{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:17:30Z","timestamp":1785428250617,"version":"3.56.0"},"reference-count":100,"publisher":"National Academy of Sciences","issue":"19","license":[{"start":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T00:00:00Z","timestamp":1778025600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004410","name":"European Molecular Biology Organization","doi-asserted-by":"publisher","award":["ALTF 371-2022"],"award-info":[{"award-number":["ALTF 371-2022"]}],"id":[{"id":"10.13039\/100004410","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["SPI.2017.028"],"award-info":[{"award-number":["SPI.2017.028"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,5,12]]},"abstract":"<jats:p>Immunoglobulin A (IgA) is the most abundant antibody in humans, with high concentrations in both mucosae\/secretions and circulation. While mucosal IgA has been studied extensively, characterization of human IgA in serum and its distinctive functions lags behind. Circulatory IgA is regularly assumed to be monomeric, despite some reports describing a minor population of J-chain-coupled dimers. Here, we first charted the compositional landscape of human serum IgA in individual healthy donors. In addition to the expected predominating monomers, we consistently observed J-coupled dimers, even representing ~30% of one donor\u2019s total serum IgA. To determine whether these structurally distinct populations were also clonally distinct, we employed mass spectrometry\u2013based IgA1 clonal profiling in sera of two donors. Our data revealed the majority of IgA1 clones are present solely as monomers, with a smaller number exclusively dimeric. Strikingly, a third population of IgA1 clones is present in circulation as both monomers and J-coupled dimers. In fact, these shared, structurally promiscuous IgA1 clones dominated both individuals\u2019 serum IgA1 clonal repertoires. Our findings suggest every unique IgA1 clone could potentially be produced as a variable mixture of monomers and J-coupled dimers, but what exactly determines this ratio requires further investigation. This finding is important, as monomers and J-coupled dimers have distinct characteristics in antigen binding, receptor activation, and clearance from circulation, with several reports highlighting, for instance, the enhanced neutralization capacity of dimeric IgA. As we show here, the human immune system is not merely capable of producing both forms but apparently prefers doing so in parallel.<\/jats:p>","DOI":"10.1073\/pnas.2533440123","type":"journal-article","created":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T16:20:47Z","timestamp":1778084447000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":3,"title":["Structural promiscuity in the human circulatory IgA1 clonal repertoire"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7905-8250","authenticated-orcid":false,"given":"Amber D.","family":"Rolland","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04pp8hn57","id-type":"ROR","asserted-by":"publisher"}],"name":"Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University","place":["Utrecht, The Netherlands"]},{"id":[{"id":"https:\/\/ror.org\/02z3zn824","id-type":"ROR","asserted-by":"publisher"}],"name":"Netherlands Proteomics Center","place":["Utrecht, The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9442-0040","authenticated-orcid":false,"given":"Sofia","family":"Kalaidopoulou Nteak","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04pp8hn57","id-type":"ROR","asserted-by":"publisher"}],"name":"Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University","place":["Utrecht, The Netherlands"]},{"id":[{"id":"https:\/\/ror.org\/02z3zn824","id-type":"ROR","asserted-by":"publisher"}],"name":"Netherlands Proteomics Center","place":["Utrecht, The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5621-003X","authenticated-orcid":false,"given":"Gestur","family":"Vidarsson","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04pp8hn57","id-type":"ROR","asserted-by":"publisher"}],"name":"Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University","place":["Utrecht, The Netherlands"]},{"id":[{"id":"https:\/\/ror.org\/02z3zn824","id-type":"ROR","asserted-by":"publisher"}],"name":"Netherlands Proteomics Center","place":["Utrecht, The Netherlands"]},{"name":"Sanquin Research and Landsteiner Laboratory, Department of Experimental Immunohematology, Amsterdam University Medical Center","place":["Amsterdam, The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0985-7903","authenticated-orcid":false,"given":"Albert","family":"Bondt","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04pp8hn57","id-type":"ROR","asserted-by":"publisher"}],"name":"Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University","place":["Utrecht, The Netherlands"]},{"id":[{"id":"https:\/\/ror.org\/02z3zn824","id-type":"ROR","asserted-by":"publisher"}],"name":"Netherlands Proteomics Center","place":["Utrecht, The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2405-4404","authenticated-orcid":false,"given":"Albert J. R.","family":"Heck","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04pp8hn57","id-type":"ROR","asserted-by":"publisher"}],"name":"Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University","place":["Utrecht, The Netherlands"]},{"id":[{"id":"https:\/\/ror.org\/02z3zn824","id-type":"ROR","asserted-by":"publisher"}],"name":"Netherlands Proteomics Center","place":["Utrecht, The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,5,6]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-415847-4.00017-3"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.3390\/antib8040057"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-106-6-892"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-101320-123742"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.iy.03.040185.002233"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/12.1.19"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2311265120"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaz5807"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/febs.17089"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.1992.tb06404.x"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1051\/vetres:2006010"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13992-8"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2023.130536"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.191.12.2171"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-025-02088-0"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-415847-4.15001-3"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41385-019-0227-4"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1111\/imcb.12306"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1089\/dna.2014.2639"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1165394"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-024-00885-3"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-023-00476-9"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.3389\/fchem.2022.974854"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-030-76912-3_14"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcpro.2023.100690"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abd2223"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abf1555"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1111\/imcb.12682"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI110777"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2019.1622940"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