{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T13:00:34Z","timestamp":1791291634720,"version":"4.1.0"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2014,2,1]],"date-time":"2014-02-01T00:00:00Z","timestamp":1391212800000},"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":[[2014,2,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Autoreactive B lymphocytes are essential for the development of T cell\u2013mediated type 1 diabetes (T1D). Cytoplasmic Bruton\u2019s tyrosine kinase (BTK) is a key component of B cell signaling, and its deletion in T1D-prone NOD mice significantly reduces diabetes. However, the role of BTK in the survival and function of autoreactive B cells is not clear. To evaluate the contributions of BTK, we used mice in which B cells express an anti-insulin BCR (125Tg) and promote T1D, despite being anergic. Crossing Btk deficiency onto 125Tg mice reveals that, in contrast to immature B cells, mature anti-insulin B cells are exquisitely dependent upon BTK, because their numbers are reduced by 95%. BTK kinase domain inhibition reproduces this effect in mature anti-insulin B cells, with less impact at transitional stages. The increased dependence of anti-insulin B cells on BTK became particularly evident in an Ig\u03ba locus site\u2013directed model, in which 50% of B cells edit their BCRs to noninsulin specificities; Btk deficiency preferentially depletes insulin binders from the follicular and marginal zone B cell subsets. The persistent few Btk-deficient anti-insulin B cells remain competent to internalize Ag and invade pancreatic islets. As such, loss of BTK does not significantly reduce diabetes incidence in 125Tg\/NOD mice as it does in NOD mice with a normal B cell repertoire. Thus, BTK targeting may not impair autoreactive anti-insulin B cell function, yet it may provide protection in an endogenous repertoire by decreasing the relative availability of mature autoreactive B cells.<\/jats:p>","DOI":"10.4049\/jimmunol.1300125","type":"journal-article","created":{"date-parts":[[2014,1,23]],"date-time":"2014-01-23T04:55:34Z","timestamp":1390452934000},"page":"1459-1470","source":"Crossref","is-referenced-by-count":26,"title":["Bruton\u2019s Tyrosine Kinase Promotes Persistence of Mature Anti-Insulin B Cells"],"prefix":"10.1093","volume":"192","author":[{"given":"Rachel H","family":"Bonami","sequence":"first","affiliation":[{"name":"Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University School of Medicine , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison M","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James B","family":"Case","sequence":"additional","affiliation":[{"name":"Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah E","family":"Steinberg","sequence":"additional","affiliation":[{"name":"Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen L","family":"Hoek","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wasif N","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Miller School of Medicine, University of Miami , Miami, FL 33136"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peggy L","family":"Kendall","sequence":"additional","affiliation":[{"name":"Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine , Nashville, TN 37232"},{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,2,15]]},"reference":[{"key":"2025032404131447600_r1","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1016\/j.immuni.2006.10.017","article-title":"Identification of anergic B cells within a wild-type repertoire","volume":"25","author":"Merrell","year":"2006","journal-title":"Immunity"},{"key":"2025032404131447600_r2","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1084\/jem.20080611","article-title":"Functional anergy in a subpopulation of naive B cells from healthy humans that express autoreactive immunoglobulin receptors","volume":"206","author":"Duty","year":"2009","journal-title":"J. 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