{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T06:58:49Z","timestamp":1785826729445,"version":"3.56.0"},"reference-count":40,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2021,5,2]],"date-time":"2021-05-02T00:00:00Z","timestamp":1619913600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82001704"],"award-info":[{"award-number":["82001704"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81671589"],"award-info":[{"award-number":["81671589"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81871272"],"award-info":[{"award-number":["81871272"]}],"id":[{"id":"10.13039\/501100001809","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":[[2021,6]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Adult\u2010onset Still\u2019s disease (AOSD) is a severe autoinflammatory disease. Neutrophil activation with enhanced neutrophil extracellular trap (NET) formation is involved in the pathogenesis of AOSD. Functional leukocyte immunoglobulin\u2010like receptor A3 (LIR\u2010A3; gene name <jats:italic>LILRA3<\/jats:italic>) has been reported to be associated with many autoimmune diseases. We aimed to investigate the association of <jats:italic>LILRA3<\/jats:italic> with disease susceptibility and neutrophil activation in AOSD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The <jats:italic>LILRA3<\/jats:italic> deletion polymorphism and its tagging single\u2010nucleotide polymorphism rs103294 were genotyped in 164 patients with AOSD and 305 healthy controls. The impact of <jats:italic>LILRA3<\/jats:italic> on clinical features and messenger RNA expression was evaluated. Plasma levels of LIR\u2010A3 were detected using enzyme\u2010linked immunosorbent assay (ELISA), and the correlation between LIR\u2010A3 plasma levels and disease activity and levels of circulating NET\u2010DNA was investigated. LIR\u2010A3\u2013induced NETs were determined using PicoGreen double\u2010stranded DNA dye and immunofluorescence analysis in human neutrophils and a neutrophil\u2010like differentiated NB4 cell line transfected with LIR\u2010B2 small interfering RNA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The findings from genotyping demonstrated that functional <jats:italic>LILRA3<\/jats:italic> was a risk factor for AOSD (11% in AOSD patients versus 5.6% in healthy controls; odds ratio 2.089 [95% confidence interval 1.030\u20134.291], <jats:italic>P<\/jats:italic>\u00a0=\u00a00.034), and associated with leukocytosis (<jats:italic>P<\/jats:italic> = 0.039) and increased levels of circulating neutrophils (<jats:italic>P<\/jats:italic> = 0.027). Functional <jats:italic>LILRA3<\/jats:italic> messenger RNA expression was higher in the peripheral blood mononuclear cells (<jats:italic>P &lt;<\/jats:italic> 0.0001) and neutrophils (<jats:italic>P<\/jats:italic> &lt; 0.001) of <jats:italic>LILRA3<\/jats:italic><jats:sup>+\/+<\/jats:sup> patients. Plasma levels of LIR\u2010A3 were elevated in patients with AOSD (<jats:italic>P<\/jats:italic> &lt; 0.0001) and correlated with disease activity indicators and levels of circulating NET\u2013DNA complexes. Finally, enhanced NET formation was identified in neutrophils from healthy controls and patients with inactive AOSD after stimulation of the neutrophils with LIR\u2010A3. Moreover, NET formation was impaired in NB4 cells after knockdown of <jats:italic>LILRB2<\/jats:italic> gene expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study provides the first evidence that functional <jats:italic>LILRA3<\/jats:italic> is a novel genetic risk factor for the development of AOSD and that functional LIR\u2010A3 may play a pathogenic role by inducing formation of NETs.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41635","type":"journal-article","created":{"date-parts":[[2020,12,31]],"date-time":"2020-12-31T03:21:27Z","timestamp":1609384887000},"page":"1033-1043","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Association of the Leukocyte Immunoglobulin\u2010like Receptor A3 Gene With Neutrophil Activation and Disease Susceptibility in Adult\u2010Onset Still\u2019s Disease"],"prefix":"10.1002","volume":"73","author":[{"given":"Mengyan","family":"Wang","sequence":"first","affiliation":[{"name":"Ruijin Hospital and Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengru","family":"Liu","sequence":"additional","affiliation":[{"name":"Ruijin Hospital and Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinchao","family":"Jia","sequence":"additional","affiliation":[{"name":"Ruijin Hospital and Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3574-8807","authenticated-orcid":false,"given":"Hui","family":"Shi","sequence":"additional","affiliation":[{"name":"Ruijin Hospital and Shanghai Jiao Tong University School of Medicine  Shanghai 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