{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T14:59:54Z","timestamp":1772117994070,"version":"3.50.1"},"reference-count":44,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2020,6,26]],"date-time":"2020-06-26T00:00:00Z","timestamp":1593129600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["K23\u2010AR\u2010071473"],"award-info":[{"award-number":["K23\u2010AR\u2010071473"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01\u2010AR\u2010073208"],"award-info":[{"award-number":["R01\u2010AR\u2010073208"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["P30\u2010AR\u2010070254"],"award-info":[{"award-number":["P30\u2010AR\u2010070254"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006260","name":"Rheumatology Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006260","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001845","name":"Scleroderma Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001845","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis & Rheumatology"],"published-print":{"date-parts":[[2020,8]]},"abstract":"\n Objective<\/jats:title>\n \n Autoimmune responses to\n DNA<\/jats:styled-content>\n topoisomerase I (topo I) are found in a subset of scleroderma patients who are at high risk for interstitial lung disease (\n ILD<\/jats:styled-content>\n ) and mortality. Anti\u2013topo I antibodies (\n ATA<\/jats:styled-content>\n s) are associated with specific\n \n HLA<\/jats:styled-content>\n \u2013\n DRB<\/jats:styled-content>\n 1\n <\/jats:italic>\n alleles, and the frequency of\n HLA<\/jats:styled-content>\n \u2013\n DR<\/jats:styled-content>\n \u2013restricted topo I\u2013specific\n CD<\/jats:styled-content>\n 4+ T cells is associated with the presence, severity, and progression of\n ILD<\/jats:styled-content>\n . Although this strongly implicates the presentation of topo I peptides by\n HLA<\/jats:styled-content>\n \u2013\n DR<\/jats:styled-content>\n in scleroderma pathogenesis, the processing and presentation of topo I has not been studied.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We developed a natural antigen processing assay (\n NAPA<\/jats:styled-content>\n ) to identify putative\n CD<\/jats:styled-content>\n 4+ T cell epitopes of topo I presented by monocyte\u2010derived dendritic cells (mo\u2010DCs) from 6\u00a0\n ATA<\/jats:styled-content>\n \u2010positive patients with scleroderma. Mo\u2010DCs were pulsed with\u00a0topo I\u00a0protein,\n HLA<\/jats:styled-content>\n \u2013\n DR<\/jats:styled-content>\n \u2013peptide complexes were isolated, and eluted peptides were analyzed by mass spectrometry. We then examined the ability of these naturally presented peptides to induce\n CD<\/jats:styled-content>\n 4+ T cell activation in 11\n ATA<\/jats:styled-content>\n \u2010positive and 11\n ATA<\/jats:styled-content>\n \u2010negative scleroderma patients.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n We found that a common set of 10 topo I epitopes was presented by Mo\u2010DCs from scleroderma patients with diverse\n HLA<\/jats:styled-content>\n \u2013\n DR<\/jats:styled-content>\n variants. Sequence analysis revealed shared peptide\u2010binding motifs within the\n HLA<\/jats:styled-content>\n \u2013\n DR<\/jats:styled-content>\n \u03b2 chains of\n ATA<\/jats:styled-content>\n \u2010positive patients and a subset of topo I epitopes with distinct sets of anchor residues capable of binding to multiple different\n HLA<\/jats:styled-content>\n \u2013\n DR<\/jats:styled-content>\n variants. The\n NAPA<\/jats:styled-content>\n \u2010derived epitopes elicited robust\n CD<\/jats:styled-content>\n 4+ T cell responses in 73% of\n ATA<\/jats:styled-content>\n \u2010positive patients (8 of 11), and the number of epitopes recognized correlated with\n ILD<\/jats:styled-content>\n severity (\n P<\/jats:italic>\n = 0.025).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n These findings mechanistically implicate the presentation of a convergent set of topo I epitopes in the development of scleroderma.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/art.41248","type":"journal-article","created":{"date-parts":[[2020,3,12]],"date-time":"2020-03-12T05:52:41Z","timestamp":1583992361000},"page":"1375-1384","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Definition of Naturally Processed Peptides Reveals Convergent Presentation of Autoantigenic Topoisomerase I Epitopes in Scleroderma"],"prefix":"10.1002","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4749-870X","authenticated-orcid":false,"given":"Eleni","family":"Tiniakou","sequence":"first","affiliation":[{"name":"Johns Hopkins University School of Medicine Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Fava","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6461-8940","authenticated-orcid":false,"given":"Zsuzsanna H.","family":"McMahan","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tara","family":"Guhr","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert N.","family":"O'Meally","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ami A.","family":"Shah","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fredrick M.","family":"Wigley","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert N.","family":"Cole","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Boin","sequence":"additional","affiliation":[{"name":"University of California San 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