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

Pfeifer, John; Thurner, Bernhard; Kessel, Christoph; Fadle, Natalie; Kheiroddin, Parastoo; Regitz, Evi; Hoffmann, Michael K.; Kos, Igor; Preuss, Klaus‐Dieter; Fischer, Yvan; Roemer, Klaus; Lohse, Stefan; Heyne, Kristina; Detemple, Marie-Claire; Fedlmeier, Michael; Juenger, Hendrik; Sauer, Harald; Meyer, Sascha; Rohrer, Tilman; Wittkowski, Helmut; Becker, Sören L.; Masjosthusmann, Katja; Bals, Robert; Gerling, Stephan; Smola, Sigrun; Bewarder, Moritz; Birk, Einat; Keren, Andre; Böhm, Michael; Jakob, André; Abdul‐Khaliq, Hashim; Antón, Jordi; Kabesch, Michael; Pino-Ramírez, Rosa Maria; Foell, Dirk; Thurner, Lorenz

doi:10.1016/s2665-9913(22)00064-9

Cited by 42 publications

(54 citation statements)

References 37 publications

(52 reference statements)

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“…Limitations of the study are mainly associated with sample availability, since MIS-C is a rare and novel disease. First, the number of cases is relatively low, although it is in line with previous studies defining molecular profiles in MIS-C. 27 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 It should be highlighted, to the best of our knowledge, this is the first epigenomic profiling of MIS-C cases. A second limitation is the lack of ethnic heterogeneity, directly related to the ethnic distribution in the studied population, enriched in West-Eurasia origin.…”

Section: Discussionsupporting

confidence: 84%

Epigenetic profiling linked to multisystem inflammatory syndrome in children (MIS-C): A multicenter, retrospective study

et al. 2022

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Section: Discussionsupporting

confidence: 84%

Epigenetic profiling linked to multisystem inflammatory syndrome in children (MIS-C): A multicenter, retrospective study

et al. 2022

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“…Furthermore, this subset of patients demonstrated strong imprints of antigenic selection in their BCR repertoires and increased usage of autoantibody associated IGHV genes ( 125 ). Neutralizing autoantibodies against interleukin-1 receptor antagonist (IL-1Ra), an anti-inflammatory protein that binds IL-1 receptor (IL-1R) and blocks IL-1α and IL-1β signaling, have been detected in a high proportion of MIS-C patients, but not in healthy controls, pediatric COVID-19 or KD samples ( 134 ). Although in that study the presence of autoantibodies against IL-1Ra did not correlate with MIS-C severity, these functional autoantibodies might exert a pathogenic role by impairing IL-1Ra bioactivity and promoting hyperinflammation during MIS-C ( 134 ).…”

Section: The Autoimmune Signatures Of Long Covid and Mis-cmentioning

confidence: 99%

“…Neutralizing autoantibodies against interleukin-1 receptor antagonist (IL-1Ra), an anti-inflammatory protein that binds IL-1 receptor (IL-1R) and blocks IL-1α and IL-1β signaling, have been detected in a high proportion of MIS-C patients, but not in healthy controls, pediatric COVID-19 or KD samples ( 134 ). Although in that study the presence of autoantibodies against IL-1Ra did not correlate with MIS-C severity, these functional autoantibodies might exert a pathogenic role by impairing IL-1Ra bioactivity and promoting hyperinflammation during MIS-C ( 134 ). Notably, the autoantibody signatures observed in MIS-C patients cannot be explained by the history of IVIG therapy, as multiple studies have observed autoantibody enrichment prior to treatment ( 125 , 126 ).…”

Section: The Autoimmune Signatures Of Long Covid and Mis-cmentioning

confidence: 99%

Multisystem Inflammatory Syndrome in Children and Long COVID: The SARS-CoV-2 Viral Superantigen Hypothesis

