{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T11:00:43Z","timestamp":1762254043497,"version":"3.41.2"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,2,8]],"date-time":"2022-02-08T00:00:00Z","timestamp":1644278400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014837","name":"Rudolf Ackermann Stiftung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100014837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004426","name":"Dr. Werner Jackst\u00e4dt-Stiftung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004426","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Objectives<\/jats:title><jats:p>Chloroquine (CQ) is approved for treatment of B-cell mediated diseases such as rheumatoid arthritis and systemic lupus erythematosus. However, the exact mode of action in these diseases has not been studied and it remains unclear which effect CQ has on B-cells. Thus, it was the aim of this study to investigate to which extent CQ affects functionality of effector and regulatory B-cell.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>For this purpose, B-cells were isolated from peripheral blood of healthy controls and renal transplant patients. B-cells were stimulated in presence or absence of CQ and Interleukin-10 (IL-10) and Granzyme B (GrB) secretion were assessed. In addition, effector functions such as plasma cell formation, and Immunoglobulin G (IgG) secretion were studied.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CQ suppressed Toll-Like-Receptor (TLR)-9 induced B-cell proliferation in a dose-dependent manner. IL-10<jats:sup>pos<\/jats:sup> regulatory B-cells were suppressed by CQ already at low concentrations whereas anti-IgG\/IgM-induced GrB secreting regulatory B-cells were less susceptible. Plasma blast formation and IgG secretion was potently suppressed by CQ. Moreover, purified B-cells from renal transplant patients were also susceptible to CQ-induced suppression of effector B-cell functions as observed by diminished IgG secretion.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In conclusion, CQ had a suppressive effect on IL-10 regulatory B-cells whereas GrB secreting regulatory B-cells were less affected. Effector functions of B-cells such as plasma blast formation and IgG secretion were also inhibited by CQ. Effector B-cells derived from renal transplant patients already under immunosuppression could be suppressed by CQ. These findings may partly explain the clinical efficacy of CQ in B-cell mediated autoimmune diseases. The application of CQ in other disease contexts where suppression of effector B-cells could offer a benefit, such as renal transplantation, may hypothetically be advantageous.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.818704","type":"journal-article","created":{"date-parts":[[2022,2,8]],"date-time":"2022-02-08T04:32:36Z","timestamp":1644294756000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Chloroquine Suppresses Effector B-Cell Functions and Has Differential Impact on Regulatory B-Cell Subsets"],"prefix":"10.3389","volume":"13","author":[{"given":"Xin","family":"Ma","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Dai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oliver","family":"Witzke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shilei","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monika","family":"Lindemann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Kribben","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sebastian","family":"Dolff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Wilde","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,2,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199101173240303","article-title":"A Randomized Study of the Effect of Withdrawing Hydroxychloroquine Sulfate in Systemic Lupus Erythematosus","volume":"324","author":"Canadian Hydroxychloroquine Study","year":"1991","journal-title":"N Engl J Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9343(99)80399-4","article-title":"A Randomized Trial of Hydroxychloroquine in Early Rheumatoid Arthritis: The HERA Study","volume":"98","year":"1995","journal-title":"Am J Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202012476","article-title":"Hydroxychloroquine in Rheumatic Autoimmune Disorders and Beyond","volume":"12","author":"Nirk","year":"2020","journal-title":"EMBO Mol Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-020-0372-x","article-title":"Mechanisms of Action of Hydroxychloroquine and Chloroquine: Implications for Rheumatology","volume":"16","author":"Schrezenmeier","year":"2020","journal-title":"Nat Rev Rheumatol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2012.03587.x","article-title":"Regulation of B-Cell Responses by Toll-Like