{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:27:23Z","timestamp":1787030843603,"version":"build-2736575974"},"reference-count":64,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2015,8,1]],"date-time":"2015-08-01T00:00:00Z","timestamp":1438387200000},"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":[[2015,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Autoreactive B lymphocytes that escape central tolerance and mature in the periphery are a liability for developing autoimmunity. IgG insulin autoantibodies that predict type 1 diabetes and complicate insulin therapies indicate that mechanisms for tolerance to insulin are flawed. To examine peripheral tolerance in anti-insulin B cells, we generated C57BL\/6 mice that harbor anti-insulin VDJH-125 site directed to the native IgH locus (VH125SD). Class switch\u2013competent anti-insulin B cells fail to produce IgG Abs following T cell\u2013dependent immunization of VH125SD mice with heterologous insulin, and they exhibit markedly impaired proliferation to anti-CD40 plus insulin in vitro. In contrast, costimulation with LPS plus insulin drives robust anti-insulin B cell proliferation. Furthermore, VH125SD mice produce both IgM and IgG2a anti-insulin Abs following immunization with insulin conjugated to type 1 T cell\u2013independent Brucella abortus ring test Ag (BRT). Anti-insulin B cells undergo clonal expansion in vivo and emerge as IgM+ and IgM\u2212 GL7+Fas+ germinal center (GC) B cells following immunization with insulin-BRT, but not BRT alone. Analysis of Ig\u03ba genes in VH125SD mice immunized with insulin-BRT reveals that anti-insulin V\u03ba from the preimmune repertoire is selected into GCs. These data demonstrate that class switch\u2013competent anti-insulin B cells remain functionally silent in T cell\u2013dependent immune responses, yet these B cells are vulnerable to reversal of anergy following combined BCR\/TLR engagement that promotes Ag-specific GC responses and Ab production. Environmental factors that lead to infection and inflammation could play a critical yet underappreciated role in driving loss of tolerance and promoting autoimmune disease.<\/jats:p>","DOI":"10.4049\/jimmunol.1403114","type":"journal-article","created":{"date-parts":[[2015,6,24]],"date-time":"2015-06-24T21:36:11Z","timestamp":1435181771000},"page":"853-864","source":"Crossref","is-referenced-by-count":23,"title":["Reversing Tolerance in Isotype Switch\u2013Competent Anti-Insulin B Lymphocytes"],"prefix":"10.1093","volume":"195","author":[{"given":"Jonathan M","family":"Williams","sequence":"first","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University , Nashville, TN 37232"},{"name":"Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel H","family":"Bonami","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chrys","family":"Hulbert","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James W","family":"Thomas","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University , Nashville, TN 37232"},{"name":"Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,8,1]]},"reference":[{"key":"2025030703584716700_r1","doi-asserted-by":"crossref","first-page":"a007146","DOI":"10.1101\/cshperspect.a007146","article-title":"Central B-cell tolerance: where selection begins","volume":"4","author":"Pelanda","year":"2012","journal-title":"Cold Spring Harb. 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