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In this study, we aimed to explore the physiologic target of CCP\u2010Ab1 and the role of molecular evolution, through affinity maturation, of this ACPA in the onset and the exacerbation of RA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The target protein of CCP\u2010Ab1 was identified in the plasma of a patient with RA and purified under native conditions. Germline\u2010reverted (GL\u2010rev) CCP\u2010Ab1 was generated, and its reactivity was compared to that of mature CCP\u2010Ab1. The functions of CCP\u2010Ab1 and GL\u2010rev CCP\u2010Ab1 in the onset or exacerbation of autoimmune arthritis were analyzed using autoimmune arthritis\u2013prone SKG mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CCP\u2010Ab1 bound citrullinated fibrinogen under native conditions. In cultures with GL\u2010rev CCP\u2010Ab1, the binding affinity to citrullinated fibrinogen was drastically reduced (<jats:italic>P<\/jats:italic> &lt; 0.05). The elements implicated in GL\u2010rev CCP\u2010Ab1 binding to a citrullinated peptide, cfc1\u2010cyc, were almost identical to those implicated in CCP\u2010Ab1 binding. In arthritis\u2010prone SKG mice, CCP\u2010Ab1, but not GL\u2010rev CCP\u2010Ab1, induced significant exacerbation of experimental arthritis (<jats:italic>P<\/jats:italic> &lt; 0.05). Increased production of interleukin\u20106, both in the joint tissue and in the serum, was observed in SKG mice treated with CCP\u2010Ab1 compared to those treated with GL\u2010rev CCP\u2010Ab1 (<jats:italic>P<\/jats:italic> &lt; 0.05). Furthermore, the immune complex formed by CCP\u2010Ab1 and fibrinogen was detected at higher concentrations in the synovial tissue of SKG mice administered CCP\u2010Ab1 (<jats:italic>P<\/jats:italic> &lt; 0.05 versus control treatment groups).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These data show that germline\u2010encoded CCP\u2010Ab1, which binds weakly to citrullinated fibrinogen, undergoes hypermutation through the activation of naive B cells by citrullinated peptides\/proteins, thereby stimulating high reactivity to citrullinated fibrinogen. These findings deepen our understanding of the role of molecular evolution of ACPAs in the onset and exacerbation of RA.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41426","type":"journal-article","created":{"date-parts":[[2020,7,4]],"date-time":"2020-07-04T09:35:20Z","timestamp":1593855320000},"page":"2040-2049","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Physiologic Target, Molecular Evolution, and Pathogenic Functions of a Monoclonal Anti\u2013Citrullinated Protein Antibody Obtained From a Patient With Rheumatoid Arthritis"],"prefix":"10.1002","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3112-452X","authenticated-orcid":false,"given":"Tatsuhiko","family":"Ozawa","sequence":"first","affiliation":[{"name":"University of Toyama Faculty of Medicine Academic Assembly  Toyama 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