Receptors","volume":"136","author":"Browne","year":"2012","journal-title":"Immunology"},{"key":"B6","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1007\/s12026-014-8523-2","article-title":"Toll-Like Receptors and B Cells: Functions and Mechanisms","volume":"59","author":"Buchta","year":"2014","journal-title":"Immunologic Res"},{"key":"B7","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1016\/j.jaci.2011.04.052","article-title":"Toll-Like Receptor 9, Transmembrane Activator and Calcium-Modulating Cyclophilin Ligand Interactor, and CD40 Synergize in Causing B-Cell Activation","volume":"128","author":"Ozcan","year":"2011","journal-title":"J Allergy Clin Immunol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1016\/j.jaci.2008.09.018","article-title":"Toll-Like Receptor 7\u2013Induced Naive Human B-Cell Differentiation and Immunoglobulin Production","volume":"123","author":"Glaum","year":"2009","journal-title":"J Allergy Clin Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2011.498","article-title":"Toll-Like Receptors in Transplantation: Sensing and Reacting to Injury","volume":"81","author":"Leventhal","year":"2012","journal-title":"Kidney Int"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0400937101","article-title":"Recognition of Single-Stranded RNA Viruses by Toll-Like Receptor 7","volume":"101","author":"Lund","year":"2004","journal-title":"Proc Natl Acad Sci USA"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/ncprheum0802","article-title":"Primer: Toll-Like Receptor Signaling Pathways\u2014What Do Rheumatologists Need to Know","volume":"4","author":"O\u2019Neill","year":"2008","journal-title":"Nat Clin Pract Rheumatol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.clim.2018.07.003","article-title":"Hydroxychloroquine Efficiently Suppresses Inflammatory Responses of Human Class-Switched Memory B Cells via Toll-Like Receptor 9 Inhibition","volume":"195","author":"Torigoe","year":"2018","journal-title":"Clin Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/416603a","article-title":"Chromatin-Igg Complexes Activate B Cells by Dual Engagement of Igm and Toll-Like Receptors","volume":"416","author":"Leadbetter","year":"2002","journal-title":"Nature"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.3.1636","article-title":"TLR7\/8-Mediated Activation of Human NK Cells Results in Accessory Cell-Dependent IFN-Gamma Production","volume":"175","author":"Hart","year":"2005","journal-title":"J Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1700730","article-title":"Extracellular Micrornas Induce Potent Innate Immune Responses via TLR7\/Myd88-Dependent Mechanisms","volume":"199","author":"Feng","year":"2017","journal-title":"J Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.4049\/immunohorizons.2000075","article-title":"Extracellular Mir-146a-5p Induces Cardiac Innate Immune Response and Cardiomyocyte Dysfunction","volume":"4","author":"Shimada","year":"2020","journal-title":"ImmunoHorizons"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0060702","article-title":"Expression of Mir-142-5p in Peripheral Blood Mononuclear Cells From Renal Transplant Patients With Chronic Antibody-Mediated Rejection","volume":"8","author":"Danger","year":"2013","journal-title":"PloS One"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1590\/2175-8239-jbn-2018-0098","article-title":"Micro RNA 146a-5p Expression in Kidney Transplant Recipients With Delayed Graft Function","volume":"41","author":"Milhoransa","year":"2019","journal-title":"J Bras Nefrol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.trim.2015.05.002","article-title":"Differential Expression of Micrornas in Renal Transplant Patients With Acute T-Cell Mediated Rejection","volume":"33","author":"Soltaninejad","year":"2015","journal-title":"Transplant Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1802677","article-title":"Antibody-Mediated Rejection of Solid-Organ Allografts","volume":"379","author":"Loupy","year":"2018","journal-title":"N Engl J Med"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0000000000003095","article-title":"Recommended Treatment for Antibody-Mediated Rejection After Kidney Transplantation: The 2019 Expert Consensus From the Transplantion Society Working Group","volume":"104","author":"Schinstock","year":"2020","journal-title":"Transplantation"},{"key":"B22","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1111\/ajt.15859","article-title":"What Have We Learned About How to Prevent and Treat Antibody-Mediated Rejection in Kidney Transplantation","volume":"20","author":"Nickerson","year":"2020","journal-title":"Am J Transplant"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1111\/tri.13436","article-title":"The Therapeutic Challenge of Late Antibody-Mediated Kidney Allograft Rejection","volume":"32","author":"B\u00f6hmig","year":"2019","journal-title":"Transplant