et al. 2022

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Multisystem inflammatory syndrome in children (MIS-C) is a febrile pediatric inflammatory disease that may develop weeks after initial SARS-CoV-2 infection or exposure. MIS-C involves systemic hyperinflammation and multiorgan involvement, including severe cardiovascular, gastrointestinal (GI) and neurological symptoms. Some clinical attributes of MIS-C—such as persistent fever, rashes, conjunctivitis and oral mucosa changes (red fissured lips and strawberry tongue)—overlap with features of Kawasaki disease (KD). In addition, MIS-C shares striking clinical similarities with toxic shock syndrome (TSS), which is triggered by bacterial superantigens (SAgs). The remarkable similarities between MIS-C and TSS prompted a search for SAg-like structures in the SARS-CoV-2 virus and the discovery of a unique SAg-like motif highly similar to a Staphylococcal enterotoxin B (SEB) fragment in the SARS-CoV-2 spike 1 (S1) glycoprotein. Computational studies suggest that the SAg-like motif has a high affinity for binding T-cell receptors (TCRs) and MHC Class II proteins. Immunosequencing of peripheral blood samples from MIS-C patients revealed a profound expansion of TCR β variable gene 11-2 (TRBV11-2), which correlates with MIS-C severity and serum cytokine levels, consistent with a SAg-triggered immune response. Computational sequence analysis of SARS-CoV-2 spike further identified conserved neurotoxin-like motifs which may alter neuronal cell function and contribute to neurological symptoms in COVID-19 and MIS-C patients. Additionally, autoantibodies are detected during MIS-C, which may indicate development of post-SARS-CoV-2 autoreactive and autoimmune responses. Finally, prolonged persistence of SARS-CoV-2 RNA in the gut, increased gut permeability and elevated levels of circulating S1 have been observed in children with MIS-C. Accordingly, we hypothesize that continuous and prolonged exposure to the viral SAg-like and neurotoxin-like motifs in SARS-CoV-2 spike may promote autoimmunity leading to the development of post-acute COVID-19 syndromes, including MIS-C and long COVID, as well as the neurological complications resulting from SARS-CoV-2 infection.

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“…Results found autoantibodies against IL-1Ra together with a hyperphosphorylated isoform of IL-1Ra in most patients with MIS-C. Despite the reduced number of enrolled MIS-C subjects, many control patients both with inflammatory and non-inflammatory pathologies have proved the appearance of autoantibodies in MIS-C, obviously connected and relevant to, and potentially triggering, the hyperinflammatory condition characteristic of this disease [ 119 ].…”

Section: Molecular Mechanisms Of Sars-cov-2 Infection and How CD Led ...mentioning

confidence: 99%

Celiac Disease and Targeting the Molecular Mechanisms of Autoimmunity in COVID Pandemic

Ailioaie

Litscher

et al. 2022

IJMS

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Celiac disease (CD) comprises over 1% of the world’s population and is a chronic multisystem immune-mediated condition manifested by digestive and/or extradigestive symptoms caused by food intake of gluten. This review looked at the risk of children diagnosed with CD developing SARS-CoV-2 infection and possible severe forms of COVID-19. A better understanding of the interaction and effects of SARS-CoV-2 infection in CD is very important, as is the role of environmental and genetic factors, but especially the molecular mechanisms involved in modulating intestinal permeability with impact on autoimmunity. CD inspired the testing of a zonulin antagonist for the fulminant form of multisystem inflammatory syndrome in children (MIS-C) and paved the way for the discovery of new molecules to regulate the small intestine barrier function and immune responses. Original published works on COVID-19 and CD, new data and points of view have been analyzed because this dangerous virus SARS-CoV-2 is still here and yet influencing our lives. Medical science continues to focus on all uncertainties triggered by SARS-CoV-2 infection and its consequences, including in CD. Although the COVID-19 pandemic seems to be gradually extinguishing, there is a wealth of information and knowledge gained over the last two years and important life lessons to analyze, as well as relevant conclusions to be drawn to deal with future pandemics. Zonulin is being studied extensively in immunoengineering as an adjuvant to improving the absorption of new drugs and oral vaccines.

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

Cited by 42 publications

References 37 publications

Epigenetic profiling linked to multisystem inflammatory syndrome in children (MIS-C): A multicenter, retrospective study

Epigenetic profiling linked to multisystem inflammatory syndrome in children (MIS-C): A multicenter, retrospective study

Multisystem Inflammatory Syndrome in Children and Long COVID: The SARS-CoV-2 Viral Superantigen Hypothesis

Celiac Disease and Targeting the Molecular Mechanisms of Autoimmunity in COVID Pandemic

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