{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T09:26:05Z","timestamp":1793352365628,"version":"4.5.0"},"reference-count":52,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2023,6,30]],"date-time":"2023-06-30T00:00:00Z","timestamp":1688083200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["FRN 148948"],"award-info":[{"award-number":["FRN 148948"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Elevated levels of serum interferon\u2010\u03b1 (IFN\u03b1) and the disruption of B cell tolerance are central to systemic lupus erythematosus (SLE) immunopathogenesis; however, the relationship between these 2 processes remains unclear. The purpose of this study was to investigate the impact of elevated IFN\u03b1 levels on B cell tolerance mechanisms in vivo and determine whether any changes observed were due to the direct effect of IFN\u03b1 on B cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Two classical mouse models of B cell tolerance were used in conjunction with an adenoviral vector encoding IFN\u03b1 to mimic the sustained elevations of IFN\u03b1 seen in SLE. The role of B cell IFN\u03b1 signaling, T cells, and Myd88 signaling was determined using B cell\u2013specific IFN\u03b1 receptor\u2013knockout, CD4+ T cell\u2013depleted, or Myd88\u2010knockout mice, respectively. Flow cytometry, enzyme\u2010linked immunosorbent assay, real\u2010time quantitative polymerase chain reaction, and cell cultures were used to study the effects of elevated IFN\u03b1 on the immunologic phenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Elevation of serum IFN\u03b1 disrupts multiple B cell tolerance mechanisms and leads to autoantibody production. This disruption was dependent upon B cell expression of IFN\u03b1 receptor. Many of the IFN\u03b1\u2010mediated alterations also required the presence of CD4+ T cells as well as Myd88, suggesting that IFN\u03b1 acts directly on B cells to modify their response to Myd88 signaling and their ability to interact with T cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The results provide evidence that elevated IFN\u03b1 levels act directly on B cells to facilitate autoantibody production and further highlight the importance of IFN signaling as a potential therapeutic target in SLE.<\/jats:p><jats:p><jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art42482-toc-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42482","type":"journal-article","created":{"date-parts":[[2023,2,21]],"date-time":"2023-02-21T02:38:40Z","timestamp":1676947120000},"page":"1542-1555","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Elevated Levels of Interferon\u2010\u03b1 Act Directly on B Cells to Breach Multiple Tolerance Mechanisms Promoting Autoantibody Production"],"prefix":"10.1002","volume":"75","author":[{"given":"Dario M.","family":"Ferri","sequence":"first","affiliation":[{"name":"Schroeder Arthritis Institute Krembil Research Institute, University Health Network  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Nassar","sequence":"additional","affiliation":[{"name":"Schroeder Arthritis Institute Krembil Research 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