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Notably, anergic B cells, but not nonautoreactive B cells, contributed to ABC formation in these models. Anergic B cells also showed a greater propensity for in vitro differentiation into ABCs, which was inhibited by the expression of the transcription factor Nr4a1. Bruton\u2019s tyrosine kinase (Btk), a key BCR signaling component, was constitutively activated in ABCs from aged and autoimmune mice as well as patients with lupus. Inhibiting Btk reduced ABC numbers and ameliorated the pathogenicity of lupus mice. Our findings reveal critical mechanisms underlying ABC development and offer previously unrecognized therapeutic insights for autoimmune diseases.<\/jats:p>","DOI":"10.1126\/sciadv.adt8199","type":"journal-article","created":{"date-parts":[[2025,4,18]],"date-time":"2025-04-18T13:58:46Z","timestamp":1744984726000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":29,"title":["Critical roles of chronic BCR signaling in the differentiation of anergic B cells into age-associated B cells in aging and autoimmunity"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3896-0536","authenticated-orcid":true,"given":"Keisuke","family":"Imabayashi","sequence":"first","affiliation":[{"name":"Division of Immunology and Genome Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan."},{"name":"Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7519-7336","authenticated-orcid":true,"given":"Yutaro","family":"Yada","sequence":"additional","affiliation":[{"name":"Division of Immunology and Genome Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4425-6798","authenticated-orcid":true,"given":"Kazuhiko","family":"Kawata","sequence":"additional","affiliation":[{"name":"Division of Immunology and Genome Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motoki","family":"Yoshimura","sequence":"additional","affiliation":[{"name":"Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5277-2932","authenticated-orcid":true,"given":"Takeshi","family":"Iwasaki","sequence":"additional","affiliation":[{"name":"Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akemi","family":"Baba","sequence":"additional","affiliation":[{"name":"Division of Immunology and Genome Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1420-4549","authenticated-orcid":true,"given":"Akihito","family":"Harada","sequence":"additional","affiliation":[{"name":"Department of Multi-Omics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Akashi","sequence":"additional","affiliation":[{"name":"Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Niiro","sequence":"additional","affiliation":[{"name":"Department of Medical Education, Faculty of Medical Sciences, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7753-0905","authenticated-orcid":true,"given":"Yoshihiro","family":"Baba","sequence":"additional","affiliation":[{"name":"Division of Immunology and Genome Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature03724"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/334676a0"},{"key":"e_1_3_2_4_2","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1084\/jem.179.1.125","article-title":"Reduced life span of anergic self-reactive B cells in a double-transgenic model","volume":"179","author":"Fulcher D. 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