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Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Dysregulated complement activation, increased protein citrullination, and production of autoantibodies against citrullinated proteins are hallmarks of rheumatoid arthritis (RA). Citrullination is induced by immune cell-derived peptidyl-Arg deiminases (PADs), which are overactivated in the inflamed synovium. We characterized the effect of PAD2- and PAD4-induced citrullination on the ability of the plasma-derived serpin C1-inhibitor (C1-INH) to inhibit complement and contact system activation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Citrullination of the C1-INH was confirmed by ELISA and Western blotting using a biotinylated phenylglyoxal probe. C1-INH-mediated inhibition of complement activation was analyzed by C1-esterase activity assay. Downstream inhibition of complement was studied by C4b deposition on heat-aggregated IgGs by ELISA, using pooled normal human serum as a complement source. Inhibition of the contact system was investigated by chromogenic activity assays for factor XIIa, plasma kallikrein, and factor XIa. In addition, autoantibody reactivity to native and citrullinated C1-INH was measured by ELISA in 101 RA patient samples.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>C1-INH was efficiently citrullinated by PAD2 and PAD4. Citrullinated C1-INH was not able to bind the serine protease C1s and inhibit its activity. Citrullination of the C1-INH abrogated its ability to dissociate the C1-complex and thus inhibit complement activation. Consequently, citrullinated C1-INH had a decreased capacity to inhibit C4b deposition <jats:italic>via<\/jats:italic> the classical and lectin pathways. The inhibitory effect of C1-INH on the contact system components factor XIIa, plasma kallikrein, and factor XIa was also strongly reduced by citrullination. In RA patient samples, autoantibody binding to PAD2- and PAD4-citrullinated C1-INH was detected. Significantly more binding was observed in anti-citrullinated protein antibody (ACPA)-positive than in ACPA-negative samples.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Citrullination of the C1-INH by recombinant human PAD2 and PAD4 enzymes impaired its ability to inhibit the complement and contact systems <jats:italic>in vitro<\/jats:italic>. Citrullination seems to render C1-INH more immunogenic, and citrullinated C1-INH might thus be an additional target of the autoantibody response observed in RA patients.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1203506","type":"journal-article","created":{"date-parts":[[2023,6,24]],"date-time":"2023-06-24T05:12:25Z","timestamp":1687583545000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Citrullination of C1-inhibitor as a mechanism of impaired complement regulation in rheumatoid arthritis"],"prefix":"10.3389","volume":"14","author":[{"given":"Myriam","family":"Martin","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara C.","family":"Nilsson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Eikrem","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karin","family":"Fromell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carsten","family":"Scavenius","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leonie M.","family":"Vogt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ewa","family":"Bielecka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Potempa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan J.","family":"Enghild","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Nilsson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristina N.","family":"Ekdahl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meliha C.","family":"Kapetanovic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna M.","family":"Blom","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,6,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1080\/07853890701477546","article-title":"Rheumatoid arthritis and the complement system","volume":"39","author":"Okroj","year":"2007","journal-title":"Ann Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1097\/01.rhu.0000130687.75646.44","article-title":"Pathogenesis of rheumatoid arthritis","volume":"10","author":"Weissmann","year":"2004","journal-title":"J Clin Rheumatol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/art.11223","article-title":"Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis","volume":"48","author":"Rantapaa-Dahlqvist","year":"2003","journal-title":"Arthritis Rheum"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2017.04.009","article-title":"The 2010 ACR\/EULAR criteria are not sufficiently accurate in the early identification of autoantibody-negative rheumatoid arthritis: results from the Leiden-EAC and ESPOIR cohorts","volume":"47","author":"Boeters","year":"2017","journal-title":"Semin Arthritis Rheum"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kem193","article-title":"IgG, IgA, IgM antibodies to a viral citrullinated peptide in patients affected by rheumatoid arthritis, chronic arthritides and connective tissue disorders","volume":"46","author":"Anzilotti","year":"2007","journal-title":"Rheumatol (Oxford)"},{"key":"B6","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1038\/nri.2016.124","article-title":"The immunopathogenesis of seropositive rheumatoid arthritis: from triggering to targeting","volume":"17","author":"Malmstrom","year":"2017","journal-title":"Nat Rev Immunol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1016\/j.chembiol.2018.03.002","article-title":"The rheumatoid arthritis-associated citrullinome","volume":"25","author":"Tilvawala","year":"2018","journal-title":"Cell Chem Biol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1136\/rmdopen-2019-001085","article-title":"Recherche clinique en rhumatismes i. 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