{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T10:52:11Z","timestamp":1789901531778,"version":"4.0.1"},"reference-count":72,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2020,7,1]],"date-time":"2020-07-01T00:00:00Z","timestamp":1593561600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI56363"],"award-info":[{"award-number":["AI56363"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>BCR transgenic mice dominate studies of B cell tolerance; consequently, tolerance in normal mice expressing diverse sets of autoreactive B cells is poorly characterized. We have used single B cell cultures to trace self-reactivity in BCR repertoires across the first and second tolerance checkpoints and in tolerized B cell compartments of normal mice. This approach reveals affinity \u201csetpoints\u201d that define each checkpoint and a subset of tolerized, autoreactive B cells that is long-lived. In normal mice, the numbers of B cells avidly specific for DNA fall significantly as small pre-B become immature and transitional-1 B cells, revealing the first tolerance checkpoint. By contrast, DNA reactivity does not significantly change when immature and transitional-1 B cells become mature follicular B cells, showing that the second checkpoint does not reduce DNA reactivity. In the spleen, autoreactivity was high in transitional-3 (T3) B cells, CD93+IgM\u2212\/loIgDhi anergic B cells, and a CD93\u2212 anergic subset. Whereas splenic T3 and CD93+ anergic B cells are short-lived, CD93\u2212IgM\u2212\/loIgDhi B cells have half-lives comparable to mature follicular B cells. B cell\u2013specific deletion of proapoptotic genes, Bak and Bax, resulted in increased CD93\u2212IgM\u2212\/loIgDhi B cell numbers but not T3 B cell numbers, suggesting that apoptosis regulates differently persistent and ephemeral autoreactive B cells. The self-reactivity and longevity of CD93\u2212IgM\u2212\/loIgDhi B cells and their capacity to proliferate and differentiate into plasmacytes in response to CD40 activation in vitro lead us to propose that this persistent, self-reactive compartment may be the origin of systemic autoimmunity and a potential target for vaccines to elicit protective Abs cross-reactive with self-antigens.<\/jats:p>","DOI":"10.4049\/jimmunol.1901015","type":"journal-article","created":{"date-parts":[[2020,5,15]],"date-time":"2020-05-15T23:31:20Z","timestamp":1589585480000},"page":"90-101","source":"Crossref","is-referenced-by-count":13,"title":["Tracing Self-Reactive B Cells in Normal Mice"],"prefix":"10.1093","volume":"205","author":[{"given":"Takuya","family":"Nojima","sequence":"first","affiliation":[{"name":"Department of Immunology, Duke University , Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander E","family":"Reynolds","sequence":"additional","affiliation":[{"name":"Department of Immunology, Duke University , Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5195-0474","authenticated-orcid":false,"given":"Daisuke","family":"Kitamura","sequence":"additional","affiliation":[{"name":"Research Institute for Biomedical Sciences, Tokyo University of Science , Noda, Chiba 278-0022 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8770-040X","authenticated-orcid":false,"given":"Garnett","family":"Kelsoe","sequence":"additional","affiliation":[{"name":"Department of Immunology, Duke University , Durham, NC 27710"},{"name":"Duke Human Vaccine Institute, Duke University , Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayuki","family":"Kuraoka","sequence":"additional","affiliation":[{"name":"Department of Immunology, Duke University , Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,7,1]]},"reference":[{"key":"2025030417504123000_r1","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1126\/science.1086907","article-title":"Predominant autoantibody production by early human B cell precursors","volume":"301","author":"Wardemann","year":"2003","journal-title":"Science"},{"key":"2025030417504123000_r2","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/334676a0","article-title":"Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice","volume":"334","author":"Goodnow","year":"1988","journal-title":"Nature"},{"key":"2025030417504123000_r3","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1038\/337562a0","article-title":"Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody genes","volume":"337","author":"Nemazee","year":"1989","journal-title":"Nature"},{"key":"2025030417504123000_r4","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1038\/349331a0","article-title":"Expression of anti-DNA immunoglobulin transgenes in non-autoimmune mice","volume":"349","author":"Erikson","year":"1991","journal-title":"Nature"},{"key":"2025030417504123000_r5","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1038\/353765a0","article-title":"Elimination from peripheral lymphoid tissues of self-reactive B lymphocytes recognizing membrane-bound antigens","volume":"353","author":"Hartley","year":"1991","journal-title":"Nature"},{"key":"2025030417504123000_r6","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1084\/jem.177.4.999","article-title":"Receptor editing: an approach by autoreactive B cells to escape tolerance","volume":"177","author":"Gay","year":"1993","journal-title":"J. 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