{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:59:40Z","timestamp":1791248380932,"version":"4.1.0"},"reference-count":63,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2014,5,3]],"date-time":"2014-05-03T00:00:00Z","timestamp":1399075200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Eur J Immunol"],"published-print":{"date-parts":[[2014,6]]},"abstract":"<jats:p>Extensive genome\u2010wide association studies have recently shed some light on the causes of chronic autoimmune diseases and have confirmed a central role of the adaptive immune system. Moreover, better diagnostics using disease\u2010associated autoantibodies have been developed, and treatment has improved through the development of biologicals with precise molecular targets. Here, we use rheumatoid arthritis (<jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content>) as a prototype for chronic autoimmune disease to propose that the pathogenesis of autoimmune diseases could be divided into three discrete stages. First, yet unknown environmental challenges seem to activate innate immunity thereby providing an adjuvant signal for the induction of adaptive immune responses that lead to the production of autoantibodies and determine the subsequent disease development. Second, a joint\u2010specific inflammatory reaction occurs. This inflammatory reaction might be clinically diagnosed as the earliest signs of the disease. Third, inflammation is converted to a chronic process leading to tissue destruction and remodeling. In this review, we discuss the stages involved in RA pathogenesis and the experimental approaches, mainly involving animal models that can be used to investigate each disease stage. Although we focus on RA, it is possible that a similar stepwise development of disease also occurs in other chronic autoimmune settings such as multiple sclerosis (MS), type 1 diabetes, and systemic lupus erythematosus.<\/jats:p>","DOI":"10.1002\/eji.201444486","type":"journal-article","created":{"date-parts":[[2014,4,15]],"date-time":"2014-04-15T18:20:47Z","timestamp":1397586047000},"page":"1593-1599","source":"Crossref","is-referenced-by-count":106,"title":["Autoimmune priming, tissue attack and chronic inflammation \u2014 <scp>T<\/scp>he three stages of rheumatoid arthritis"],"prefix":"10.1002","volume":"44","author":[{"given":"Rikard","family":"Holmdahl","sequence":"first","affiliation":[{"name":"Department of Medical Biochemistry and Biophysics Medical Inflammation Research, Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivianne","family":"Malmstr\u00f6m","sequence":"additional","affiliation":[{"name":"Rheumatology Unit Department of Medicine, Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"Burkhardt","sequence":"additional","affiliation":[{"name":"Division of Rheumatology University, Hospital Frankfurt, and Fraunhofer IME\u2010Project\u2010Group Translational Medicine and Pharmacology, Goethe University  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,5,3]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197804202981602"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780301102"},{"key":"e_1_2_9_4_1","first-page":"1","article-title":"Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis","author":"Sandor C.","year":"2012","journal-title":"Nat. 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