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- Title
An Immunological Axis Involving Interleukin 1β and Leucine-Rich-α2-Glycoprotein Reflects Therapeutic Response of Children with Kawasaki Disease: Implications from the KAWAKINRA Trial.
- Authors
Kessel, Christoph; Koné-Paut, Isabelle; Tellier, Stéphanie; Belot, Alexandre; Masjosthusmann, Katja; Wittkowski, Helmut; Fuehner, Sabrina; Rossi-Semerano, Linda; Dusser, Perrine; Marie, Isabelle; Boukhedouni, Nadja; Agostini, Helène; Piedvache, Céline; Foell, Dirk
- Abstract
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.
- Subjects
MUCOCUTANEOUS lymph node syndrome; JUVENILE diseases; HIERARCHICAL clustering (Cluster analysis); LEUKOCYTE count; ENDOTHELIAL cells
- Publication
Journal of Clinical Immunology, 2022, Vol 42, Issue 6, p1330
- ISSN
0271-9142
- Publication type
Article
- DOI
10.1007/s10875-022-01301-w