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Although traditionally viewed as primarily T-cell-driven, B cells play essential roles in disease pathogenesis. In addition to producing islet autoantibodies, B cells contribute to immune activation through antigen presentation and cytokine secretion, thereby shaping autoreactive T-cell responses. The earliest clinical predictor of T1D is the appearance of islet autoantibodies in the blood, reflecting a breach in B-cell tolerance well before symptomatic disease onset. In individuals at high genetic risk, type I interferon (IFN) signatures are detectable in peripheral blood prior to seroconversion, suggesting that type I IFNs may act as upstream regulators of B-cell tolerance. Peripheral tolerance is enforced through layered checkpoints including transitional selection, maintenance of anergy, germinal center regulation, and regulatory B-cell differentiation. Studies in systemic autoimmunity demonstrate that type I IFN signaling lowers B-cell activation thresholds, enhances BCR and TLR responsiveness, promotes survival of autoreactive transitional clones via BAFF induction, destabilizes anergy, and skews differentiation toward inflammatory phenotypes such as T-bet+ age-associated B cells. Consistent with this model, single-cell transcriptomic and BCR repertoire analyses in T1D reveal clonal expansion and proinflammatory signatures in islet-reactive B cells during the preclinical stage. Together, these findings implicate the IFN\u2013B-cell axis as a potential target for early disease modification.<\/jats:p>","DOI":"10.3390\/biom16040563","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T10:20:16Z","timestamp":1775816416000},"page":"563","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Type I Interferons as Contextual Regulators of B-Cell Tolerance in Type 1 Diabetes"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0903-3269","authenticated-orcid":false,"given":"Mebrahtu G.","family":"Tedla","sequence":"first","affiliation":[{"name":"Division of Pediatric Endocrinology, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA"},{"name":"Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6170-1156","authenticated-orcid":false,"given":"Jamie L.","family":"Felton","sequence":"additional","affiliation":[{"name":"Division of Pediatric Endocrinology, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA"},{"name":"Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA"},{"name":"Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1056\/NEJM198605223142106","article-title":"Type I diabetes mellitus. 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