{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T08:20:22Z","timestamp":1793089222843,"version":"4.5.0"},"reference-count":55,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T00:00:00Z","timestamp":1736208000000},"content-version":"vor","delay-in-days":586,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Islet autoantibodies, including those directed at insulin, predict type 1 diabetes (T1D) in mice and humans and signal immune tolerance breach by B lymphocytes. High-affinity insulin autoantibodies and T follicular helper cell involvement implicate germinal centers (GCs) in T1D. The VH125SD BCR transgenic model, in which 1\u20132% of peripheral B lymphocytes recognize insulin, enables direct study of insulin-binding B cells. Our prior studies showed that anti-insulin B cell receptor transgene site-directed to H chain locus mice fail to generate insulin Ab following T-dependent immunization, but it was unclear whether anti-insulin B cells were blocked for GC initiation, survival, or differentiation into Ab-secreting cells. Here, we show that insulin-binding B cells in T1D-prone anti-insulin B cell receptor transgene site-directed to H chain locus mice can spontaneously adopt a GC phenotype and undergo class switching to the IgG1 isotype, with little if any switching to IgG2b. T-dependent immunizations with insulin SRBC or insulin CFA drove anti-insulin B lymphocytes to adopt a GC phenotype, despite blunted insulin Ab production. Dual immunization against self (insulin) and foreign (4-hydroxy-3-nitrophenylacetyl hapten conjugated to keyhole limpet hemocyanin) Ags showed an anti-insulin (but not anti-4-hydroxy-3-nitrophenylacetyl) Ab block that tracked with increased expression of the apoptosis marker, activated caspase 3, in self-reactive GC B cells. Finally, T-independent immunization with insulin conjugated to Brucella abortus ring test Ag released immune tolerance to allow robust expansion of anti-insulin GC B cells and IgG-switched insulin Ab production. Overall, these data pinpoint GC survival and Ab-secreting cell differentiation as immune tolerance blocks that limit T-dependent, but not T-independent, stimulation of anti-insulin B cell responses.<\/jats:p>","DOI":"10.4049\/immunohorizons.2300036","type":"journal-article","created":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T10:08:32Z","timestamp":1685614112000},"page":"384-397","source":"Crossref","is-referenced-by-count":6,"title":["Productive Germinal Center Responses Depend on the Nature of Stimuli Received by Anti-Insulin B Cells in Type 1 Diabetes\u2013Prone Mice"],"prefix":"10.1093","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8592-4015","authenticated-orcid":false,"given":"Dudley H","family":"McNitt","sequence":"first","affiliation":[{"name":"Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center , Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan A","family":"Joosse","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center , Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James W","family":"Thomas","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center , Nashville, TN"},{"name":"Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center , Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7575-6943","authenticated-orcid":false,"given":"Rachel H","family":"Bonami","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center , Nashville, TN"},{"name":"Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center , Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,6,1]]},"reference":[{"key":"2025010703555785700_r1","doi-asserted-by":"crossref","first-page":"2049","DOI":"10.1084\/jem.184.5.2049","article-title":"B lymphocytes are essential for the initiation of T cell-mediated autoimmune diabetes: analysis of a new \u201cspeed congenic\u201d stock of NOD.Ig mu null mice","volume":"184","author":"Serreze","year":"1996","journal-title":"J. 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