{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T19:23:37Z","timestamp":1791141817104,"version":"4.1.0"},"reference-count":39,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2014,5,27]],"date-time":"2014-05-27T00:00:00Z","timestamp":1401148800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2014,6]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Peptidylarginine deiminase 4 (PAD4) is a citrullinating enzyme that has multiple associations with inflammation. In rheumatoid arthritis, PAD4 and protein citrullination are increased in inflamed joints, and anti\u2013citrullinated protein antibodies (ACPAs) form against citrullinated antigens are formed. ACPA immune complexes can deposit in the joint and induce the production of tumor necrosis factor \u03b1 (TNF\u03b1), a critical inflammatory cytokine in the pathogenesis of rheumatoid arthritis. Further, in other settings, TNF\u03b1 has been shown to induce PAD4 activity and modulate antibody formation. We undertook this study to investigate whether TNF\u03b1 and PAD4 may synergistically exacerbate autoantibody production and inflammatory arthritis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To determine whether TNF\u03b1 and PAD4 augment autoantibody production and inflammatory arthritis, we first used a multiplex assay to determine whether mice with chronic inflammatory arthritis due to overexpression of TNF\u03b1 develop autoantibodies against native and citrullinated antigens. With TNF<jats:sup>+<\/jats:sup> PAD4<jats:sup>+\/+<\/jats:sup> and TNF<jats:sup>+<\/jats:sup>PAD4<jats:sup>\u2212\/\u2212<\/jats:sup> mice, we then compared serum autoantibody levels by multiplex array, lymphocyte activation by flow cytometry, total serum IgG levels by enzyme\u2010linked immunosorbent assay, arthritis by clinical and histologic scoring, and systemic inflammation using microfluidic devices.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>TNF\u03b1\u2010overexpressing mice had increased levels of autoantibodies reactive against native and citrullinated antigens. PAD4<jats:sup>\u2212\/\u2212<\/jats:sup> mice with TNF\u03b1\u2010induced arthritis had lower levels of autoantibodies reactive against native and citrullinated antigens, decreased T cell activation and total IgG levels, and reduced inflammation and arthritis compared to PAD4<jats:sup>+\/+<\/jats:sup> TNF\u03b1\u2010overexpressing mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>PAD4 mediates autoantibody production and inflammatory arthritis downstream of TNF\u03b1.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.38393","type":"journal-article","created":{"date-parts":[[2014,2,4]],"date-time":"2014-02-04T18:31:54Z","timestamp":1391538714000},"page":"1482-1491","source":"Crossref","is-referenced-by-count":56,"title":["Peptidylarginine Deiminase 4 Contributes to Tumor Necrosis Factor \u03b1\u2013Induced Inflammatory Arthritis"],"prefix":"10.1002","volume":"66","author":[{"given":"Miriam A.","family":"Shelef","sequence":"first","affiliation":[{"name":"University of Wisconsin\u2013Madison and William S. Middleton Memorial VA Hospital Madison, Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Sokolove","sequence":"additional","affiliation":[{"name":"Stanford University and VA Palo Alto Health Care System Palo Alto, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren J.","family":"Lahey","sequence":"additional","affiliation":[{"name":"Stanford University and VA Palo Alto Health Care System Palo Alto, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catriona A.","family":"Wagner","sequence":"additional","affiliation":[{"name":"Stanford University and VA Palo Alto Health Care System Palo Alto, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric K.","family":"Sackmann","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2013 Madison"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas F.","family":"Warner","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2013 Madison"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanming","family":"Wang","sequence":"additional","affiliation":[{"name":"Pennsylvania State University, University Park"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Beebe","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2013 Madison"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William H.","family":"Robinson","sequence":"additional","affiliation":[{"name":"Stanford University and VA Palo Alto Health Care System Palo Alto, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Huttenlocher","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2013 Madison"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,5,27]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar2498"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2011.06.006"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2011.01.014"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.21575"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mehy.2008.12.040"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keh414"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1001620"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.22983"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12016-012-8346-7"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20100239"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3005580"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar3829"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.167.3.1601"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/cb200258q"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2005.049403"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar3702"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.20316"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.3.1895"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0048111"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.15.7007"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar3542"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0035296"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.30081"},{"key":"e_1_2_7_25_1","first-page":"27","article-title":"Transgenic and knockout analyses of the role of TNF in immune regulation and disease pathogenesis","volume":"47","author":"Douni E","year":"1995","journal-title":"J Inflamm"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.2741\/E379"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1006\/abio.2000.4805"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-03-416453"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-003-0125-3"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2009.04753.x"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI1316"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.37839"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1201098"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2013.00067"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0061045"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12124"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00435.2010"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2010.51"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.20431"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kes304"}],"container-title":["Arthritis &amp; Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fart.38393","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.38393","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T16:32:05Z","timestamp":1759941125000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/art.38393"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,5,27]]},"references-count":39,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2014,6]]}},"alternative-id":["10.1002\/art.38393"],"URL":"https:\/\/doi.org\/10.1002\/art.38393","archive":["Portico"],"relation":{},"ISSN":["2326-5191","2326-5205"],"issn-type":[{"value":"2326-5191","type":"print"},{"value":"2326-5205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,5,27]]}}}