{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T18:35:46Z","timestamp":1785868546890,"version":"3.56.0"},"reference-count":34,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T00:00:00Z","timestamp":1757894400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T00:00:00Z","timestamp":1757894400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001677","name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001677","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100031376","name":"Soci\u00e9t\u00e9 Fran\u00e7aise de Rhumatologie","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100031376","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":[[2026,1]]},"abstract":"\n Objective<\/jats:title>\n Rheumatoid arthritis (RA) is usually preceded and likely mediated by autoantibodies to citrullinated proteins (ACPAs) that recognize citrulline residues on multiple proteins. Conversion of arginine into citrulline is performed by enzymes called peptidyl arginine deiminases (PADs). We have previously demonstrated that the human PAD4 (hPAD4) is a T cell target whose recognition provides help for the production of ACPAs by a hapten\/carrier mechanism. Human PAD4 is thus an attractive therapeutic target to stop ACPA production. Here, we tested whether tolerization to hPAD4 may block the production of anti\u2010citrullinated peptide antibodies.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n We used a tolerogenic plasmid encoding hPAD4 and transforming growth factor (TGF) \u03b21, interleukin (IL) 10, and IL\u20102 in a model where C3H mice immunized with hPAD4 develop anti\u2010citrullinated peptide antibodies. As controls, we used a plasmid encoding TGF\u2010\u03b21, IL\u201010, IL\u20102, or a plasmid without hPAD4 or cytokines. T cell activation in hPAD4\u2010immunized mice injected with plasmids was analyzed by flow cytometry. Autoantibody profile was analyzed in hPAD4\u2010immunized mice before and after plasmid injection by peptide array using 33 arginine\u2010containing peptides and their 136 citrulline\u2010substituted variants.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n Injection of the plasmid encoding hPAD4 and TGF\u2010\u03b21, IL\u201010, and IL\u20102 in hPAD4\u2010immunized C3H mice significantly inhibited the T cell activation to hPAD4 and decreased antibody production to arginine and citrullinated peptides.<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Tolerizing to hPAD4 decreases the production of anti\u2010citrullinated peptide antibodies in mice immunized with hPAD4. This suggests that tolerization to hPAD4 may allow one to switch off ACPAs in RA.<\/jats:p>\n \n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/art.43295","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T00:58:12Z","timestamp":1750726692000},"page":"80-89","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A Tolerogenic Plasmid Inhibits Autoantibody Production Triggered by Immunization With Human Peptidyl Arginine Deiminase 4"],"prefix":"10.1002","volume":"78","author":[{"given":"Philippe P.","family":"Pagni","sequence":"first","affiliation":[{"name":"Novo Nordisk Research Center Seattle, Inc Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijetha","family":"Kumar","sequence":"additional","affiliation":[{"name":"Novo Nordisk Research Center Seattle, Inc Seattle 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