{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T08:42:52Z","timestamp":1790066572681,"version":"4.0.1"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2013,6,1]],"date-time":"2013-06-01T00:00:00Z","timestamp":1370044800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,6,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Effective central tolerance is required to control the large extent of autoreactivity normally present in the developing B cell repertoire. Insulin-reactive B cells are required for type 1 diabetes in the NOD mouse, because engineered mice lacking this population are protected from disease. The Cg-Tg(Igh-6\/Igh-V125)2Jwt\/JwtJ (VH125Tg) model is used to define this population, which is found with increased frequency in the periphery of NOD mice versus nonautoimmune C57BL\/6 VH125Tg mice; however, the ontogeny of this disparity is unknown. To better understand the origins of these pernicious B cells, anti-insulin B cells were tracked during development in the polyclonal repertoire of VH125Tg mice. An increased proportion of insulin-binding B cells is apparent in NOD mice at the earliest point of Ag commitment in the bone marrow. Two predominant L chains were identified in B cells that bind heterologous insulin. Interestingly, V\u03ba4-57-1 polymorphisms that confer a CDR3 Pro-Pro motif enhance self-reactivity in VH125Tg\/NOD mice. Despite binding circulating autoantigen in vivo, anti-insulin B cells transition from the parenchyma to the sinusoids in the bone marrow of NOD mice and enter the periphery unimpeded. Anti-insulin B cells expand at the site of autoimmune attack in the pancreas and correlate with increased numbers of IFN-\u03b3\u2013producing cells in the repertoire. These data identify the failure to cull autoreactive B cells in the bone marrow as the primary source of anti-insulin B cells in NOD mice and suggest that dysregulation of central tolerance permits their escape into the periphery to promote disease.<\/jats:p>","DOI":"10.4049\/jimmunol.1201359","type":"journal-article","created":{"date-parts":[[2013,5,16]],"date-time":"2013-05-16T04:23:15Z","timestamp":1368678195000},"page":"5992-6003","source":"Crossref","is-referenced-by-count":34,"title":["B Lymphocyte \u201cOriginal Sin\u201d in the Bone Marrow Enhances Islet Autoreactivity in Type 1 Diabetes\u2013Prone Nonobese Diabetic Mice"],"prefix":"10.1093","volume":"190","author":[{"given":"Rachel A","family":"Henry-Bonami","sequence":"first","affiliation":[{"name":"Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University , Nashville TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan M","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology, Vanderbilt University , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amita B","family":"Rachakonda","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University , Nashville TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariam","family":"Karamali","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University , Nashville TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peggy L","family":"Kendall","sequence":"additional","affiliation":[{"name":"Division of Allergy, Pulmonary, and Critical Care, Department of Medicine, Vanderbilt University , Nashville TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James W","family":"Thomas","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University , Nashville TN 37232"},{"name":"Department of Pathology, Microbiology and Immunology, Vanderbilt University , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,6,15]]},"reference":[{"key":"2025032407050935800_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":"2025032407050935800_r2","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1084\/jem.20042251","article-title":"Defective B cell tolerance checkpoints in systemic lupus erythematosus","volume":"201","author":"Yurasov","year":"2005","journal-title":"J. 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