{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T23:18:41Z","timestamp":1793056721748,"version":"4.5.0"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T00:00:00Z","timestamp":1750204800000},"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>Atypical B cell (atBC) subsets display significant heterogeneity across autoimmune diseases, complicating efforts to define their role and therapeutic potential. We hypothesized that this heterogeneity reflects the responses to specific immunopathology, resulting in disease-specific profiles. The myasthenia gravis (MG) subtypes acetylcholine receptor (AChR)-positive MG and muscle-specific kinase (MuSK)-positive MG provide an ideal model to explore atBCs due to the distinct immune mechanisms driven by IgG1-3 and IgG4 autoantibodies, respectively in the disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      CD11c\n                      <jats:sup>+<\/jats:sup>\n                      and IgD\n                      <jats:sup>\u2212<\/jats:sup>\n                      CD27\n                      <jats:sup>\u2212<\/jats:sup>\n                      double-negative (DN) B cells were analyzed by spectral flow cytometry in non-autoimmune controls, AChR-MG, and MuSK-MG. Results were correlated with clinical parameters and antibody levels. In MG subtypes, atBC subsets were further examined for the impact of disease onset and prior rituximab treatment. CD11c\n                      <jats:sup>+<\/jats:sup>\n                      B cells were stimulated\n                      <jats:italic>in vitro<\/jats:italic>\n                      to assess antibody secreting cell (ASC) differentiation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CD11c\n                      <jats:sup>+<\/jats:sup>\n                      and DN2 B cells were increased in late-onset AChR-MG, while MuSK-MG featured expanded DN3 B cells linked to disease severity. CD20 expression in atBCs was differentially expressed between MG subtypes, with higher levels in late-onset AChR-MG and significantly reduced levels in MuSK-MG. CD11c\n                      <jats:sup>+<\/jats:sup>\n                      B cells were reduced after anti-CD20 treatment in MuSK-MG, whereas DN B cells were unaffected. Functionally, CD11c\n                      <jats:sup>+<\/jats:sup>\n                      B cells from MuSK-MG exhibited greater ASC differentiation and autoantibody production.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>MG subtypes exhibit distinct atBC profiles linked to immunopathology and disease onset. These findings reveal subtype-specific pathways that regulate atBCs and highlight their potential as therapeutic targets in both IgG1-3- and IgG4-mediated autoimmunity.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1608160","type":"journal-article","created":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T00:15:22Z","timestamp":1750205722000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Subtype-specific atypical B cell profiles in myasthenia gravis reveal distinct immunopathological pathways"],"prefix":"10.3389","volume":"16","author":[{"given":"Patricia M.","family":"Sikorski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry J.","family":"Kaminski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Vincent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor","family":"Bauman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie","family":"Jacobson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda L.","family":"Kusner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2022.102227","article-title":"Atypical B cells in chronic infectious diseases and systemic autoimmunity: puzzles with many missing pieces","volume":"77","author":"Ambegaonkar","year":"2022","journal-title":"Curr Opin Immunol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/j.immuni.2020.06.013","article-title":"An integrated multi-omic single-cell atlas of human B cell identity","volume":"53","author":"Glass","year":"2020","journal-title":"Immunity"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.979060","article-title":"The development and function of CD11c+ atypical B cells - insights from single cell analysis","volume":"13","author":"Gao","year":"2022","journal-title":"Front Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abg8384","article-title":"Shared transcriptional profiles of atypical B cells suggest common drivers of expansion and function in malaria, HIV, and autoimmunity","volume":"7","author":"Holla","year":"2021","journal-title":"Sci Adv"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-092419-031130","article-title":"Age-associated B cells","volume":"38","author":"Cancro","year":"2020","journal-title":"Annu Rev Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1093\/cei\/uxac103","article-title":"A close-up on the expanding landscape of CD21-\/low B cells in humans","volume":"210","author":"Gjertsson","year":"2022","journal-title":"Clin Exp Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtauto.2024.100252","article-title":"Extrafollicular CD19lowCXCR5\u2013CD11c\u2013 double negative 3 (DN3) B cells are significantly associated with disease activity in females with systemic lupus erythematosus","volume":"9","author":"Chizzolini","year":"2024","journal-title":"J Transl Autoimmun"},{"key":"B8","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1016\/j.immuni.2018.08.015","article-title":"Distinct effector B cells induced by unregulated toll-like receptor 7 contribute to pathogenic responses in systemic lupus erythematosus","volume":"49","author":"Jenks","year":"2018","journal-title":"Immunity"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1758","DOI":"10.1038\/s41467-018-03750-7","article-title":"IL-21 drives expansion and plasma cell differentiation of autoreactive CD11chiT-bet+ B cells in SLE","volume":"9","author":"Wang","year":"2018","journal-title":"Nat Commun"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2400193","article-title":"CD9 and aryl hydrocarbon receptor are markers of human CD19+CD14+ Atypical B cells and are dysregulated in systemic lupus erythematous disease","volume":"213","author":"Blevins","year":"2024","journal-title":"J Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1111\/sji.12792","article-title":"CD21-\/low B cells associate with joint damage in rheumatoid arthritis patients","volume":"90","author":"Thorarinsdottir","year":"2019","journal-title":"Scand J Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1241474","article-title":"Double-negative-2 B cells are the major synovial plasma cell precursor in rheumatoid arthritis","volume":"14","author":"Wing","year":"2023","journal-title":"Front Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.112630","article-title":"Extrafollicular IgD\u2013CD27\u2013CXCR5\u2013CD11c\u2013 DN3 B cells infiltrate inflamed tissues in autoimmune fibrosis and in severe COVID-19","volume":"42","author":"Allard-Chamard","year":"2023","journal-title":"Cell Rep"},{"key":"B14","doi-asserted-by":"publisher","first-page":"56","DOI":"10.55563\/clinexprheumatol\/1b9d13","article-title":"Expansion and surface makers of age-associated B cells in IgG4-related disease","volume":"42","author":"Zhang","year":"2024","journal-title":"Clin Exp Rheumatol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-00814-z","article-title":"Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19","volume":"21","author":"Woodruff","year":"2020","journal-title":"Nat Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.836347","article-title":"CD11c+ B cells participate in the pathogenesis of graves\u2019 Disease by secreting thyroid autoantibodies and cytokines","volume":"13","author":"Cao","year":"2022","journal-title":"Front Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1002\/eji.202350736","article-title":"Regulation of B-cell function and expression of CD11c, T-bet, and FcRL5 in response to different activation signals","volume":"54","author":"Kleberg","year":"2024","journal-title":"Eur J Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.41641","article-title":"IFN\u03b3 induces epigenetic programming of human T-bethi B cells and promotes TLR7\/8 and IL-21 induced differentiation","volume":"8","author":"Zumaquero","year":"2019","journal-title":"eLife"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1172\/JCI179742","article-title":"Myasthenia gravis: the future is here","volume":"134","author":"Kaminski","year":"2024","journal-title":"J Clin Invest"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00776","article-title":"Autoimmune pathology in myasthenia gravis disease subtypes is governed by divergent mechanisms of immunopathology","volume":"11","author":"Fichtner","year":"2020","journal-title":"Front Immunol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1111\/j.1749-6632.1987.tb51282.x","article-title":"The role of the thymus in myasthenia gravis: immunohistological and immunological studies in 115 cases","volume":"505","author":"Berrih-Aknin","year":"1987","journal-title":"Ann N Y Acad Sci"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.988125","article-title":"Autoantibodies elicited with SARS-CoV-2 infection are linked to alterations in double negative B cells","volume":"13","author":"Castleman","year":"2022","journal-title":"Front Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00032","article-title":"CD11c+ B cells are mainly memory cells, precursors of antibody secreting cells in healthy donors","volume":"11","author":"Golinski","year":"2020","journal-title":"Front Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1276014","article-title":"Upregulated Fcrl5 disrupts B cell anergy and causes autoimmune disease","volume":"14","author":"Ono","year":"2023","journal-title":"Front Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1502193","article-title":"Efficient culture of human naive and memory B cells for use as APCs","volume":"197","author":"Su","year":"2016","journal-title":"J Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.mad.2009.08.003","article-title":"A double-negative (IgD\u2013CD27\u2013) B cell population is increased in the peripheral blood of elderly people","volume":"130","author":"Colonna-Romano","year":"2009","journal-title":"Mech Ageing Dev"},{"key":"B27","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1001\/jamaneurol.2014.4103","article-title":"A genome-wide association study of myasthenia gravis","volume":"72","author":"Renton","year":"2015","journal-title":"JAMA Neurol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26169","article-title":"Genomic insights into myasthenia gravis identify distinct immunological mechanisms in early and late onset disease","volume":"90","author":"Handunnetthi","year":"2021","journal-title":"Ann Neurol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.2119\/molmed.2015.00232","article-title":"Genome-wide association study of late-onset myasthenia gravis: confirmation of TNFRSF11A and identification of ZBTB10 and three distinct HLA associations","volume":"21","author":"Seldin","year":"2015","journal-title":"Mol Med"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1007\/s12016-016-8558-3","article-title":"Thymic germinal centers and corticosteroids in myasthenia gravis: an immunopathological study in 1035 cases and a critical review","volume":"52","author":"Truffault","year":"2017","journal-title":"Clin Rev Allergy Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)62960-4","article-title":"Increased toll-like receptor 4 expression in thymus of myasthenic patients with thymitis and thymic involution","volume":"167","author":"Bernasconi","year":"2005","journal-title":"Am J Pathol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2013.03.010","article-title":"Etiology of myasthenia gravis: innate immunity signature in pathological thymus","volume":"12","author":"Cavalcante","year":"2013","journal-title":"Autoimmun Rev"},{"key":"B33","doi-asserted-by":"publisher","first-page":"7934","DOI":"10.1038\/s41586-022-05273-0","article-title":"Dysregulated naive B cells and de novo autoreactivity in severe COVID-19","volume":"611","author":"Woodruff","year":"2022","journal-title":"Nature"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004894","article-title":"FCRL5 delineates functionally impaired memory B cells associated with plasmodium falciparum exposure","volume":"11","author":"Sullivan","year":"2015","journal-title":"PloS Pathog"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1608160\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T00:15:24Z","timestamp":1750205724000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1608160\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,18]]},"references-count":34,"alternative-id":["10.3389\/fimmu.2025.1608160"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1608160","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,18]]},"article-number":"1608160"}}