{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:51:24Z","timestamp":1790743884500,"version":"4.1.0"},"reference-count":48,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2020,1,1]],"date-time":"2020-01-01T00:00:00Z","timestamp":1577836800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100001218","name":"Lupus Research Institute","doi-asserted-by":"publisher","award":["519414"],"award-info":[{"award-number":["519414"]}],"id":[{"id":"10.13039\/100001218","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2020,2]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Neutrophils are key immune cells participating in host defense through several mechanisms, including the formation of neutrophil extracellular traps (<jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content>s). This study was undertaken to investigate the role of neutrophils in juvenile dermatomyositis (<jats:styled-content style=\"fixed-case\">JDM<\/jats:styled-content>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Electron microscopy was used to identify neutrophils in tissue. <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content>s were also imaged using fluorescence microscopy and quantified using a myeloperoxidase\u2010<jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> enzyme\u2010linked immunosorbent assay (<jats:styled-content style=\"fixed-case\">ELISA<\/jats:styled-content>) in plasma obtained from healthy children (n = 20), disease controls (n = 29), <jats:styled-content style=\"fixed-case\">JDM<\/jats:styled-content> patients (n = 66), and <jats:styled-content style=\"fixed-case\">JDM<\/jats:styled-content> patients with history of calcifications (n = 20). Clinical data included disease activity scores and complement C4 levels. Levels of immune complexes (<jats:styled-content style=\"fixed-case\">IC<\/jats:styled-content>s) and calprotectin were analyzed using <jats:styled-content style=\"fixed-case\">ELISA<\/jats:styled-content>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Using electron microscopy, neutrophils were found to infiltrate affected muscle tissue, engulfing deposited calcium crystals. Uptake of the crystals led to neutrophil activation (<jats:italic>P<\/jats:italic> &lt; 0.01) and subsequent phosphatidylinositol 3\u2010kinase\u2013 and <jats:styled-content style=\"fixed-case\">NADPH<\/jats:styled-content> oxidase\u2013dependent but peptidylarginine deiminase 4\u2013independent formation of NETs, which contained mitochondrial <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> (<jats:italic>P<\/jats:italic> &lt; 0.05), as confirmed in vivo (<jats:italic>P<\/jats:italic> &lt; 0.001) and in vitro (<jats:italic>P<\/jats:italic> &lt; 0.01). Peripheral <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content> levels were associated with calcinosis (<jats:italic>P<\/jats:italic> = 0.01), <jats:styled-content style=\"fixed-case\">IC<\/jats:styled-content>s (<jats:italic>P<\/jats:italic> = 0.008), and interleukin\u20108 levels (<jats:italic>P<\/jats:italic> = 0.004). Children with <jats:styled-content style=\"fixed-case\">JDM<\/jats:styled-content> had impaired <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content> clearance (<jats:italic>P<\/jats:italic> = 0.01), associated with autoantibody profiles including melanoma differentiation\u2013associated protein 5 (<jats:italic>P<\/jats:italic> = 0.005), and depressed complement C4 levels (r = \u22120.72, <jats:italic>P<\/jats:italic> = 0.002). Furthermore, children with <jats:styled-content style=\"fixed-case\">JDM<\/jats:styled-content> showed evidence of neutrophil activation, with elevated levels of peroxidase activity (<jats:italic>P<\/jats:italic> = 0.02) and calprotectin (<jats:italic>P<\/jats:italic> &lt; 0.01), which were associated with disease activity (<jats:italic>P<\/jats:italic> = 0.007), and dyslipidemia (odds ratio 4.7, <jats:italic>P<\/jats:italic> &lt; 0.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We found novel mechanisms of both calcium crystal\u2013mediated neutrophil activation and cell death in <jats:styled-content style=\"fixed-case\">JDM<\/jats:styled-content> pathophysiology. Targeting this pathway may reduce the frequency and extent of calcinosis, as well as prevent long\u2010term development of comorbidities, including atherosclerosis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41078","type":"journal-article","created":{"date-parts":[[2019,8,12]],"date-time":"2019-08-12T05:44:46Z","timestamp":1565588686000},"page":"348-358","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":79,"title":["Neutrophil Extracellular Traps in Tissue and Periphery in Juvenile Dermatomyositis"],"prefix":"10.1002","volume":"72","author":[{"given":"Bhargavi","family":"Duvvuri","sequence":"first","affiliation":[{"name":"University of Washington  Seattle"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren M.","family":"Pachman","sequence":"additional","affiliation":[{"name":"Cure JM Center of Excellence, Ann &amp; Robert H. 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