Autoantibodies against interleukin-1 receptor antagonist in multisystem inflammatory syndrome in children: a multicentre, retrospective, cohort study.

Autor:	Pfeifer J; Department of Pediatric Cardiology, Saarland University, Homburg, Germany., Thurner B; Department of Pediatrics, Klinikum Kempten, Kempten, Germany., Kessel C; Department of Pediatric Rheumatology and Immunology, University Children's Hospital Münster, Münster, Germany., Fadle N; José Carreras Center for Immuno and Gene Therapy and Department of Internal Medicine I, Saarland University, Homburg, Germany., Kheiroddin P; Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg at the Hospital St Hedwig of the Order of St John, University of Regensburg, Regensburg, Germany., Regitz E; José Carreras Center for Immuno and Gene Therapy and Department of Internal Medicine I, Saarland University, Homburg, Germany., Hoffmann MC; José Carreras Center for Immuno and Gene Therapy and Department of Internal Medicine I, Saarland University, Homburg, Germany., Kos IA; José Carreras Center for Immuno and Gene Therapy and Department of Internal Medicine I, Saarland University, Homburg, Germany., Preuss KD; José Carreras Center for Immuno and Gene Therapy and Department of Internal Medicine I, Saarland University, Homburg, Germany., Fischer Y; Institute of Physiology, Medical Faculty, RWTH Aachen, Aachen, Germany., Roemer K; José Carreras Center for Immuno and Gene Therapy and Department of Internal Medicine I, Saarland University, Homburg, Germany., Lohse S; Institute of Virology, Saarland University, Homburg, Germany., Heyne K; José Carreras Center for Immuno and Gene Therapy and Department of Internal Medicine I, Saarland University, Homburg, Germany., Detemple MC; Department of Pediatrics, Klinikum Saarbrücken, Saarbrücken, Germany., Fedlmeier M; Department of Pediatrics, Klinikum Kempten, Kempten, Germany., Juenger H; Department of Pediatrics, Klinikum Kempten, Kempten, Germany., Sauer H; Department of Pediatric Cardiology, Saarland University, Homburg, Germany., Meyer S; Department of General Pediatrics and Neonatology, Saarland University, Homburg, Germany., Rohrer T; Department of General Pediatrics and Neonatology, Saarland University, Homburg, Germany., Wittkowski H; Department of Pediatric Rheumatology and Immunology, University Children's Hospital Münster, Münster, Germany., Becker SL; Institute of Medical Microbiology and Hygiene, Saarland University, Homburg, Germany., Masjosthusmann K; Department of General Pediatrics, University Hospital Münster, Münster, Germany., Bals R; Department of Internal Medicine V, Saarland University, Homburg, Germany., Gerling S; Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg at the Hospital St Hedwig of the Order of St John, University of Regensburg, Regensburg, Germany., Smola S; Institute of Virology, Saarland University, Homburg, Germany.; Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research, Saarland University, Saarbrücken, Germany., Bewarder M; José Carreras Center for Immuno and Gene Therapy and Department of Internal Medicine I, Saarland University, Homburg, Germany., Birk E; Pediatric Heart Institute, Schneider Children's Medical Center of Israel, Petach Tikva, Israel., Keren A; Heart Institute, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.; Heart Failure Center, Clalit Health Services, Jerusalem, Israel., Böhm M; Department of Internal Medicine III, Saarland University, Homburg, Germany., Jakob A; Department of Pediatric Cardiology and Pediatric Intensive Care, Ludwig Maximilian University, Munich, Germany., Abdul-Khaliq H; Department of Pediatric Cardiology, Saarland University, Homburg, Germany., Anton J; Department of of Pediatrics and Pediatric Rheumatology, Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain., Kabesch M; Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg at the Hospital St Hedwig of the Order of St John, University of Regensburg, Regensburg, Germany., Pino-Ramirez RM; Department of of Pediatrics and Pediatric Rheumatology, Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain., Foell D; Department of Pediatric Rheumatology and Immunology, University Children's Hospital Münster, Münster, Germany., Thurner L; José Carreras Center for Immuno and Gene Therapy and Department of Internal Medicine I, Saarland University, Homburg, Germany.
Jazyk:	angličtina
Zdroj:	The Lancet. Rheumatology [Lancet Rheumatol] 2022 May; Vol. 4 (5), pp. e329-e337. Date of Electronic Publication: 2022 Mar 29.
DOI:	10.1016/S2665-9913(22)00064-9
Abstrakt:	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-1β-signalling 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 immune-complexes 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-1β 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-1β-signalling in MIS-C. Funding: NanoBioMed fund of the University of Saarland, José Carreras Center for Immuno and Gene Therapy, Dr Rolf M Schwiete Stiftung, Staatskanzlei Saarland, German Heart Foundation, Charity of the Blue Sisters, Bavarian Ministry of Health, the Center for Interdisciplinary Clinical Research at University Hospital Münster, EU Horizon 2020. Competing Interests: LT has received research grants from Wilhelm Sander-Stiftung, BioNanoMed, and the Homburger Forschungsförderung programme of the University of Saarland; travel grants for meeting attendance from AbbVie, Janssen, and EUSA-Pharm; and has participated in advisory boards for Takeda, AstraZeneca, Merck, and EUSA Pharma. LT and K-DP were listed among inventors of a patent on progranulin antibodies as marker for autoimmune diseases filed by University of Saarland, which expired in 2017. CK has received consulting fees from Novartis and Swedish Orphan Biovitrum (SOBI) and receives research support from Novartis. MBö has received speakers honoraria from or participated in advisory boards for Abbott, Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Cyotkinetics, Medtronic, Novartis, Servier, and Vifor. HW has received honoraria (lecture fees) from Novartis and Takeda, and travel support from Octapharma and CSL-Behring. DF has received speaker fees or honoraria from Chugai-Roche, Novartis, and SOBI, and research support from Novartis, Pfizer, and SOBI. JA has received grants and travel grants for meeting attendance from SOBI and Novartis, and participated in advisory boards for SOBI and Novartis. BT has received honoraria for lectures from Nutricia Milupa and is a private shareholder of BioNTech. MK has received research support for the CoKiBa trial from Roche, who provided the diagnostic antibodies at a time when they were not yet commercially available. In addition, MK has received honoraria for lectures from Pädnetz Bayern, Ärztlicher Kreisverband, and Bayerischer Berufsverband der Kinder- und Jugendärzte, and participated in the advisory board for COVID-19 in children of the Bavarian Ministry of Health. SLB has participated in advisory boards and received honoraria for lectures from Shinogi and Pfizer. RB has received grants and personal fees from AstraZeneca, Boehringer Ingelheim, and Novartis; personal fees from GlaxoSmithKline, Grifols, and CSL Behring; grants from the German Ministry of Education and Research, Competence Network on Asthma and COPD, Sander Stiftung, Schwiete Stiftung, Krebshilfe, and Mukosviszidose; and has a leadership role at the Alpha-1-Center in Bad Lippspringe, Germany. All other authors declare no competing interests. (© 2022 Elsevier Ltd. All rights reserved.)
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