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Yet, the precise disease\u2010relevant autoantigens that are targeted by ACPAs remains a matter of debate. This study utilized patient\u2010derived monoclonal ACPAs, rather than serum autoantibody analysis, to characterize the multireactivity to different protein modifications and to reveal autoantibody subsets in patients with RA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Twelve human monoclonal ACPAs (positive by the second\u2010generation cyclic citrullinated peptide test) were generated from 6 RA patients, and a head\u2010to\u2010head comparison of their reactivities was performed. For profiling, we used a complementary DNA\u2013based protein array (Engine GmbH) and 3 peptide\u2010screening platforms with RA autoantigens (Thermo Fisher Scientific), citrullinated and carbamylated peptides (NimbleGen\/Roche), or histone\u2010derived peptides with different posttranslational modifications (JPT Histone Code), covering &gt;207,000 peptides (&gt;7,800 gene products).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The fine\u2010specificity profiles of the investigated ACPAs varied, but all of the monoclonal ACPAs displayed multireactivity to a large number of citrullinated peptides\/proteins, each characterized by specific binding properties. ACPA subsets could be defined by clone\u2010distinct consensus binding motifs (e.g., Cit\u2013Gly, Gly\u2013Cit, or Arg\u2013Cit\u2013Asp), with the most common ACPA recognition being that of a Gly in the +1 flanking position, but with additional amino acid preferences. For ACPA protein recognition, we observed a preference for citrullinated RNA\u2010binding proteins with high Arg\/Gly content. Six of the 12 ACPA clones also bound acetylated lysine (KAc) or homocitrulline peptide motifs, displaying a similar affinity or higher apparent affinity than that for citrullinated peptides.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>ACPAs and anti\u2013modified protein autoantibodies represent overlapping facets of RA autoimmunity and bind to a wide variety of modified proteins, extending well beyond the historically recognized set of RA autoantigens. So far, KAc reactivity has been detected only in the context of anti\u2013carbamylated and anti\u2013citrullinated peptide autoantibody responses, postulating the existence of hierarchies of autoreactivity in RA. Future investigations of ACPA fine specificities and functionality should take into consideration the presence of consensus Cit\/Carb\/KAc motifs and the multireactivity of these autoantibodies in patients with RA.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41385","type":"journal-article","created":{"date-parts":[[2020,6,5]],"date-time":"2020-06-05T09:42:23Z","timestamp":1591350143000},"page":"1643-1657","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":81,"title":["Different Hierarchies of Anti\u2013Modified Protein Autoantibody Reactivities in Rheumatoid Arthritis"],"prefix":"10.1002","volume":"72","author":[{"given":"Peter","family":"Sahlstr\u00f6m","sequence":"first","affiliation":[{"name":"Karolinska Institutet Karolinska University Hospital, Stockholm, Sweden, and Charit\u00e9 Universit\u00e4tsmedizin  Berlin 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