{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T12:41:10Z","timestamp":1773751270518,"version":"3.50.1"},"reference-count":52,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2021,1,19]],"date-time":"2021-01-19T00:00:00Z","timestamp":1611014400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Malaria is a potentially life-threatening disease with approximately half of the world\u2019s population at risk. Young children and pregnant women are hit hardest by the disease. B cells and antibodies are part of an adaptive immune response protecting individuals continuously exposed to the parasite. An infection with <jats:italic>Plasmodium falciparum<\/jats:italic> can cause dysregulation of B cell homeostasis, while antibodies are known to be key in controlling symptoms and parasitemia. BAFF is an instrumental cytokine for the development and maintenance of B cells. Pregnancy alters the immune status and renders previously clinically immune women at risk of severe malaria, potentially due to altered B cell responses associated with changes in BAFF levels. In this prospective study, we investigated the levels of BAFF in a malaria-endemic area in mothers and their infants from birth up to 9 months. We found that BAFF-levels are significantly higher in infants than in mothers. BAFF is highest in cord blood and then drops rapidly, but remains significantly higher in infants compared to mothers even at 9 months of age. We further correlated BAFF levels to <jats:italic>P<\/jats:italic>. <jats:italic>falciparum-<\/jats:italic>specific antibody levels and B cell frequencies and found a negative correlation between BAFF and both <jats:italic>P<\/jats:italic>. <jats:italic>falciparum<\/jats:italic>-specific and total proportions of IgG<jats:sup>+<\/jats:sup> memory B cells, as well as CD27<jats:sup>\u2212<\/jats:sup> memory B cells, indicating that exposure to both malaria and other diseases affect the development of B-cell memory and that BAFF plays a part in this. In conclusion, we have provided new information on how natural immunity against malaria is formed.<\/jats:p>","DOI":"10.1371\/journal.pone.0245431","type":"journal-article","created":{"date-parts":[[2021,1,19]],"date-time":"2021-01-19T18:37:50Z","timestamp":1611081470000},"page":"e0245431","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["A longitudinal study of plasma BAFF levels in mothers and their infants in Uganda, and correlations with subsets of B cells"],"prefix":"10.1371","volume":"16","author":[{"given":"Caroline","family":"R\u00f6nnberg","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Allan","family":"Lugaajju","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Nyman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulf","family":"Hammar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matteo","family":"Bottai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maximilian Julius","family":"Lautenbach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher","family":"Sundling","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fred","family":"Kironde","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2661-3115","authenticated-orcid":true,"given":"Kristina E. M.","family":"Persson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,1,19]]},"reference":[{"key":"pone.0245431.ref001","unstructured":"WHO. World malaria report 2019 2019 [Available from: https:\/\/www.who.int\/publications\/i\/item\/world-malaria-report-2019."},{"issue":"4","key":"pone.0245431.ref002","doi-asserted-by":"crossref","first-page":"e107","DOI":"10.1016\/S1473-3099(18)30066-5","article-title":"Burden, pathology, and costs of malaria in pregnancy: new developments for an old problem","volume":"18","author":"SJ Rogerson","year":"2018","journal-title":"The Lancet Infectious diseases"},{"issue":"2","key":"pone.0245431.ref003","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/S1473-3099(07)70022-1","article-title":"Malaria in pregnancy: pathogenesis and immunity","volume":"7","author":"SJ Rogerson","year":"2007","journal-title":"The Lancet Infectious diseases"},{"key":"pone.0245431.ref004","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1038\/192733a0","article-title":"Gamma-globulin and acquired immunity to human malaria","volume":"192","author":"S Cohen","year":"1961","journal-title":"Nature"},{"issue":"6705","key":"pone.0245431.ref005","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1038\/27570","article-title":"Maternal antibodies block malaria","volume":"395","author":"M Fried","year":"1998","journal-title":"Nature"},{"issue":"9405","key":"pone.0245431.ref006","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/S0140-6736(03)15386-X","article-title":"Variant surface antigen-specific IgG and protection against clinical consequences of pregnancy-associated Plasmodium falciparum malaria","volume":"363","author":"T