{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T03:29:41Z","timestamp":1792553381896,"version":"4.5.0"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,2,10]],"date-time":"2023-02-10T00:00:00Z","timestamp":1675987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Autoimmune diseases vary in the magnitude and diversity of autoantibody profiles, and these differences may be a consequence of different types of breaks in tolerance. Here, we compared the disparate autoimmune diseases autoimmune polyendocrinopathy\u2013candidiasis\u2013ecto-dermal dystrophy (APECED), systemic lupus erythematosus (SLE), and Sjogren\u2019s syndrome (SjS) to gain insight into the etiology of breaks in tolerance triggering autoimmunity. APECED was chosen as a prototypical monogenic disease with organ-specific pathology while SjS and SLE represent polygenic autoimmunity with focal or systemic disease. Using protein microarrays for autoantibody profiling, we found that APECED patients develop a focused but highly reactive set of shared mostly anti-cytokine antibodies, while SLE patients develop broad and less expanded autoantibody repertoires against mostly intracellular autoantigens. SjS patients had few autoantibody specificities with the highest shared reactivities observed against Ro-52 and La. RNA-seq B-cell receptor analysis revealed that APECED samples have fewer, but highly expanded, clonotypes compared with SLE samples containing a diverse, but less clonally expanded, B-cell receptor repertoire. Based on these data, we propose a model whereby the presence of autoreactive T-cells in APECED allows T-dependent B-cell responses against autoantigens, while SLE is driven by breaks in peripheral B-cell tolerance and extrafollicular B-cell activation. These results highlight differences in the autoimmunity observed in several monogenic and polygenic disorders and may be generalizable to other autoimmune diseases.<\/jats:p>","DOI":"10.3389\/fimmu.2023.1106537","type":"journal-article","created":{"date-parts":[[2023,2,10]],"date-time":"2023-02-10T06:42:12Z","timestamp":1676011332000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Autoantibody repertoire characterization provides insight into the pathogenesis of monogenic and polygenic autoimmune diseases"],"prefix":"10.3389","volume":"14","author":[{"given":"Thomas","family":"Clarke","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satyendra","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinji L.","family":"Okitsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Schuette","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"An","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evgeni","family":"Tzvetkov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Jensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy B.","family":"Niewold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elise M. 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