{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T02:26:05Z","timestamp":1784168765081,"version":"3.55.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,9]],"date-time":"2023-01-09T00:00:00Z","timestamp":1673222400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004391","name":"China Medical University Hospital","doi-asserted-by":"publisher","award":["DMR-111-200"],"award-info":[{"award-number":["DMR-111-200"]}],"id":[{"id":"10.13039\/501100004391","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 110-2314-B-039-051"],"award-info":[{"award-number":["MOST 110-2314-B-039-051"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Neutralizing anti-interferon (IFN)-\u03b3 autoantibodies are linked to opportunistic infections (OIs). To explore the association between anti-IFN-\u03b3 autoantibodies and OIs in patients with adult-onset Still's disease (AOSD), we aimed to examine the ability of these autoantibodies to blockade signal transducer and activator of transcription (STAT1)-phosphorylation and chemokines production.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Serum titers of anti-IFN-\u03b3 autoantibodies were quantified using ELISA in 29 AOSD and 22 healthy controls (HC). The detectable autoantibodies were verified with immunoblotting assay, and their neutralizing capacity against IFN-\u03b3-signaling was evaluated with flow-cytometry analysis and immunoblotting. IFN-\u03b3-mediated production of supernatant chemokines, including monocyte chemoattractant protein-1 (MCP-1) and IFN-\u03b3 inducible protein-10 (IP-10), were measured by ELISA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Among 29 AOSD patients, high titers of anti-IFN-\u03b3 neutralizing autoantibodies were detectable in two patients with OIs. Immunoblotting assay revealed more effective inhibition of STAT1-phosphorylation in THP-1 cells treated with sera from autoantibody-positive AOSD patients (56.7 \u00b1 34.79%) compared with those from HC (104.3 \u00b129.51%), which was also demonstrated in flow-cytometry analysis (47.13 \u00b1 40.99 vs. 97.92 \u00b1 9.48%, <jats:italic>p<\/jats:italic> &amp;lt; 0.05). Depleted serum IgG from anti-IFN-\u03b3 autoAbs-positive AOSD patients with OIs restored phosphorylated STAT-1 upon IFN-\u03b3 treatment. Sera from autoantibody-positive AOSD patients more effectively inhibited IFN-\u03b3-mediated production of MCP-1 (45.65 pg\/ml) and IP-10 (22.44 pg\/ml) than sera from HC (263.1 pg\/ml and 104.0 pg\/ml, both <jats:italic>p<\/jats:italic> &amp;lt; 0.05). Serum samples showing the strongest inhibition of IFN-\u03b3-signaling were from two patients with high-titer autoantibodies and OIs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>AOSD patients have a high positive rate and titers of anti-IFN-\u03b3 autoantibodies. The remarkable blockade effect of high-titer autoantibodies on IFN-\u03b3-mediated STAT1-phosphorylation and chemokines could make these patients susceptible to OIs.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmed.2022.1097514","type":"journal-article","created":{"date-parts":[[2023,1,9]],"date-time":"2023-01-09T12:17:46Z","timestamp":1673266666000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["High-titer anti-interferon-\u03b3 neutralizing autoantibodies linked to opportunistic infections in patients with adult-onset still's disease"],"prefix":"10.3389","volume":"9","author":[{"given":"Po-Ku","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsai-Ling","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Hsin","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai-Jieh","family":"Yeo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Hui","family":"Chou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Der-Yuan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,1,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/S0065-2776(07)96002-2","article-title":"Regulation of interferon-gamma during innate and adaptive immune responses","volume":"96","author":"Schoenborn","year":"2007","journal-title":"Adv Immunol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1189\/jlb.0603252","article-title":"Interferon-gamma: an overview of signals, mechanisms and functions","volume":"75","author":"Schroder","year":"2004","journal-title":"J Leukoc Biol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"4769","DOI":"10.4049\/jimmunol.175.7.4769","article-title":"Anti-IFN-gamma autoantibodies in disseminated nontuberculous mycobacterial infections","volume":"175","author":"Patel","year":"2005","journal-title":"J Immunol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1177\/1535370218764086","article-title":"Characterization of anti-interferon-\u03b3 antibodies in HIV-negative immunodeficient patients infected with unusual intracellular microorganisms","volume":"243","author":"Wipasa","year":"2018","journal-title":"Exp Biol Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1157","DOI":"10.1016\/j.micinf.2005.10.029","article-title":"Human host genetic factors in nontuberculous mycobacterial infection: lessons from single gene disorders affecting innate and adaptive immunity and lessons from molecular defects in interferon-gamma-dependent signaling","volume":"8","author":"Haverkamp","year":"2006","journal-title":"Microbes Infect."},{"key":"B6","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1056\/NEJMoa1111160","article-title":"Adult-onset immunodeficiency in Thailand and Taiwan","volume":"367","author":"Browne","year":"2012","journal-title":"N Engl J Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"e3927","DOI":"10.1097\/MD.0000000000003927","article-title":"Clinical manifestations, course, and outcome of patients with neutralizing anti-interferon-\u03b3 autoantibodies and disseminated nontuberculous mycobacterial infections","volume":"95","author":"Chi","year":"2016","journal-title":"Medicine."},{"key":"B8","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1016\/j.diagmicrobio.2017.05.011","article-title":"Patient ethnicity and causative species determine the manifestations of anti-interferon-gamma autoantibody-associated nontuberculous mycobacterial disease: a review","volume":"88","author":"Hase","year":"2017","journal-title":"Diagnostic Microbiol Infectious Dis."},{"key":"B9","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1007\/s10875-015-0161-5","article-title":"Late-onset disseminated Mycobacterium avium intracellulare complex infection (MAC), cerebral toxoplasmosis and salmonella sepsis in a German Caucasian patient with unusual anti-interferon-gamma IgG1 autoantibodies","volume":"35","author":"Hanitsch","year":"2015","journal-title":"J Clin Immunol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1093\/cid\/ciz786","article-title":"Natural history and evolution of anti-interferon-\u03b3 autoantibody-associated immunodeficiency syndrome in Thailand and the United States","volume":"71","author":"Hong","year":"2020","journal-title":"Clin Infect Dis."},{"key":"B11","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1016\/j.autrev.2015.01.007","article-title":"Swizing the clinical presentation in adult-onset Still's disease. 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