{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T18:53:40Z","timestamp":1771008820992,"version":"3.50.1"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,26]],"date-time":"2021-05-26T00:00:00Z","timestamp":1621987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008659","name":"European Committee for Treatment and Research in Multiple Sclerosis","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004497","name":"Onderzoeksraad, KU Leuven","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004497","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Although fingolimod and interferon-\u03b2 are two mechanistically different multiple sclerosis (MS) treatments, they both induce B cell activating factor (BAFF) and shift the B cell pool towards a regulatory phenotype. However, whether there is a shared mechanism between both treatments in how they influence the B cell compartment remains elusive. In this study, we collected a cross-sectional study population of 112 MS patients (41 untreated, 42 interferon-\u03b2, 29 fingolimod) and determined B cell subsets, cell-surface and RNA expression of BAFF-receptor (BAFF-R) and transmembrane activator and cyclophilin ligand interactor (TACI) as well as plasma and\/or RNA levels of BAFF, BAFF splice forms and interleukin-10 (IL-10) and -35 (IL-35). We added an <jats:italic>in vitro<\/jats:italic> B cell culture with four stimulus conditions (Medium, CpG, BAFF and CpG+BAFF) for untreated and interferon-\u03b2 treated patients including measurement of intracellular IL-10 levels. Our flow experiments showed that interferon-\u03b2 and fingolimod induced BAFF protein and mRNA expression (P \u2264 3.15 x 10<jats:sup>-4<\/jats:sup>) without disproportional change in the antagonizing splice form. Protein BAFF correlated with an increase in transitional B cells (P = 5.70 x 10<jats:sup>-6<\/jats:sup>), decrease in switched B cells (P = 3.29 x 10<jats:sup>-4<\/jats:sup>), and reduction in B cell-surface BAFF-R expression (P = 2.70 x 10<jats:sup>-10<\/jats:sup>), both on TACI-positive and -negative cells. TACI and BAFF-R RNA levels remained unaltered. RNA, plasma and <jats:italic>in vitro<\/jats:italic> experiments demonstrated that BAFF was not associated with increased IL-10 and IL-35 levels. In conclusion, treatment-induced BAFF correlates with a shift towards transitional B cells which are enriched for cells with an immunoregulatory function. However, BAFF does not directly influence the expression of the immunoregulatory cytokines IL-10 and IL-35. Furthermore, the post-translational mechanism of BAFF-induced BAFF-R cell surface loss was TACI-independent. These observations put the failure of pharmaceutical anti-BAFF strategies in perspective and provide insights for targeted B cell therapies.<\/jats:p>","DOI":"10.3389\/fimmu.2021.676619","type":"journal-article","created":{"date-parts":[[2021,5,26]],"date-time":"2021-05-26T06:20:38Z","timestamp":1622010038000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Treatment-Induced BAFF Expression and B Cell Biology in Multiple Sclerosis"],"prefix":"10.3389","volume":"12","author":[{"given":"Ide","family":"Smets","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa","family":"Prezzemolo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maya","family":"Imbrechts","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klara","family":"Mallants","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tania","family":"Mitera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"St\u00e9phanie","family":"Humblet-Baron","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B\u00e9n\u00e9dicte","family":"Dubois","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick","family":"Matthys","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adrian","family":"Liston","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"An","family":"Goris","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000000240","article-title":"Immunologic Profiles of Multiple Sclerosis Treatments Reveal Shared Early B Cell Alterations","volume":"3","author":"Dooley","year":"2016","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awn077","article-title":"Interferon-Beta Increases BAFF Levels in Multiple Sclerosis: Implications for B Cell Autoimmunity","volume":"131","author":"Krumbholz","year":"2008","journal-title":"Brain"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2014.02.001","article-title":"Suppressed Pro-Inflammatory Properties of Circulating B Cells in Patients With Multiple Sclerosis Treated With Fingolimod, Based on Altered Proportions of B-Cell Subpopulations","volume":"151","author":"Miyazaki","year":"2014","journal-title":"Clin Immunol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1016\/j.celrep.2018.09.048","article-title":"Genetic Architecture of Adaptive Immune System Identifies Key Immune Regulators","volume":"25","author":"Lagou","year":"2018","journal-title":"Cell Rep"},{"key":"B5","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.clim.2017.10.009","article-title":"Fingolimod