Pfeifer, Jochen and Thurner, Bernhard and Kessel, Christoph and Fadle, Natalie and Kheiroddin, Parastoo and Regitz, Evi and Hoffmann, Marie-Christin and Kos, Igor Age and Preuss, Klaus-Dieter and Fischer, Yvan and Roemer, Klaus and Lohse, Stefan and Heyne, Kristina and Detemple, Marie-Claire and Fedlmeier, Michael and Juenger, Hendrik and Sauer, Harald and Meyer, Sascha and Rohrer, Tilman and Wittkowski, Helmut and Becker, Soren L. and Masjosthusmann, Katja and Bals, Robert and Gerling, Stephan and Smola, Sigrun and Bewarder, Moritz and Birk, Einat and Keren, Andre and Boehm, Michael and Jakob, Andre and Abdul-Khaliq, Hashim and Anton, Jordi and Kabesch, Michael and Pino-Ramirez, Rosa Maria and Foell, Dirk and Thurner, Lorenz (2022) Autoantibodies against interleukin-1 receptor antagonist in multisystem inflammatory syndrome in children: a multicentre, retrospective, cohort study. LANCET RHEUMATOLOGY, 4 (5). E329-E337. ISSN 2665-9913
Full text not available from this repository. (Request a copy)Abstract
Background Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious complication of infection with SARS-CoV-2. A possible involvement of pathogenetically relevant autoantibodies has been discussed. Recently, neutralising autoantibodies against inflammatory receptor antagonists progranulin and interleukin-1 receptor antagonist (IL-1Ra) were found in adult patients with critical COVID-19. The aim of this study was to investigate the role of such autoantibodies in MIS-C. Methods In this multicentre, retrospective, cohort study, plasma and serum samples were collected from patients (0-18 years) with MIS-C (as per WHO criteria) treated at five clinical centres in Germany and Spain. As controls, we included plasma or serum samples from children with Kawasaki disease, children with inactive systemic juvenile idiopathic arthritis, and children with suspected growth retardation (non-inflammatory control) across four clinical centres in Germany and Spain (all aged =18 years). Serum samples from the CoKiBa trial were used as two further control groups, from healthy children (negative for SARS-CoV-2 antibodies) and children with previous mild or asymptomatic COVID-19 (aged =17 years). MIS-C and control samples were analysed for autoantibodies against IL-1Ra and progranulin, and for IL-1Ra concentrations, by ELISA. Biochemical analysis of plasma IL-1Ra was performed with native Western blots and isoelectric focusing. Functional activity of the autoantibodies was examined by an in vitro IL-1 beta 7signalling reporter assay. Findings Serum and plasma samples were collected between March 6, 2011, and June 2, 2021. Autoantibodies against IL-1Ra could be detected in 13 (62%) of 21 patients with MIS-C (11 girls and ten boys), but not in children with Kawasaki disease (n=24; nine girls and 15 boys), asymptomatic or mild COVID-19 (n=146; 72 girls and 74 boys), inactive systemic juvenile idiopathic arthritis (n=10; five girls and five boys), suspected growth retardation (n=33; 13 girls and 20 boys), or in healthy controls (n=462; 230 girls and 232 boys). Anti-IL-1Ra antibodies in patients with MIS-C belonged exclusively to the IgG1 subclass, except in one patient who had additional IL-1Ra-specific IgM antibodies. Autoantibodies against progranulin were only detected in one (5%) patient with MIS-C. In patients with MIS-C who were positive for anti-IL-1Ra antibodies, free plasma IL-1Ra concentrations were reduced, and immunecomplexes of IL-1Ra were detected. Notably, an additional, hyperphosphorylated, transiently occurring atypical isoform of IL-1Ra was observed in all patients with MIS-C who were positive for anti-IL-1Ra antibodies. Anti-IL-1Ra antibodies impaired IL-1Ra function in reporter cell assays, resulting in amplified IL-1 beta signalling. Interpretation Anti-IL-1Ra autoantibodies were observed in a high proportion of patients with MIS-C and were specific to these patients. Generation of these autoantibodies might be triggered by an atypical, hyperphosphorylated isoform of IL-1Ra. These autoantibodies impair IL-1Ra bioactivity and might thus contribute to increased IL-1 beta-signalling in MIS-C. Copyright (C) 2022 Elsevier Ltd. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | KAWASAKI-LIKE DISEASE; ELASTASE |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Kinder- und Jugendmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 26 Jan 2024 13:52 |
| Last Modified: | 26 Jan 2024 13:52 |
| URI: | https://pred.uni-regensburg.de/id/eprint/58534 |
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