{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T08:10:11Z","timestamp":1756800611305,"version":"3.44.0"},"reference-count":20,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T00:00:00Z","timestamp":1756771200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To identify new autoantibodies in rheumatoid arthritis (RA) patients\u2019 sera.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We tested serum samples from 55 patients with RA and 25 controls on arrays containing 188 peptides from the alpha and beta chains of fibrinogen, vimentin, histon 4, enolase, proteoglycan, filaggrin, collagen, and human peptidyl arginine deiminase 4 (hPAD4). To confirm the validity of our peptide array detection, we tested serum samples from 50 patients with RA and 42 controls on purified peptides by luminescent enzyme-linked immunosorbent assay (ELISA).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found citrullinated peptides from hPAD4 that were recognized almost uniquely by sera from patients with RA on peptide arrays and ELISA. Peptide P22\/60 from hPAD4 is a better RA diagnostic tool than the major classical citrullinated B-cell epitopes from histon 4, proteoglycan, alpha fibrinogen, and enolase.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We identified citrullinated peptides from hPAD4 as RA-specific autoantigens.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1640291","type":"journal-article","created":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T07:55:11Z","timestamp":1756799711000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Citrullinated peptides of peptidyl arginine deiminase 4 as major B-cell epitopes in patients with rheumatoid arthritis"],"prefix":"10.3389","volume":"16","author":[{"given":"Mathilde","family":"Giassi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Toussirot","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathalie C.","family":"Lambert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean","family":"Roudier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabelle","family":"Auger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27584","article-title":"Rheumatoid arthritis classification criteria: An American College of Rheumatology\/ European League Against Rheumatism collaborative initiative","volume":"62","author":"Aletaha","year":"2010","journal-title":"Arthritis Rheumatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/art.20044","article-title":"Autoantibodies to cyclic citrullinated peptides predict progression to rheumatoid arthritis in patients with undifferentiated arthritis: a prospective cohort study","volume":"50","author":"van Gaalen","year":"2004","journal-title":"Arthritis Rheumatol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2007.080267","article-title":"Serum IgG antibodies to peptidylarginine deiminase 4 in rheumatoid arthritis and associations with disease severity","volume":"67","author":"Halvorsen","year":"2008","journal-title":"Ann Rheumatol Dis"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2008.096917","article-title":"New autoantigens in rheumatoid arthritis (RA): screening 8268 protein arrays with sera from patients with RA","volume":"68","author":"Auger","year":"2009","journal-title":"Ann Rheumatol Dis"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/art.27570","article-title":"Autoimmunity to peptidyl arginine deiminase type 4 precedes clinical onset of rheumatoid arthritis","volume":"62","author":"Kolfenbach","year":"2010","journal-title":"Arthritis Rheumatol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1007\/s00296-010-1765-y","article-title":"Anti-PAD4 autoantibodies in rheumatoid arthritis: levels in serum over time and impact on PAD4 activity as measured with a small synthetic substrate","volume":"32","author":"Pollmann","year":"2012","journal-title":"Rheumatol Int"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1002\/art.41189","article-title":"Peptidyl arginine deiminase autoimmunity and the development of ACPA in rheumatoid arthritis, the hapten carrier model","volume":"72","author":"Auger","year":"2020","journal-title":"Arthritis Rheumatol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2012.121","article-title":"Spondyloarthritis: CASPAR criteria in early psoriatic arthritis","volume":"8","author":"Chandran","year":"2012","journal-title":"Nat Rev Rheumatol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200535790","article-title":"Epitopes of human fibrin recognized by the rheumatoid arthritis-specific autoantibodies to citrullinated proteins","volume":"36","author":"Sebbag","year":"2006","journal-title":"Eur J Immunol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1e0165501","DOI":"10.1371\/journal.pone.0165501","article-title":"Characterization of autoantigens targeted by anti-citrullinated protein antibodies in vivo: prominent role for epitopes derived from histone 4 proteins","volume":"11","author":"Meng","year":"2016","journal-title":"PloS One"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1186\/ar1845","article-title":"Identification of citrullinated alpha-enolase as a candidate autoantigen in rheumatoid arthritis","volume":"7","author":"Kinloch","year":"2005","journal-title":"Arthritis Res Ther"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0160284","article-title":"Immune recognition of citrullinated proteoglycan aggrecan epitopes in mice with proteoglycan-induced arthritis and in patients with rheumatoid arthritis","volume":"11","author":"Markovics","year":"2016","journal-title":"PLoS One"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1002\/art.10472","article-title":"Epitope-specific recognition of type II collagen by rheumatoid arthritis antibodies is shared with recognition by antibodies that are arthritogenic in collagen-induced arthritis in the mouse","volume":"46","author":"Burkhardt","year":"2002","journal-title":"Arthritis Rheumatol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0144707","article-title":"Contribution of peptide backbone to anti-citrullinated peptide antibody reactivity","volume":"10","author":"Trier","year":"2015","journal-title":"PLoS One"},{"key":"B15","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/s41467-020-20279-w","article-title":"Site-specific incorporation of citrulline into proteins in mammalian cells","volume":"12","author":"Mondal","year":"2021","journal-title":"Nat Commun"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1713112114","article-title":"Peptidyl arginine deiminase immunization induces anti-citrullinated protein antibodies in mice with particular MHC types","volume":"114","author":"Arnoux","year":"2017","journal-title":"Proc Natl Acad Sci USA"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.840035","article-title":"PAD4 immunization triggers anti-citrullinated peptide antibodies in normal mice: analysis with peptide arrays","volume":"13","author":"Hemon","year":"2022","journal-title":"Front Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1002\/eji.202249889","article-title":"PAD2 immunization induces ACPA in wild type and HLA-DR4 humanized mice","volume":"52","author":"Hemon","year":"2022","journal-title":"Eur J Immunol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.930112","article-title":"How RA associated HLA-DR molecules contribute to the development of antibodies to citrullinated proteins: the hapten carrier model","volume":"13","author":"Roudier","year":"2022","journal-title":"Front Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1002\/art.43295","article-title":"A tolerogenic plasmid inhibits autoantibody production triggered by immunization with human peptidyl arginine deiminase 4","author":"Pagni","year":"2025","journal-title":"Arthritis Rheum"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1640291\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T07:55:12Z","timestamp":1756799712000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1640291\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,2]]},"references-count":20,"alternative-id":["10.3389\/fimmu.2025.1640291"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1640291","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,2]]},"article-number":"1640291"}}