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Immunol."],"abstract":"<jats:p>Autoimmune diseases are characterized by a loss of immune system tolerance to self-antigens, which can trigger an immune response capable of affecting various organs and tissues. An increase in the prevalence of these diseases has been reported in recent years. Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disorder characterized by persistent synovial inflammation. While it predominantly targets small and medium-sized joints, its pathogenesis frequently extends to diverse extra-articular manifestations. In line with other autoimmune diseases, the presence of neoantigens derived from post-translational modifications represents a critical checkpoint in RA pathogenesis, driving the loss of self-tolerance and the subsequent perpetuation of the autoreactive immune response. The primary therapeutic goal in RA is to achieve clinical remission or, alternatively, to maintain low disease activity. Therapeutic strategies designed to reach these targets are currently available in clinical practice. However, most of these agents act systemically, potentially leading to significant adverse effects. This review article explores the molecular landscape of post-translational modifications and analyzes how these chemical alterations generate neoantigens, which contribute to the pathogenesis of RA. Furthermore, the identification of these specific molecular signatures offers a pathway toward precision medicine, moving beyond conventional treatments to targeted therapies that could potentially restore tolerance, improving patient quality of life and clinical outcomes.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1876035","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T09:22:02Z","timestamp":1787217722000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular basis of post-translational neoantigen generation in rheumatoid arthritis: breaking immunological tolerance and implications for targeted therapy"],"prefix":"10.3389","volume":"17","author":[{"given":"Alba","family":"P\u00e9rez Linaza","sequence":"first","affiliation":[{"name":"Rheumatology Service, Puerta del Mar University Hospital","place":["C\u00e1diz, Spain"]},{"name":"Biomedical Research and Innovation Institute of Cadiz (INiBICA), Research Unit, Puerta del Mar University Hospital","place":["C\u00e1diz, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sussel","family":"Picallo D\u00edaz","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Biotechnology and Public Health, School of Medicine, University of C\u00e1diz","place":["C\u00e1diz, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel Serrano","family":"Garc\u00eda","sequence":"additional","affiliation":[{"name":"Rheumatology Service, Puerta del Mar University Hospital","place":["C\u00e1diz, Spain"]},{"name":"Biomedical Research and Innovation Institute of Cadiz (INiBICA), Research Unit, Puerta del Mar University Hospital","place":["C\u00e1diz, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjie","family":"Yi","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Biotechnology and Public Health, School of Medicine, University of C\u00e1diz","place":["C\u00e1diz, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1lvaro","family":"Guerrero Lores","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Biotechnology and Public Health, School of Medicine, University of C\u00e1diz","place":["C\u00e1diz, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Manuel","family":"Arag\u00f3n Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Cardiology Service, Virgen del Roc\u00edo University Hospital","place":["Seville, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Garcia-Cozar","sequence":"additional","affiliation":[{"name":"Biomedical Research and Innovation Institute of Cadiz (INiBICA), Research Unit, Puerta del Mar University Hospital","place":["C\u00e1diz, Spain"]},{"name":"Department of Biomedicine, Biotechnology and Public Health, School of Medicine, University of C\u00e1diz","place":["C\u00e1diz, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Fernandez-Ponce","sequence":"additional","affiliation":[{"name":"Biomedical Research and Innovation Institute of Cadiz (INiBICA), Research Unit, Puerta del Mar University Hospital","place":["C\u00e1diz, Spain"]},{"name":"Department of Biomedicine, Biotechnology and Public Health, School of Medicine, University of C\u00e1diz","place":["C\u00e1diz, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Fernandez-Cisnal","sequence":"additional","affiliation":[{"name":"Biomedical Research and Innovation Institute of Cadiz (INiBICA), Research Unit, Puerta del Mar University Hospital","place":["C\u00e1diz, Spain"]},{"name":"Department of Biomedicine, Biotechnology and Public Health, School of Medicine, University of C\u00e1diz","place":["C\u00e1diz, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2009.05.005","article-title":"Infections and autoimmunity - 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