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Hoffmann, Marie-Christin; Cavalli, Giulio; Fadle, Natalie; Cantoni, Eleonora; Regitz, Evi; Fleser, Octavian; Klemm, Philipp; Zaks, Marina; Stöger, Elisabeth; Campochiaro, Corrado; Tomelleri, Alessandro; Baldissera, Elena; Bittenbring, Jörg Thomas; Zimmer, Vincent; Pfeifer, Jochen; Fischer, Yvan; Preuss, Klaus-Dieter; Bewarder, Moritz; Thurner, Bernhard; Fuehner, Sabrina; Foell, Dirk; Dagna, Lorenzo; Kessel, Christoph; Thurner, Lorenz

Autoantibody-Mediated Depletion of IL-1RA in Still’s Disease and Potential Impact of IL-1 Targeting Therapies

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  • Medientyp: E-Artikel
  • Titel: Autoantibody-Mediated Depletion of IL-1RA in Still’s Disease and Potential Impact of IL-1 Targeting Therapies
  • Beteiligte: Hoffmann, Marie-Christin; Cavalli, Giulio; Fadle, Natalie; Cantoni, Eleonora; Regitz, Evi; Fleser, Octavian; Klemm, Philipp; Zaks, Marina; Stöger, Elisabeth; Campochiaro, Corrado; Tomelleri, Alessandro; Baldissera, Elena; Bittenbring, Jörg Thomas; Zimmer, Vincent; Pfeifer, Jochen; Fischer, Yvan; Preuss, Klaus-Dieter; Bewarder, Moritz; Thurner, Bernhard; Fuehner, Sabrina; Foell, Dirk; Dagna, Lorenzo; Kessel, Christoph; Thurner, Lorenz
  • Erschienen: Springer Science and Business Media LLC, 2024
  • Erschienen in: Journal of Clinical Immunology
  • Sprache: Englisch
  • DOI: 10.1007/s10875-023-01642-0
  • ISSN: 0271-9142; 1573-2592
  • Schlagwörter: Immunology ; Immunology and Allergy
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>Adult-onset Still’s disease (AOSD) and systemic juvenile idiopathic arthritis (sJIA) resemble a continuum of a rare, polygenic IL-1β-driven disease of unknown etiology.</jats:p> </jats:sec><jats:sec> <jats:title>Objective</jats:title> <jats:p>In the present study we sought to investigate a potential role of recently described autoantibodies neutralizing the interleukin-1(IL-1)-receptor antagonist (IL-1-Ra) in the pathogenesis of Still’s disease.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>Serum or plasma samples from Still’s disease patients (AOSD, <jats:italic>n</jats:italic> = 23; sJIA, <jats:italic>n</jats:italic> = 40) and autoimmune and/or inflammatory disease controls (<jats:italic>n</jats:italic> = 478) were analyzed for autoantibodies against progranulin (PGRN), IL-1Ra, IL-18 binding protein (IL-18BP), and IL-36Ra, as well as circulating IL-1Ra and IL-36Ra levels by ELISA. Biochemical analyses of plasma IL-1Ra were performed by native Western blots and isoelectric focusing. Functional activity of the autoantibodies was examined by an in vitro IL-1β-signaling reporter assay.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>Anti-IL-1-Ra IgG were identified in 7 (27%) out of 29 Still’s disease patients, including 4/23 with AOSD and 3/6 with sJIA and coincided with a hyperphosphorylated isoform of endogenous IL-1Ra. Anti-IL-36Ra antibodies were found in 2 AOSD patients. No anti-PGRN or anti-IL-18BP antibodies were detected. Selective testing for anti-IL-1Ra antibodies in an independent cohort (sJIA, n = 34) identified 5 of 34 (14.7%) as seropositive. Collectively, 8/12 antibody-positive Still’s disease patients were either new-onset active disease or unresponsive to IL-1 blocking drugs. Autoantibody-seropositivity associated with decreased IL-1Ra plasma/serum levels. Seropositive plasma impaired in vitro IL-1Ra bioactivity, which could be reversed by anakinra or canakinumab treatment.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusion</jats:title> <jats:p>Autoantibodies neutralizing IL-1Ra may represent a novel patho-mechanism in a subgroup of Still’s disease patients, which is sensitive to high-dose IL-1 blocking therapy.</jats:p> </jats:sec>