or conditioned medium from normal B cells was used as controls, respectively. We stimulated the B cells in a T-cell-dependent fashion and incubated them in the respective serum or conditioned medium for 5 days. We measured plasma cell differentiation, proliferation, cell death, and B-cell activation, the latter using the markers CD80, CD86, and CD25.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We did not detect significant differences supporting the hypothesis that CLL-derived soluble factors negatively influence the proliferation, activation, or cell death levels of normal B cells from healthy individuals in\n                      <jats:italic>in vitro<\/jats:italic>\n                      coculture.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Our analysis suggests no major direct inhibitory effects of CLL-derived soluble factors on normal mature B cells. Thus, it is likely that other factors lead to the known B-cell dysfunction in CLL.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1794418","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T05:43:30Z","timestamp":1778823810000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["CLL cell-derived soluble factors do not influence the functionality of normal B cells"],"prefix":"10.3389","volume":"17","author":[{"given":"Michelle Maria","family":"Elbert","sequence":"first","affiliation":[{"name":"Institute of Cell Biology (Cancer Research), University Medicine Essen","place":["Essen, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bettina","family":"Budeus","sequence":"additional","affiliation":[{"name":"Institute of Cell Biology (Cancer Research), University Medicine Essen","place":["Essen, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Dampmann","sequence":"additional","affiliation":[{"name":"Institute of Cell Biology (Cancer Research), University Medicine Essen","place":["Essen, Germany"]},{"name":"Department of Hematology and Stem Cell Transplantation, University Medicine Essen","place":["Essen, Germany"]},{"name":"Department of Medical Oncology, University Hospital Essen, West German Cancer Center","place":["Essen, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nele","family":"Kahlert","sequence":"additional","affiliation":[{"name":"Institute of Cell Biology (Cancer Research), University Medicine Essen","place":["Essen, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Artur","family":"Kibler","sequence":"additional","affiliation":[{"name":"Department of Immunodynamics, Institute for Experimental Immunology and Imaging, University Medicine Essen","place":["Essen, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gero","family":"Knittel","sequence":"additional","affiliation":[{"name":"Department of Hematology and Stem Cell Transplantation, University Medicine Essen","place":["Essen, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans Christian","family":"Reinhardt","sequence":"additional","affiliation":[{"name":"Department of Hematology and Stem Cell Transplantation, University Medicine Essen","place":["Essen, Germany"]},{"name":"German Cancer Consortium (DKTK), site Essen","place":["Essen, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ralf","family":"K\u00fcppers","sequence":"additional","affiliation":[{"name":"Institute of Cell Biology (Cancer Research), University Medicine Essen","place":["Essen, Germany"]},{"name":"German Cancer Consortium (DKTK), site Essen","place":["Essen, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"B1","unstructured":"The surveillance E, and end results (SEER) program of the national cancer institute. Cancer stat facts: leukemia-chronic lymphocytic leukemia (CLL)\n          \n          2021"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-09-806398","article-title":"iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL","volume":"131","author":"Hallek","year":"2018","journal-title":"Blood"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1182\/blood.v94.6.1840.418k06_1840_1847","article-title":"Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia","volume":"94","author":"Damle","year":"1999","journal-title":"Blood"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1182\/blood.v94.6.1848.418k05_1848_1854","article-title":"Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia","volume":"94","author":"Hamblin","year":"1999","journal-title":"Blood"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1080\/10428194.2025.2513005","article-title":"Insights into the pathogenesis and biology of chronic lymphocytic leukemia through analysis of its B-cell receptor","volume":"66","author":"Dampmann","year":"2025","journal-title":"Leuk Lymphoma"},{"key":"B6","article-title":"Chronische lymphatische leuk\u00e4mie (CLL), leitlinienreport","volume-title":"Onkopedia","author":"Wendtner","year":"2025"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-03-567388","article-title":"Perturbation of the normal immune system in patients with