Int"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-202986","article-title":"Regulatory B Cells in ANCA-Associated Vasculitis","volume":"72","author":"Wilde","year":"2013","journal-title":"Ann Rheum Dis"},{"key":"B25","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1007\/978-1-4939-8938-6_5","article-title":"Identification and Isolation of Regulatory B Cells in Mouse and Human","volume":"1899","author":"Menon","year":"2019","journal-title":"Methods Mol Biol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kez133","article-title":"Th17 Cells: Do Regulatory B-Cells (Breg) Take Control in ANCA-Vasculitis","volume":"58","author":"Dolff","year":"2019","journal-title":"Rheumatol (Oxford)"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3109\/03009742.2015.1126346","article-title":"Decreased IL-10(+) Regulatory B Cells (Bregs) in Lupus Nephritis Patients","volume":"45","author":"Heinemann","year":"2016","journal-title":"Scand J Rheumatol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2016.07.006","article-title":"Role of Regulatory B Cells in Immune Tolerance to Allergens and Beyond","volume":"138","author":"van de Veen","year":"2016","journal-title":"J Allergy Clin Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2016.08.028","article-title":"Reduced Human Transitional B Cell T1\/T2 Ratio Is\u00a0Associated With Subsequent Deterioration in\u00a0Renal Allograft Function","volume":"91","author":"Cherukuri","year":"2017","journal-title":"Kidney Int"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abe4929","article-title":"Transitional B Cell Cytokines Predict Renal Allograft Outcomes","volume":"13","author":"Cherukuri","year":"2021","journal-title":"Sci Trans Med"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.627496","article-title":"Elevated Circulating Il-10 Producing Breg, But Not Regulatory B Cell Levels, Restrain Antibody-Mediated Rejection After Kidney Transplantation","volume":"11","author":"Luo","year":"2021","journal-title":"Front Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.14013","article-title":"Prospective Analyses of Circulating B Cell Subsets in ABO-Compatible and ABO-Incompatible Kidney Transplant Recipients","volume":"17","author":"Schl\u00f6\u00dfer","year":"2017","journal-title":"Am J Transplant"},{"key":"B33","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.clim.2017.04.016","article-title":"Granzyme B Producing B-Cells in Renal Transplant Patients","volume":"184","author":"Zhu","year":"2017","journal-title":"Clin Immunol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.clim.2017.12.005","article-title":"IL-21 Dependent Granzyme B Production of B-Cells Is Decreased in Patients With Lupus Nephritis","volume":"188","author":"Rabani","year":"2018","journal-title":"Clin Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2000335","article-title":"Efficient Expansion of Human Granzyme B-Expressing B Cells With Potent Regulatory Properties","volume":"205","author":"Chesneau","year":"2020","journal-title":"J Immunol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"2588","DOI":"10.1681\/ASN.2014040404","article-title":"Tolerant Kidney Transplant Patients Produce B Cells With Regulatory Properties","volume":"26","author":"Chesneau","year":"2015","journal-title":"J Am Soc Nephrol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"2468","DOI":"10.1158\/0008-5472.CAN-12-3450","article-title":"Interleukin 21\u2013Induced Granzyme B\u2013Expressing B Cells Infiltrate Tumors and Regulate T Cells","volume":"73","author":"Lindner","year":"2013","journal-title":"Cancer Res"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1109173109","article-title":"A Tolerogenic Role for Toll-Like Receptor 9 Is Revealed by B-Cell Interaction With DNA Complexes Expressed on Apoptotic Cells","volume":"109","author":"Miles","year":"2012","journal-title":"Proc Natl Acad Sci USA"},{"key":"B39","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1016\/j.cellimm.2012.05.009","article-title":"Decrease in Circulating DNA, IL-10 and BAFF Levels in Newly-Diagnosed SLE Patients After Corticosteroid and Chloroquine Treatment","volume":"276","author":"Cepika","year":"2012","journal-title":"Cell Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.818704\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,8]],"date-time":"2022-02-08T04:32:41Z","timestamp":1644294761000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.818704\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,8]]},"references-count":39,"alternative-id":["10.3389\/fimmu.2022.818704"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.818704","relation":{},"ISSN":["1664-3224"],"issn-type":[{"type":"electronic","value":"1664-3224"}],"subject":[],"published":{"date-parts":[[2022,2,8]]},"article-number":"818704"}}