{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T15:53:29Z","timestamp":1787932409577,"version":"build-2784847793"},"reference-count":20,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2020,4,7]],"date-time":"2020-04-07T00:00:00Z","timestamp":1586217600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01 AR069569"],"award-info":[{"award-number":["R01 AR069569"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis & Rheumatology"],"published-print":{"date-parts":[[2020,6]]},"abstract":"Objective<\/jats:title>To address the independent roles of peptidylarginine deiminase type 2 (PAD<\/jats:styled-content>2) and PAD<\/jats:styled-content>4 in generating rheumatoid arthritis (RA<\/jats:styled-content>) autoantigens by using a system that mimics intracellular citrullination in the RA<\/jats:styled-content> joint.<\/jats:p><\/jats:sec>Methods<\/jats:title>PAD<\/jats:styled-content>2\u2010 or PAD<\/jats:styled-content>4\u2010expressing 293T cells and mock\u2010transfected cells were used as targets in cytotoxic assays using lymphokine\u2010activated killer cells, cytotoxic YT<\/jats:styled-content> cell granule contents, or purified human perforin. Protein citrullination and autoantigen production were determined by immunoblotting using the anti\u2013modified citrulline\u2013Senshu method and RA<\/jats:styled-content> sera (n = 30), respectively.<\/jats:p><\/jats:sec>Results<\/jats:title>RA<\/jats:styled-content> sera recognized at least 3 categories of autoantigens in PAD<\/jats:styled-content>\u2010expressing target cells killed by the cytotoxic lymphocyte granule\u2013induced death pathway. These included: 1) autoantigens targeted in their native form, 2) citrullinated antigens, and 3) antigens cleaved by cytotoxic proteases (e.g., granzymes). Interestingly, although target cells expressing PAD<\/jats:styled-content>2 or PAD<\/jats:styled-content>4 showed prominent hypercitrullination of a broad range of proteins during cytotoxic granule\u2013induced cell damage, autoantibodies in RA<\/jats:styled-content> sera targeted only a very limited number of antigens in hypercitrullinated cells. Furthermore, RA<\/jats:styled-content> sera showed distinct reactivities to autoantigens generated by PAD<\/jats:styled-content>2 or PAD<\/jats:styled-content>4.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>The cytotoxic granule\u2013induced death pathway has the capacity to modify antigens by inducing hypercitrullination and antigen cleavage in target cells. Interestingly, among a large number of citrullinated proteins generated by PAD<\/jats:styled-content>2 and PAD<\/jats:styled-content>4 in cells, only a few are likely involved in the production of autoantibodies in RA<\/jats:styled-content>.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41196","type":"journal-article","created":{"date-parts":[[2019,12,26]],"date-time":"2019-12-26T00:19:25Z","timestamp":1577319565000},"page":"912-918","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Generation of Distinct Patterns of Rheumatoid Arthritis Autoantigens by Peptidylarginine Deiminase Types 2 and 4 During Perforin\u2010Induced Cell Damage"],"prefix":"10.1002","volume":"72","author":[{"given":"Violeta","family":"Romero","sequence":"first","affiliation":[{"name":"The Johns Hopkins University School of Medicine Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1119-0279","authenticated-orcid":false,"given":"Erika","family":"Darrah","sequence":"additional","affiliation":[{"name":"The Johns Hopkins University School of Medicine Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3415-0704","authenticated-orcid":false,"given":"Felipe","family":"Andrade","sequence":"additional","affiliation":[{"name":"The Johns Hopkins University School of Medicine Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,4,7]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0000000000000452"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.22983"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2011.151712"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbapap.2014.02.019"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.40035"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0203214"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3006869"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaj1921"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.39313"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-016-1000-7"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01200"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80550-6"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/1523-1747.ep12317070"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2008.165"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.190.6.815"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2008.08.014"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.RA118.000696"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.40699"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M208795200"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.6b00617"}],"container-title":["Arthritis & Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fart.41196","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.41196","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/art.41196","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.41196","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T16:41:09Z","timestamp":1759941669000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/art.41196"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,7]]},"references-count":20,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2020,6]]}},"alternative-id":["10.1002\/art.41196"],"URL":"https:\/\/doi.org\/10.1002\/art.41196","archive":["Portico"],"relation":{},"ISSN":["2326-5191","2326-5205"],"issn-type":[{"value":"2326-5191","type":"print"},{"value":"2326-5205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,7]]},"assertion":[{"value":"2019-05-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-12-19","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-04-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}