Induces BAFF and Expands Circulating Transitional B Cells Without Activating Memory B Cells and Plasma Cells in Multiple Sclerosis","volume":"187","author":"Miyazaki","year":"2018","journal-title":"Clin Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1080\/14728222.2020.1821647","article-title":"The BAFF \/ APRIL System as Therapeutic Target in Multiple Sclerosis","volume":"24","author":"Magliozzi","year":"2020","journal-title":"Expert Opin Ther Targets"},{"key":"B7","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.coi.2019.07.007","article-title":"Understanding Regulatory B Cells in Autoimmune Diseases: The Case of Multiple Sclerosis","volume":"61","author":"Thi Cuc","year":"2019","journal-title":"Curr Opin Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awy239","article-title":"Learning From Other Autoimmunities to Understand Targeting of B Cells to Control Multiple Sclerosis","volume":"141","author":"Baker","year":"2018","journal-title":"Brain"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2008.04.006","article-title":"TACI, an Enigmatic BAFF\/APRIL Receptor, With New Unappreciated Biochemical and Biological Properties","volume":"19","author":"Mackay","year":"2008","journal-title":"Cytokine Growth Factor Rev"},{"key":"B10","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1038\/icb.2011.111","article-title":"BAFF and Innate Immunity: New Therapeutic Targets for Systemic Lupus Erythematosus","volume":"90","author":"Vincent","year":"2012","journal-title":"Immunol Cell Biol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1080\/1744666X.2017.1291343","article-title":"Inhibition of B Cell Activating Factor (BAFF) in the Management of Systemic Lupus Erythematosus (SLE)","volume":"13","author":"Stohl","year":"2017","journal-title":"Expert Rev Clin Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(14)70028-6","article-title":"Atacicept in Multiple Sclerosis (ATAMS): A Randomised, Placebo-Controlled, Double-Blind, Phase 2 Trial","volume":"13","author":"Kappos","year":"2014","journal-title":"Lancet Neurol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2015.02.019","article-title":"Results From a Phase II Randomized Trial of the B-Cell-Targeting Agent Atacicept in Patients With Optic Neuritis","volume":"351","author":"Sergott","year":"2015","journal-title":"J Neurol Sci"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.1.319","article-title":"DeltaBAFF, a Splice Isoform of BAFF, Opposes Full-Length BAFF Activity In Vivo in Transgenic Mouse Models","volume":"175","author":"Gavin","year":"2005","journal-title":"J Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M306852200","article-title":"\u0394BAFF, an Alternate Splice Isoform That Regulates Receptor Binding and Biopresentation of the B Cell Survival Cytokine, BAFF","volume":"278","author":"Gavin","year":"2003","journal-title":"J Biol Chem"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.2.807","article-title":"B Cell-Activating Factor Belonging to the TNF Family (Baff)-R Is the Principal Baff Receptor Facilitating BAFF Costimulation of Circulating T and B Cells","volume":"173","author":"Ng","year":"2004","journal-title":"J\u00a0Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.179.11.7276","article-title":"Regulated Expression of BAFF-Binding Receptors During Human B Cell Differentiation","volume":"179","author":"Darce","year":"2007","journal-title":"J Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx372","article-title":"Multiple Sclerosis Risk Variants Alter Expression of Co-Stimulatory Genes in B Cells","volume":"141","author":"Smets","year":"2018","journal-title":"Brain"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200636623","article-title":"TACI Attenuates Antibody Production Costimulated by BAFF-R and CD40","volume":"37","author":"Sakurai","year":"2007","journal-title":"Eur J Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2007.06.012","article-title":"Transmembrane Activator and Calcium Modulator and Cyclophilin Ligand Interactor Enhances CD40-Driven Plasma Cell Differentiation","volume":"120","author":"Castigli","year":"2007","journal-title":"J Allergy Clin Immunol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"497","DOI":"10.4049\/jimmunol.1102321","article-title":"Soluble BAFF Levels Inversely Correlate With Peripheral B Cell Numbers and the Expression of BAFF Receptors","volume":"188","author":"Kreuzaler","year":"2012","journal-title":"J Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2017.11.061","article-title":"Abnormal Differentiation of B Cells and Megakaryocytes in Patients With Roifman Syndrome","volume":"142","author":"Heremans","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1600017","article-title":"Cutting Edge: Baff Promotes Autoantibody Production Via TACI-Dependent Activation of Transitional B Cells","volume":"196","author":"Jacobs","year":"2016","journal-title":"J Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.02.005","article-title":"BAFF- and TACI-Dependent Processing of BAFFR by