Staalsoe","year":"2004","journal-title":"Lancet"},{"issue":"5","key":"pone.0245431.ref007","doi-asserted-by":"crossref","first-page":"813","DOI":"10.3201\/eid2105.141626","article-title":"Protective Antibodies against Placental Malaria and Poor Outcomes during Pregnancy, Benin","volume":"21","author":"NT Ndam","year":"2015","journal-title":"Emerg Infect Dis"},{"issue":"9","key":"pone.0245431.ref008","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1084\/jem.20041579","article-title":"Evidence for the involvement of VAR2CSA in pregnancy-associated malaria","volume":"200","author":"A Salanti","year":"2004","journal-title":"J Exp Med"},{"issue":"15","key":"pone.0245431.ref009","doi-asserted-by":"crossref","first-page":"6958","DOI":"10.1073\/pnas.1001323107","article-title":"A prospective analysis of the Ab response to Plasmodium falciparum before and after a malaria season by protein microarray","volume":"107","author":"PD Crompton","year":"2010","journal-title":"PNAS"},{"issue":"2","key":"pone.0245431.ref010","doi-asserted-by":"crossref","first-page":"e1000770","DOI":"10.1371\/journal.ppat.1000770","article-title":"Long-lived antibody and B Cell memory responses to the human malaria parasites, Plasmodium falciparum and Plasmodium vivax","volume":"6","author":"J Wipasa","year":"2010","journal-title":"PLoS Pathog"},{"issue":"8","key":"pone.0245431.ref011","doi-asserted-by":"crossref","first-page":"4092","DOI":"10.1128\/IAI.67.8.4092-4098.1999","article-title":"Nine-year longitudinal study of antibodies to variant antigens on the surface of Plasmodium falciparum-infected erythrocytes","volume":"67","author":"HA Giha","year":"1999","journal-title":"Infect Immun"},{"issue":"1","key":"pone.0245431.ref012","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/s12916-019-1255-3","article-title":"Antibody responses to merozoite antigens after natural Plasmodium falciparum infection: kinetics and longevity in absence of re-exposure","volume":"17","author":"V Yman","year":"2019","journal-title":"BMC Med"},{"issue":"3","key":"pone.0245431.ref013","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.4049\/jimmunol.1202438","article-title":"Chronic exposure to Plasmodium falciparum is associated with phenotypic evidence of B and T cell exhaustion","volume":"190","author":"J Illingworth","year":"2013","journal-title":"J Immunol"},{"issue":"5","key":"pone.0245431.ref014","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.pt.2013.03.002","article-title":"How malaria modulates memory: activation and dysregulation of B cells in Plasmodium infection","volume":"29","author":"A Scholzen","year":"2013","journal-title":"Trends Parasitol"},{"issue":"3","key":"pone.0245431.ref015","doi-asserted-by":"crossref","first-page":"2176","DOI":"10.4049\/jimmunol.0901297","article-title":"Atypical memory B cells are greatly expanded in individuals living in a malaria-endemic area","volume":"183","author":"GE Weiss","year":"2009","journal-title":"J Immunol"},{"issue":"7","key":"pone.0245431.ref016","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/nri844","article-title":"BAFF: a fundamental survival factor for B cells","volume":"2","author":"F Mackay","year":"2002","journal-title":"Nat Rev Immunol"},{"issue":"1","key":"pone.0245431.ref017","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1111\/j.1600-065X.2010.00944.x","article-title":"B-cell stage and context-dependent requirements for survival signals from BAFF and the B-cell receptor","volume":"237","author":"F Mackay","year":"2010","journal-title":"Immunol Rev"},{"issue":"4","key":"pone.0245431.ref018","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1128\/CMR.00046-17","article-title":"The Role of BAFF System Molecules in Host Response to Pathogens","volume":"30","author":"J Sakai","year":"2017","journal-title":"Clin Microbiol Rev"},{"issue":"2","key":"pone.0245431.ref019","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1172\/JCI18025","article-title":"BAFF selectively enhances the survival of plasmablasts generated from human memory B cells","volume":"112","author":"DT Avery","year":"2003","journal-title":"J Clin Invest"},{"issue":"9","key":"pone.0245431.ref020","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1038\/ni.1914","article-title":"The transmembrane activator TACI triggers immunoglobulin class switching by activating B cells through the adaptor MyD88","volume":"11","author":"B He","year":"2010","journal-title":"Nat Immunol"},{"issue":"1","key":"pone.0245431.ref021","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1124\/jpet.116.236075","article-title":"Unexpected Potency Differences between B-Cell-Activating Factor (BAFF) Antagonist Antibodies against Various Forms of BAFF: Trimer, 60-Mer, and Membrane-Bound","volume":"359","author":"AM Nicoletti","year":"2016","journal-title":"J Pharmacol Exp Ther"},{"key":"pone.0245431.ref022","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.coi.2015.03.005","article-title":"BAFF receptors and ligands create independent