3083.2003.01344.x"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.4.2260"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-020-0336-3"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.08.036"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.3181\/00379727-150-39061"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2020.1729683"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3795"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.789748"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2021.08.008"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-022-00954-2"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.128.2.990"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2021.05.005"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1400531"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1002\/9781394236145.ch3"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M113.031591"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.202101099"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbabio.2019.148141"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2564-6"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-023-01712-w"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2406474122"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.69.1.124"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00677a034"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj1360597"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj1360607"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1038\/s44318-024-00317-9"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830080205"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00531"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms13838"},{"key":"e_1_3_4_59_2","doi-asserted-by":"crossref","unstructured":"G. A. Pacheco Origins and diversity of pan-isotype human bone marrow plasma cells. bioRxiv [Preprint] (2024). https:\/\/doi.org\/10.1101\/2024.05.08.592267 (Accessed 18 January 2026).","DOI":"10.1101\/2024.05.08.592267"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-2776(08)60240-0"},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.112682"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2022.01.003"},{"key":"e_1_3_4_63_2","doi-asserted-by":"crossref","unstructured":"F. Vaz Distinct systemic and gut IgA responses to bacteria of the human upper gastrointestinal tract. bioRxiv [Preprint] (2025). https:\/\/doi.org\/10.1101\/2025.07.01.662496. Accessed 21 October 2025.","DOI":"10.1101\/2025.07.01.662496"},{"key":"e_1_3_4_64_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.83578"},{"key":"e_1_3_4_65_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.59850"},{"key":"e_1_3_4_66_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1290585"},{"key":"e_1_3_4_67_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.240762.114"},{"key":"e_1_3_4_68_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2021.166826"},{"key":"e_1_3_4_69_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mucimm.2023.12.002"},{"key":"e_1_3_4_70_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1904204116"},{"key":"e_1_3_4_71_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1701797114"},{"key":"e_1_3_4_72_2","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2021108518"},{"key":"e_1_3_4_73_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0291568"},{"key":"e_1_3_4_74_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.133.6.3156"},{"key":"e_1_3_4_75_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.1991.tb05730.x"},{"key":"e_1_3_4_76_2","doi-asserted-by":"crossref","unstructured":"J. Park Dissecting the clonal composition and determinants of neutralization potency enhancement of serum dimeric and monomeric IgA to human norovirus. Research Square [Preprint] (2025). https:\/\/doi.org\/10.21203\/rs.3.rs-8066364\/v1. Accessed 6 April 2026.","DOI":"10.21203\/rs.3.rs-8066364\/v1"},{"key":"e_1_3_4_77_2","first-page":"1207","article-title":"Variability in the molecular sizes of IgA secreted by individual hybridoma cell lines","volume":"216","author":"Peppard J. V.","year":"1987","unstructured":"J. V. Peppard, L. E. Jackson, Variability in the molecular sizes of IgA secreted by individual hybridoma cell lines. Adv. Exp. Med. Biol. 216B, 1207\u20131213 (1987).","journal-title":"Adv. Exp. Med. Biol."},{"key":"e_1_3_4_78_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M205502200"},{"key":"e_1_3_4_79_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.157.1.156"},{"key":"e_1_3_4_80_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.159.1.244"},{"key":"e_1_3_4_81_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.47.33771"},{"key":"e_1_3_4_82_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830241033"},{"key":"e_1_3_4_83_2","doi-asserted-by":"publisher","DOI":"10.1111\/imr.13424"},{"key":"e_1_3_4_84_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-018-2976-8"},{"key":"e_1_3_4_85_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.166.10.6250"},{"key":"e_1_3_4_86_2","doi-asserted-by":"publisher","DOI":"10.2147\/ITT.S266242"},{"key":"e_1_3_4_87_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2024.105823"},{"key":"e_1_3_4_88_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.03.027"},{"key":"e_1_3_4_89_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1007427"},{"key":"e_1_3_4_90_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3942"},{"key":"e_1_3_4_91_2","first-page":"S47","article-title":"Human peripheral blood B-cell compartments: A crossroad in B-cell traffic","volume":"78","author":"Perez-Andres M.","year":"2010","unstructured":"M. Perez-Andres , Human peripheral blood B-cell compartments: A crossroad in B-cell traffic. Cytometry B 78B, S47\u2013S60 (2010).","journal-title":"Cytometry B"},{"key":"e_1_3_4_92_2","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12980"},{"key":"e_1_3_4_93_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-04-153544"},{"key":"e_1_3_4_94_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.670290"},{"key":"e_1_3_4_95_2","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2015.38"},{"key":"e_1_3_4_96_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2018.01.005"},{"key":"e_1_3_4_97_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41385-022-00539-2"},{"key":"e_1_3_4_98_2","doi-asserted-by":"publisher","DOI":"10.1159\/000510251"},{"key":"e_1_3_4_99_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2024.01.025"},{"key":"e_1_3_4_100_2","doi-asserted-by":"crossref","unstructured":"A. D. Rolland S. Kalaidopoulou Nteak G. Vidarsson A. Bondt A. J. R. Heck Data from \u201cStructural promiscuity in the human circulatory IgA1 clonal repertoire.\u201d MassIVE. https:\/\/doi.org\/10.25345\/C5BV7B870. Deposited 23 April 2026.","DOI":"10.1101\/2025.11.13.688237"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2533440123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T16:21:36Z","timestamp":1778084496000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2533440123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,6]]},"references-count":100,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2026,5,12]]}},"alternative-id":["10.1073\/pnas.2533440123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2533440123","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.11.13.688237","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,6]]},"assertion":[{"value":"2025-11-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-06","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2533440123"}}