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A previous study delineated four SLE patient clusters based on autoantibody expression to common antigens. To further assess autoantibody diversity within these clusters, we surveyed serum autoantibody expression using a novel autoantigen discovery technology, the Antigenome Platform. This phage-based system assesses serum antibody interactions with large protein fragments (up to 250 amino acids) spanning approximately 90% of the human genome. Bound autoantibody targets were identified through next-generation sequencing and robust bioinformatics and statistical analysis. Our study revealed 88, 49, 10, and 24 autoantibodies that expand the characterization of four SLE clusters, including 24 autoantibodies that characterize a cluster of patients lacking common autoantibodies by conventional assays. Further, some autoantibodies identified have potential links to patient disease features. Although SLE is characterized by antinuclear antibody expression, a significant proportion of autoantigens (ranging from 28% to 54%) in each cluster localized to the cytoplasm, which suggests extensive autoreactivity beyond targets in the cell nucleus that formed the original basis of clustering. This study identifies new markers to aid in the clustering and understanding of SLE disease subtypes and provides a rationale for elucidating autoantibody expression in SLE beyond antinuclear antibodies.<\/jats:p>","DOI":"10.1093\/jimmun\/vkae025","type":"journal-article","created":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T20:19:59Z","timestamp":1743711599000},"page":"903-916","source":"Crossref","is-referenced-by-count":2,"title":["Characterization of autoantibody profiles in clusters of systemic lupus erythematosus using a novel autoantigen discovery technology"],"prefix":"10.1093","volume":"214","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5874-9514","authenticated-orcid":false,"given":"Europe B","family":"DiCillo","sequence":"first","affiliation":[{"name":"Department of Integrative Immunobiology, Duke University Medical Center , Durham, NC,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David 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