homeostatic niches for B cell subsets","volume":"34","author":"MS Naradikian","year":"2015","journal-title":"Curr Opin Immunol"},{"issue":"1","key":"pone.0245431.ref023","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1084\/jem.20031330","article-title":"BCMA is essential for the survival of long-lived bone marrow plasma cells","volume":"199","author":"BP O'Connor","year":"2004","journal-title":"J Exp Med"},{"issue":"11","key":"pone.0245431.ref024","doi-asserted-by":"crossref","first-page":"7276","DOI":"10.4049\/jimmunol.179.11.7276","article-title":"Regulated expression of BAFF-binding receptors during human B cell differentiation","volume":"179","author":"JR Darce","year":"2007","journal-title":"J Immunol"},{"issue":"10","key":"pone.0245431.ref025","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1016\/j.humpath.2005.08.005","article-title":"BAFF-R, the major B cell-activating factor receptor, is expressed on most mature B cells and B-cell lymphoproliferative disorders","volume":"36","author":"SJ Rodig","year":"2005","journal-title":"Hum Pathol"},{"issue":"5537","key":"pone.0245431.ref026","doi-asserted-by":"crossref","first-page":"2108","DOI":"10.1126\/science.1061965","article-title":"BAFF-R, a newly identified TNF receptor that specifically interacts with BAFF","volume":"293","author":"JS Thompson","year":"2001","journal-title":"Science"},{"issue":"40","key":"pone.0245431.ref027","doi-asserted-by":"crossref","first-page":"15517","DOI":"10.1073\/pnas.0807841105","article-title":"BLyS inhibition eliminates primary B cells but leaves natural and acquired humoral immunity intact","volume":"105","author":"JL Scholz","year":"2008","journal-title":"PNAS"},{"issue":"5","key":"pone.0245431.ref028","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.2353\/ajpath.2008.071139","article-title":"Signaling pathways for B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) in human placenta","volume":"172","author":"DL Langat","year":"2008","journal-title":"Am J Pathol"},{"issue":"6","key":"pone.0245431.ref029","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1093\/infdis\/jir438","article-title":"The plasma concentration of the B cell activating factor is increased in children with acute malaria","volume":"204","author":"E Nduati","year":"2011","journal-title":"J Infect Dis"},{"issue":"8","key":"pone.0245431.ref030","doi-asserted-by":"crossref","first-page":"3719","DOI":"10.4049\/jimmunol.1302960","article-title":"BAFF and BAFF receptor levels correlate with B cell subset activation and redistribution in controlled human malaria infection","volume":"192","author":"A Scholzen","year":"2014","journal-title":"J Immunol"},{"issue":"12","key":"pone.0245431.ref031","doi-asserted-by":"crossref","first-page":"3291","DOI":"10.1002\/eji.201242689","article-title":"Malaria infection alters the expression of B-cell activating factor resulting in diminished memory antibody responses and survival","volume":"42","author":"XQ Liu","year":"2012","journal-title":"Eur J Immunol"},{"issue":"1","key":"pone.0245431.ref032","doi-asserted-by":"crossref","first-page":"557","DOI":"10.4049\/jimmunol.179.1.557","article-title":"Genome-wide expression analysis of placental malaria reveals features of lymphoid neogenesis during chronic infection","volume":"179","author":"A Muehlenbachs","year":"2007","journal-title":"J Immunol"},{"key":"pone.0245431.ref033","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.jri.2014.12.003","article-title":"The presence of B-cell activating factor (BAFF) in umbilical cord blood in both healthy and pre-eclamptic pregnancies and in human breast milk","volume":"109","author":"J Bienertova-Vasku","year":"2015","journal-title":"J Repr Immunol"},{"issue":"1","key":"pone.0245431.ref034","doi-asserted-by":"crossref","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":"M Kreuzaler","year":"2012","journal-title":"J Immunol"},{"issue":"4","key":"pone.0245431.ref035","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1016\/j.jaci.2015.03.022","article-title":"Higher B-cell activating factor levels at birth are positively associated with maternal dairy farm exposure and negatively related to allergy development","volume":"136","author":"AC Lundell","year":"2015","journal-title":"J Allergy Clin Immunol"},{"issue":"3","key":"pone.0245431.ref036","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1111\/j.1365-2249.2006.03170.x","article-title":"Increased susceptibility of cord blood B lymphocytes to undergo spontaneous apoptosis","volume":"145","author":"A Kessel","year":"2006","journal-title":"Clin Exp Immunol"},{"issue":"5","key":"pone.0245431.ref037","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.4049\/jimmunol.1801024","article-title":"HIV, Cytomegalovirus, and Malaria Infections during Pregnancy Lead to Inflammation and Shifts in Memory B Cell Subsets in Kenyan Neonates","volume":"202","author":"KT Yeo","year":"2019","journal-title":"J