CLL","volume":"126","author":"Forconi","year":"2015","journal-title":"Blood"},{"key":"B8","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1093\/bmb\/ldn034","article-title":"The immunodeficiency of chronic lymphocytic leukaemia","volume":"87","author":"Hamblin","year":"2008","journal-title":"Br Med Bull"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.594556","article-title":"Immune dysfunctions and immune-based therapeutic interventions in chronic lymphocytic leukemia","volume":"11","author":"Griggio","year":"2020","journal-title":"Front Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(19880115)61:2<279::aid-cncr2820610215>3.0.co;2-4","article-title":"Serum immunoglobulins in B\u2010chronic lymphocytic leukemia. Natural history and prognostic significance","volume":"61","author":"Rozman","year":"1988","journal-title":"Cancer"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3109\/10428194.2016.1142082","article-title":"Hypogammaglobulinemia in newly diagnosed chronic lymphocytic leukemia is a predictor of early death","volume":"57","author":"Andersen","year":"2016","journal-title":"Leuk Lymphoma"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-018-0344-1","article-title":"IgA hypogammaglobulinemia predicts outcome in chronic lymphocytic leukemia","volume":"33","author":"Reda","year":"2019","journal-title":"Leukemia"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.23214","article-title":"Monoclonal B-cell lymphocytosis (MBL) with normal lymphocyte counts is associated with decreased numbers of normal circulating B-cell subsets","volume":"87","author":"Hauswirth","year":"2012","journal-title":"Am J Hematol"},{"key":"B14","first-page":"101","article-title":"The immune response to phichi174 in man. IV. Primary and secondary antibody production in patients with chronic lymphatic leukaemia","volume":"21","author":"Hamblin","year":"1975","journal-title":"Clin Exp Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/s0264-410x(00)00409-6","article-title":"Antibody responses to pneumococcal and haemophilus vaccinations in patients with B-cell chronic lymphocytic leukaemia","volume":"19","author":"Hartkamp","year":"2001","journal-title":"Vaccine"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020002949","article-title":"Proteomic and bioinformatic profiling of neutrophils in CLL reveals functional defects that predispose to bacterial infections","volume":"5","author":"Subramaniam","year":"2021","journal-title":"Blood"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-07-170415","article-title":"High-level expression of the T-cell chemokines CCL3 and CCL4 by chronic lymphocytic leukemia B cells in nurselike cell cocultures and after BCR stimulation","volume":"113","author":"Burger","year":"2009","journal-title":"Blood"},{"key":"B18","doi-asserted-by":"publisher","first-page":"42130","DOI":"10.18632\/oncotarget.6239","article-title":"Cross-talk between chronic lymphocytic leukemia (CLL) tumor B cells and mesenchymal stromal cells (MSCs): implications for neoplastic cell survival","volume":"6","author":"Trimarco","year":"2015","journal-title":"Oncotarget"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1380","DOI":"10.1038\/s41375-025-02590-x","article-title":"CLL cell-derived exosomes alter the immune and hematopoietic systems","volume":"39","author":"Veletic","year":"2025","journal-title":"Leukemia"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1007\/s00277-011-1218-z","article-title":"Chronic lymphocytic leukemia cells induce anti-apoptotic effects of bone marrow stroma","volume":"90","author":"Plander","year":"2011","journal-title":"Ann Hematol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.2119\/molmed.2010.00210","article-title":"Bone marrow stromal cell-derived vascular endothelial growth factor (VEGF) rather than chronic lymphocytic leukemia (CLL) cell-derived VEGF is essential for the apoptotic resistance of cultured CLL cells","volume":"17","author":"Gehrke","year":"2011","journal-title":"Mol Med"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-02-269894","article-title":"Platelet-derived growth factor (PDGF)\u2013PDGF receptor interaction activates bone marrow\u2013derived mesenchymal stromal cells derived from chronic lymphocytic leukemia: implications for an angiogenic switch","volume":"116","author":"Ding","year":"2010","journal-title":"Blood"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1182\/blood.v87.10.4382.bloodjournal87104382","article-title":"Interleukin-8 induces the accumulation of B-cell chronic lymphocytic leukemia cells by prolonging survival in an autocrine fashion","volume":"87","author":"Francia Di Celle","year":"1996","journal-title":"Blood"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1182\/blood.v82.8.2379.bloodjournal8282379","article-title":"Excessive production of transforming growth factor-beta by bone marrow stromal cells in B-cell chronic lymphocytic leukemia inhibits growth of hematopoietic precursors and interleukin-6 