Journal Article

An Immunological Axis Involving Interleukin 1β and Leucine-Rich-α2-Glycoprotein Reflects Therapeutic Response of Children with Kawasaki Disease: Implications from the KAWAKINRA Trial

Agostini, Helène, Piedvache, Céline, Belot, Alexandre, Rossi-Semerano, Linda, Masjosthusmann, Katja, Kessel, Christoph, Koné-Paut, Isabelle, Wittkowski, Helmut, Fuehner, Sabrina, Dusser, Perrine, Foell, Dirk, Tellier, Stéphanie, Boukhedouni, Nadja, Marie, Isabelle

2022

Overview

Purpose A recent phase II open-label study of the interleukin 1 (IL-1) receptor antagonist (IL-1Ra) anakinra in treating IVIG-resistant Kawasaki disease (KD) patients reported promising results. Here, we aimed to characterize the immunological impact of IL-1 blockade in this unique study population. Methods Patients’ and control sera and supernatants of cells (whole blood, neutrophils, coronary artery endothelial cells) stimulated with recombinant IL-1β were analyzed for single or multiple marker ( n  = 22) expression by ELISA or multiplexed bead array assay. Data were analyzed using unsupervised hierarchical clustering, multiple correlation, and multi-comparison statistics and were compared to retrospective analyses of KD transcriptomics. Results Inflammation in IVIG-resistant KD ( n  = 16) is hallmarked by over-expression of innate immune mediators (particularly IL-6 > CXCL10 > S100A12 > IL-1Ra). Those as well as levels of immune or endothelial cell activation markers (sICAM-1, sVCAM-1) declined most significantly in course of anakinra treatment. Prior as well as following IL-1R blockade, over-expression of leucine-rich-α2-glycoprotein 1 (LRG1) associated best with remnant inflammatory activity and the necessity to escalate anakinra dosage and separated inflammatory KD patients from sJIA-MAS ( n  = 13) and MIS-C ( n  = 4). Protein as well as retrospective gene expression analyses indicated tight association of LRG1 with IL-1β signaling and neutrophilia, while particularly neutrophil stimulation with recombinant IL-1β resulted in concentration-dependent LRG1 release. Conclusion Our study identifies LRG1 as known trigger of endothelial activation and cardiac re-modeling to associate with IL-1β signaling in KD. Besides a potential patho-mechanistic implication of these findings, our data suggest blood leukocyte and neutrophil counts to best predict response to IL-1Ra treatment in IVIG-resistant KD.

• Publisher: Springer US,Springer Nature B.V,Springer Verlag
• Subject: antagonists / Biomedical and Life Sciences / Biomedicine / Cell activation / Coronary artery / coronary vessels / CXCL10 protein / Cytokines / Endothelial cells / Enzyme-linked immunosorbent assay / Gene expression / Glycoproteins / IL-1β / Immunoglobulins / Immunology / Infectious Diseases / Inflammation / Interleukin 1 / Interleukin 1 receptor antagonist / Interleukin 1 receptors / Interleukin 6 / Internal Medicine / Intravenous administration / Kawasaki disease / Leukocytes (neutrophilic) / Life Sciences / Medical Microbiology / Mucocutaneous lymph node syndrome / Neutrophilia / Neutrophils / Original / Original Article / Overexpression / Patients / Population studies / statistics / therapeutics / Transcriptomics