Immunol"},{"key":"pone.0245431.ref038","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1186\/s12936-015-0911-0","article-title":"Novel flow cytometry technique for detection of Plasmodium falciparum specific B-cells in humans: increased levels of specific B-cells in ongoing infection","volume":"14","author":"A Lugaajju","year":"2015","journal-title":"Malar J"},{"issue":"1","key":"pone.0245431.ref039","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/s12936-017-1697-z","article-title":"Development of Plasmodium falciparum specific naive, atypical, memory and plasma B cells during infancy and in adults in an endemic area","volume":"16","author":"A Lugaajju","year":"2017","journal-title":"Malar J"},{"key":"pone.0245431.ref040","first-page":"57","article-title":"Controlling the false discovery rate\u2014a practical and powerful approach to multiple testing","author":"Y Benjamini","year":"1995","journal-title":"J R Stat Soc SerB Stat Methodol"},{"key":"pone.0245431.ref041","volume-title":"R: A Language and Environment for Statistical Computing","author":"RC Team","year":"2020"},{"issue":"3","key":"pone.0245431.ref042","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.actatropica.2010.08.012","article-title":"Blood stage Plasmodium falciparum antigens induce T cell independent immunoglobulin production via B cell activation factor of the TNF family (BAFF) pathway","volume":"116","author":"R Kumsiri","year":"2010","journal-title":"Acta Trop"},{"issue":"6","key":"pone.0245431.ref043","doi-asserted-by":"crossref","first-page":"2971","DOI":"10.4049\/jimmunol.1401037","article-title":"Pregnancy and malaria exposure are associated with changes in the B cell pool and in plasma eotaxin levels","volume":"193","author":"P Requena","year":"2014","journal-title":"J Immunol"},{"key":"pone.0245431.ref044","doi-asserted-by":"crossref","first-page":"630","DOI":"10.3389\/fimmu.2017.00630","article-title":"The Antibody-Secreting Cell Response to Infection: Kinetics and Clinical Applications","volume":"8","author":"MJ Carter","year":"2017","journal-title":"Front Immunol"},{"key":"pone.0245431.ref045","first-page":"4","article-title":"Malaria-associated atypical memory B cells exhibit markedly reduced B cell receptor signaling and effector function","author":"S Portugal","year":"2015","journal-title":"Elife"},{"issue":"5","key":"pone.0245431.ref046","doi-asserted-by":"crossref","first-page":"e1004894","DOI":"10.1371\/journal.ppat.1004894","article-title":"FCRL5 Delineates Functionally Impaired Memory B Cells Associated with Plasmodium falciparum Exposure","volume":"11","author":"RT Sullivan","year":"2015","journal-title":"PLoS Pathog"},{"key":"pone.0245431.ref047","first-page":"5","article-title":"cell profiling in malaria reveals expansion and remodelling of CD11c+ B cell subsets","author":"C Sundling","year":"2019","journal-title":"BJCI Insight"},{"issue":"7","key":"pone.0245431.ref048","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/nri2572","article-title":"Cracking the BAFF code","volume":"9","author":"F Mackay","year":"2009","journal-title":"Nat Rev Immunol"},{"issue":"1","key":"pone.0245431.ref049","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1182\/blood-2010-08-301887","article-title":"High expression levels of B lymphocyte stimulator (BLyS) by dendritic cells correlate with HIV-related B-cell disease progression in humans","volume":"117","author":"Montreal Primary HIVI","year":"2011","journal-title":"Blood"},{"issue":"9","key":"pone.0245431.ref050","doi-asserted-by":"crossref","first-page":"5412","DOI":"10.1128\/IAI.72.9.5412-5418.2004","article-title":"Identification of a polyclonal B-cell activator in Plasmodium falciparum","volume":"72","author":"D Donati","year":"2004","journal-title":"Infect Immun"},{"key":"pone.0245431.ref051","doi-asserted-by":"crossref","first-page":"201","DOI":"10.3389\/fimmu.2017.00201","article-title":"Characterization of the Highly Prevalent Regulatory CD24(hi)CD38(hi) B-Cell Population in Human Cord Blood","volume":"8","author":"A Esteve-Sole","year":"2017","journal-title":"Front Immunol"},{"issue":"3","key":"pone.0245431.ref052","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1002\/iid3.26","article-title":"B-cell subpopulations in children: National reference values","volume":"2","author":"M Duchamp","year":"2014","journal-title":"Immun Inflamm Dis"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0245431","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,19]],"date-time":"2021-01-19T18:38:27Z","timestamp":1611081507000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0245431"}},"subtitle":[],"editor":[{"given":"Yolande","family":"Richard","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,1,19]]},"references-count":52,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1,19]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0245431","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,19]]}}}