{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T08:47:43Z","timestamp":1789634863937,"version":"4.0.0"},"reference-count":15,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2018,1,23]],"date-time":"2018-01-23T00:00:00Z","timestamp":1516665600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["ZIA\u2010AR\u2010041199"],"award-info":[{"award-number":["ZIA\u2010AR\u2010041199"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2018,3]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Aberrant neutrophil extracellular trap (<jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content>) formation has been implicated as a mechanism to induce autoreactivity in individuals at risk of autoimmune diseases. The objective of this study was to assess whether medications implicated in cases of drug\u2010induced autoimmunity (hydralazine and procainamide) and medications less commonly associated with drug\u2010induced autoimmunity (minocycline and clozapine) induce <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content> formation and\/or prevent <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content> degradation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Human neutrophils were incubated with the drugs of interest and resultant <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content> formation was quantified by fluorescent microscopy. The ability of these drugs to interfere with <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content> degradation by serum nuclei was assessed. Pathways of drug\u2010induced <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content> formation were studied with pharmacologic inhibitors of reactive oxygen species (<jats:styled-content style=\"fixed-case\">ROS<\/jats:styled-content>), peptidylarginine deiminases (<jats:styled-content style=\"fixed-case\">PAD<\/jats:styled-content>s), and muscarinic receptors, and by assessment of intracellular calcium levels by flow cytometry. To determine if <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content> protein cargo varies by drug stimulus and\/or neutrophil source, proteomic analysis of <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content> lysates induced by specific medications was compared using neutrophils from healthy donors and from patients with autoimmune diseases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Hydralazine and procainamide significantly induced <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content> formation while minocycline and clozapine did not. None of the medications significantly impaired <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content> degradation. <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content>osis induced by these drugs required <jats:styled-content style=\"fixed-case\">NADPH<\/jats:styled-content> oxidase and <jats:styled-content style=\"fixed-case\">PAD<\/jats:styled-content>4 activation. Procainamide triggered <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content>s via muscarinic receptor engagement on neutrophils, while hydralazine modulated calcium release from intracellular stores. Differences in protein cargo, particularly histone content, were observed in <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content>s induced by hydralazine and procainamide.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Medications commonly implicated in drug\u2010induced autoimmunity trigger <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content> formation displaying distinct protein cargo, via common and specific pathways. <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content>osis may play a role in the pathogenesis of drug\u2010induced autoimmunity.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40372","type":"journal-article","created":{"date-parts":[[2017,11,9]],"date-time":"2017-11-09T15:42:10Z","timestamp":1510242130000},"page":"468-474","source":"Crossref","is-referenced-by-count":44,"title":["Brief Report: Drugs Implicated in Systemic Autoimmunity Modulate Neutrophil Extracellular Trap Formation"],"prefix":"10.1002","volume":"70","author":[{"given":"Jorge A.","family":"Irizarry\u2010Caro","sequence":"first","affiliation":[{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases NIH Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmelo","family":"Carmona\u2010Rivera","sequence":"additional","affiliation":[{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases NIH Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniella M.","family":"Schwartz","sequence":"additional","affiliation":[{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases NIH Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sami S.","family":"Khaznadar","sequence":"additional","affiliation":[{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases NIH Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana J.","family":"Kaplan","sequence":"additional","affiliation":[{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases NIH Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8269-9438","authenticated-orcid":false,"given":"Peter C.","family":"Grayson","sequence":"additional","affiliation":[{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases NIH Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,1,23]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1422.019"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198806023182209"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0000000000000014"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1092385"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.5BT0615-247R"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.34619"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.89780"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780330807"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780400928"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0902199"},{"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":"10.1016\/j.febslet.2010.06.006"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.2011.92"},{"key":"e_1_2_7_15_1","doi-asserted-by":"crossref","first-page":"3251","DOI":"10.1016\/S0021-9258(17)40829-5","article-title":"Cardiac muscarinic cholinergic receptors: biochemical identification and characterization","volume":"253","author":"Fields JZ","year":"1978","journal-title":"J Biol Chem"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.140.7.2197"}],"container-title":["Arthritis &amp; 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