production","volume":"82","author":"Lagneaux","year":"1993","journal-title":"Blood"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1089\/scd.2012.0255","article-title":"Study of the quantitative, functional, cytogenetic, and immunoregulatory properties of bone marrow mesenchymal stem cells in patients with B-cell chronic lymphocytic leukemia","volume":"22","author":"Pontikoglou","year":"2013","journal-title":"Stem Cells Dev"},{"key":"B26","doi-asserted-by":"publisher","first-page":"408","DOI":"10.3324\/haematol.2010.031377","article-title":"Inflammatory cytokines and signaling pathways are associated with survival of primary chronic lymphocytic leukemia cells in vitro: a dominant role of CCL2","volume":"96","author":"Schulz","year":"2010","journal-title":"Haematologica"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1182\/blood.v99.3.1030","article-title":"Distinctive features of \u201cnurselike\u201d cells that differentiate in the context of chronic lymphocytic leukemia","volume":"99","author":"Tsukada","year":"2002","journal-title":"Blood"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3109\/10428194.2014.991731","article-title":"Nurse like cells: chronic lymphocytic leukemia associated macrophages","volume":"56","author":"Boissard","year":"2015","journal-title":"Leuk Lymphoma"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1182\/blood.v91.7.2387.2387_2387_2396","article-title":"Chronic lymphocytic leukemic B cells but not normal B cells are rescued from apoptosis by contact with normal bone marrow stromal cells","volume":"91","author":"Lagneaux","year":"1998","journal-title":"Blood"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.584232","article-title":"HS-5 and HS-27A stromal cell lines to study bone marrow mesenchymal stromal cell-mediated support to cancer development","volume":"8","author":"Adamo","year":"2020","journal-title":"Front Cell Dev Biol"},{"key":"B31","doi-asserted-by":"crossref","DOI":"10.1007\/3-540-29662-X_397","article-title":"B7-1, B7-2","volume-title":"Rheumatology and immunology therapy","author":"Moreland","year":""},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-3083.2002.01093.x","article-title":"CD80 expression is induced on activated B cells following stimulation by CD86","volume":"55","author":"Sahoo","year":"2002","journal-title":"Scand J Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/366076a0","article-title":"B70 antigen is a second ligand for CTLA-4 and CD28","volume":"366","author":"Azuma","year":"1993","journal-title":"Nature"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1126\/science.7694363","article-title":"Cloning of B7-2: a CTLA-4 counter-receptor that costimulates human T cell proliferation","volume":"262","author":"Freeman","year":"1993","journal-title":"Science"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.153.5.1990","article-title":"Differential up-regulation of the B7\u20131 and B7\u20132 costimulatory molecules after Ig receptor engagement by antigen","volume":"153","author":"Lenschow","year":"1994","journal-title":"J Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1084\/jem.160.5.1450","article-title":"Expression of interleukin 2 receptors on activated human B cells","volume":"160","author":"Waldmann","year":"1984","journal-title":"J Exp Med"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2006.02331.x","article-title":"Phenotypic and functional characterization of human CD25+ B cells","volume":"117","author":"Brisslert","year":"2006","journal-title":"Immunology"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1416276112","article-title":"Functional capacities of human IgM memory B cells in early inflammatory responses and secondary germinal center reactions","volume":"112","author":"Seifert","year":"2015","journal-title":"Proc Natl Acad Sci"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2100113","article-title":"Human cord blood B cells differ from the adult counterpart by conserved Ig repertoires and accelerated response dynamics","volume":"206","author":"Budeus","year":"2021","journal-title":"J Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2016.226","article-title":"Human memory B cells","volume":"30","author":"Seifert","year":"2016","journal-title":"Leukemia"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2432","article-title":"Stromal control of cystine metabolism promotes cancer cell survival in chronic lymphocytic leukaemia","volume":"14","author":"Zhang","year":"2012","journal-title":"Nat Cell Biol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1794418\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T05:43:34Z","timestamp":1778823814000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1794418\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,15]]},"references-count":41,"alternative-id":["10.3389\/fimmu.2026.1794418"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1794418","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,15]]},"article-number":"1794418"}}