{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T15:48:50Z","timestamp":1792597730980,"version":"4.5.0"},"reference-count":44,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2017,7,5]],"date-time":"2017-07-05T00:00:00Z","timestamp":1499212800000},"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","award":["R01\u2010AR\u2010057172"],"award-info":[{"award-number":["R01\u2010AR\u2010057172"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007820","name":"Alliance for Lupus Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007820","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2017,8]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>We have previously established that the gene for neutrophil cytosolic factor 2 (NCF\u20102) predisposes to lupus, and we have identified lupus patients with point mutations that are predicted to cause reduced NADPH oxidase activity. We undertook this study to investigate the relationship between reduced leukocyte NADPH oxidase activity and immune dysregulation associated with systemic lupus erythematosus (SLE).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We generated NCF\u20102\u2013null mice, in which NADPH oxidase activity is absent, on the nonautoimmune C57BL\/6 (B6) mouse background and on the NZM 2328 mouse background, a polygenic model in which mice spontaneously develop lupus. Clinical disease, serology, and immunopathology were evaluated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>NCF\u20102\u2013null mice on the B6 background were susceptible to <jats:italic>Aspergillus fumigatus<\/jats:italic> pneumonia characteristic of chronic granulomatous disease, but did not develop systemic lupus disease. In contrast, NCF\u20102\u2013null and even NCF\u20102\u2013haploinsufficient mice on the NZM 2328 background developed accelerated full\u2010blown lupus with significantly accelerated lupus kidney disease. This was characterized by more rapid development of hyperactive B cell and T cell immune compartments, increased expression of type I interferon\u2013responsive genes, and generation of neutrophil extracellular traps, which were observed even in the absence of NADPH oxidase activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Just as patients with chronic granulomatous disease who lack NADPH oxidase rarely develop SLE, NCF\u20102\u2013null mice on a nonautoimmune background were susceptible to a chronic granulomatous disease\u2013like opportunistic infection but did not develop lupus. In contrast, on a lupus\u2010prone background, even haploinsufficiency of NCF\u20102 accelerated the development of full\u2010blown lupus disease. This establishes an interaction between reduced oxidase activity and other lupus\u2010predisposing genes, paralleling human SLE\u2013associated variants predicted to have only reduced NADPH oxidase activity.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40141","type":"journal-article","created":{"date-parts":[[2017,5,4]],"date-time":"2017-05-04T11:43:38Z","timestamp":1493898218000},"page":"1647-1660","source":"Crossref","is-referenced-by-count":58,"title":["Haploinsufficiency of NADPH Oxidase Subunit Neutrophil Cytosolic Factor 2 Is Sufficient to Accelerate Full\u2010Blown Lupus in NZM 2328 Mice"],"prefix":"10.1002","volume":"69","author":[{"given":"Chaim O.","family":"Jacob","sequence":"first","affiliation":[{"name":"University of Southern California School of Medicine Los Angeles"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Yu","sequence":"additional","affiliation":[{"name":"University of Southern California School of Medicine Los Angeles"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dae\u2010Goon","family":"Yoo","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine in St. Louis St. Louis Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lizet J.","family":"Perez\u2010Zapata","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine in St. Louis St. Louis Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilia Alina","family":"Barbu","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine in St. Louis St. Louis Missouri"}],"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 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