ADAM Proteases Regulates the Survival of B Cells","volume":"18","author":"Smulski","year":"2017","journal-title":"Cell Rep"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/s1074-7613(03)00025-6","article-title":"Loss of TACI Causes Fatal Lymphoproliferation and Autoimmunity, Establishing TACI as an Inhibitory BLyS Receptor","volume":"18","author":"Seshasayee","year":"2003","journal-title":"Immunity"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0903543106","article-title":"B-Cell Activating Factor Receptor Deficiency is Associated With an Adult-Onset Antibody Deficiency Syndrome in Humans","volume":"106","author":"Warnatz","year":"2009","journal-title":"Proc Natl Acad Sci"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02285","article-title":"BAFF and BAFF-Receptor in B Cell Selection and Survival","volume":"9","author":"Smulski","year":"2018","journal-title":"Front Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.6.3655","article-title":"Cutting Edge: The Dependence of Plasma Cells and Independence of Memory B Cells on BAFF and APRIL","volume":"180","author":"Benson","year":"2008","journal-title":"J Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0807841105","article-title":"Blys Inhibition Eliminates Primary B Cells But Leaves Natural and Acquired Humoral Immunity Intact","volume":"105","author":"Scholz","year":"2008","journal-title":"Proc Natl Acad Sci"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2009.11.009","article-title":"Cd19+Cd24hicd38hi B Cells Exhibit Regulatory Capacity in Healthy Individuals But Are Functionally Impaired in Systemic Lupus Erythematosus Patients","volume":"32","author":"Blair","year":"2010","journal-title":"Immunity"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1000271","article-title":"B Cells as a Therapeutic Target for IFN-\u03b2 in Relapsing-Remitting Multiple Sclerosis","volume":"186","author":"Ramgolam","year":"2011","journal-title":"J Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201847578","article-title":"Ifn-\u03b3 Stimulates CpG-induced Il-10 Production in B Cells Via p38 and JNK Signalling Pathways","volume":"48","author":"Imbrechts","year":"2018","journal-title":"Eur J Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0902551","article-title":"Cutting Edge: Novel Function of B Cell-Activating Factor in the Induction of IL-10-Producing Regulatory B Cells","volume":"184","author":"Yang","year":"2010","journal-title":"J Immunol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/leu.2015.174","article-title":"The BAFF Receptor TACI Controls IL-10 Production by Regulatory B Cells and CLL B Cells","volume":"30","author":"Saulep-Easton","year":"2015","journal-title":"Leukemia"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/nature12979","article-title":"IL-35-Producing B Cells are Critical Regulators of Immunity During Autoimmune and Infectious Diseases","volume":"507","author":"Shen","year":"2014","journal-title":"Nature"},{"key":"B36","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1038\/s41467-017-00838-4","article-title":"Il-12p35 Induces Expansion of IL-10 and IL-35-expressing Regulatory B Cells and Ameliorates Autoimmune Disease","volume":"8","author":"Dambuza","year":"2017","journal-title":"Nat Commun"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21438","article-title":"Helminth Infections Associated With Multiple Sclerosis Induce Regulatory B Cells","volume":"64","author":"Correale","year":"2008","journal-title":"Ann Neurol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1111\/ene.14105","article-title":"Failed B Cell Survival Factor Trials Support the Importance of Memory B Cells in Multiple Sclerosis","volume":"27","author":"Baker","year":"2020","journal-title":"Eur J Neurol"},{"key":"B39","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.ebiom.2017.01.042","article-title":"Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis","volume":"16","author":"Baker","year":"2017","journal-title":"EBioMedicine"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3008930","article-title":"Immunoglobulin Class-Switched B Cells Form an Active Immune Axis Between CNS and Periphery in Multiple Sclerosis","volume":"6","author":"Palanichamy","year":"2014","journal-title":"Sci Transl Med"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1126\/scitranslmed.3008879","article-title":"B Cells Populating the Multiple Sclerosis Brain Mature in the Draining Cervical Lymph Nodes","volume":"6","author":"Stern","year":"2014","journal-title":"Sci Transl Med"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.676619\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,26]],"date-time":"2021-05-26T06:20:40Z","timestamp":1622010040000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.676619\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,26]]},"references-count":41,"alternative-id":["10.3389\/fimmu.2021.676619"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.676619","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,26]]},"article-number":"676619"}}