S100A12 (EN-RAGE) in monitoring Kawasaki disease

doi:10.1016/S0140-6736(03)12986-8

The Lancet

Volume 361, Issue 9365, 12 April 2003, Pages 1270-1272

https://doi.org/10.1016/S0140-6736(03)12986-8 Get rights and content

Summary

The calcium-binding protein S100A12 causes inflammation through interaction with the multiligand receptor for advanced glycation end products (RAGE). Blocking of S100A12 showed promising therapeutic effects in mice. We investigated 31 individuals with Kawasaki disease, and recorded an association between expression of S100A12 and activity of Kawasaki disease. Serum concentrations of S100A12 decreased quickly in 28 patients who responded to treatment with gammaglobulin (from 463 μg/L [SD 316] to 184 μg/L [147] within 24 h, p<0·0001). Since the interaction of S100A12 with multiligand receptors has a key role in inflammatory responses, this protein could serve as a novel target for future therapeutic interventions in inflammatory disorders.

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Identification of hub biomarkers and immune-related pathways participating in the progression of Kawasaki disease by integrated bioinformatics analysis
2023, Immunobiology
Kawasaki disease (KD) is a systemic vasculitis that commonly affects children and its etiology remains unknown. Growing evidence suggests that immune-mediated inflammation and immune cells in the peripheral blood play crucial roles in the pathophysiology of KD. The objective of this research was to find important biomarkers and immune-related mechanisms implicated in KD, along with their correlation with immune cells in the peripheral blood.
Gene microarray data from the Gene Expression Omnibus (GEO) was utilized in this study. Three datasets, namely GSE63881 (341 samples), GSE73463 (233 samples), and GSE73461 (279 samples), were obtained. To find intersecting genes, we employed differentially expressed genes (DEGs) analysis and weighted gene co-expression network analysis (WGCNA). Subsequently, functional annotation, construction of protein–protein interaction (PPI) networks, and Least Absolute Shrinkage and Selection Operator (LASSO) regression were performed to identify hub genes. The accuracy of these hub genes in identifying KD was evaluated using the receiver operating characteristic curve (ROC). Furthermore, Gene Set Variation Analysis (GSVA) was employed to explore the composition of circulating immune cells within the assessed datasets and their relationship with the hub gene markers.
WGCNA yielded eight co-expression modules, with one hub module (MEblue module) exhibiting the strongest association with acute KD. 425 distinct genes were identified. Integrating WGCNA and DEGs yielded a total of 277 intersecting genes. By conducting LASSO analysis, five hub genes (S100A12, MMP9, TLR2, NLRC4 and ARG1) were identified as potential biomarkers for KD. The diagnostic value of these five hub genes was demonstrated through ROC curve analysis, indicating their high accuracy in diagnosing KD. Analysis of the circulating immune cell composition within the assessed datasets revealed a significant association between KD and various immune cell types, including activated dendritic cells, neutrophils, immature dendritic cells, macrophages, and activated CD8 T cells. Importantly, all five hub genes exhibited strong correlations with immune cells.
Activated dendritic cells, neutrophils, and macrophages were closely associated with the pathogenesis of KD. Furthermore, the hub genes (S100A12, MMP9, TLR2, NLRC4, and ARG1) are likely to participate in the pathogenic mechanisms of KD through immune-related signaling pathways.
Leukocyte proteomics coupled with serum metabolomics identifies novel biomarkers and abnormal amino acid metabolism in Kawasaki disease
2021, Journal of Proteomics
Citation Excerpt :
For example, the calcium-binding proteins S100P, A8, A9, and A12 exhibit higher expression levels during the acute phase compared with the healthy controls but decrease upon IVIG treatment. In line with our results, the mRNA level of the S100A12 gene [24], and the serum-derived S100A12 protein were shown to be increased during the acute phase and suggested as a critical inflammatory sign in KD children [25]. Moreover, the neutrophil-derived or circulating endothelial cell surface-derived S100A12 protein was previously reported to be not only increased in KD leukocytes [26,27] but also elevated in IVIG non-responders [28], and this molecule can activate coronary artery endothelial cells in an IL-1β-dependent manner [29].
Kawasaki disease (KD) is a systemic vasculitis that can lead to severe cardiovascular complications, whereas the development and clinical usage of specific biomarkers might help diagnose KD and avoid certain complications. To this end, the molecular profiles of acute KD patients with coronary artery lesions (CAL) were first investigated through leukocyte proteomics and serum metabolomics assays. A total of 269 differentially abundant proteins and 35 differentially abundant metabolites with the top fold-changed levels were identified in acute KD patients compared to those in the healthy controls. Among them, several highly promising candidate marker proteins and metabolites indicative of KD progression were further analysed, such as the increased proteins ALPL, NAMPT, and S100P, as well as the decreased proteins C1QB and apolipoprotein family members. Moreover, metabolites, including succinic acid, dGMP, hyaluronic acid, L-tryptophan, propionylcarnitine, inosine, and phosphorylcholine, were found to be highly accurate at distinguishing between KD patients and healthy controls. Interestingly, the abnormal expression levels of a distinct set of proteins and metabolites in acute KD patients can be restored to normal levels upon intravenous immunoglobulin (IVIG) treatment. Overall, this work has revealed novel biomarkers and abnormal amino-acid metabolism as a prominent feature involved in KD patients with CAL.
KD is frequently concomitant with the development of life-threatening coronary vasculitis. Here, the profiles of leukocyte proteomics and serum metabolomics in acute KD patients with CALs were first investigated, and several hub molecules identified here could be used as supplemental biomarkers for KD diagnosis. Moreover, the metabolomic abnormalities especially the amino acids are particularly prominent in KD patients. Interestingly, the abnormal expression levels of a distinct set of proteins and metabolites in acute KD patients can be restored to normal levels upon IVIG treatment. Therefore, these findings might help understand the IVIG activities and also the underlying mechanisms of IVIG-resistant patients, thereby providing a new perspective for the exploration of mechanisms related to KD.
S100 proteins: Diagnostic and prognostic biomarkers in laboratory medicine
2019, Biochimica et Biophysica Acta - Molecular Cell Research
Citation Excerpt :
S100A11 (calgizzarin) was associated with rheumatoid- and osteoarthritis and is an additional biomarker [211] to S100A/A9 and S100A12 for a more tailored diagnostic of inflammatory diseases. S100A12/calgranulin C is associated with the Kawasaki disease [212] and Mooren's ulcer [213] as well as atherosclerosis [214]. In addition, S100A12 seems to be more specific for inflammatory bowel disease in school aged children and adolescents when compared to established stool markers such as S100A8/A9 and lactoferrin [215,216].
S100 proteins are members of the superfamily of Ca²⁺-binding proteins characterized by the specific Ca²⁺-binding motif, the EF-hand. Proteins of this superfamily are of clinical use as important diagnostic and prognostic biomarkers in adult and pediatric Laboratory Medicine. For example, measurements of troponin are nowadays the ‘gold standard’ in the diagnosis of patients with acute coronary syndrome. Parvalbumins were identified as major fish allergens and blocking antibodies, induced by immunization with a hypoallergenic parvalbumin mutant, were shown to reduce allergic symptoms. Mutations in calmodulin are linked to inherited ventricular tachycardia, and cardiac arrhythmias. S100 proteins, the largest sub-group within the EF-hand protein family, are closely associated with cardiovascular diseases, various types of cancer, inflammation and autoimmune pathologies and brain diseases. The intention of this review is to focus on the clinical use of S100 proteins as biomarkers and potential drug targets helping to improve the diagnosis of these human diseases in children and adults leading to more selective therapeutic interventions.
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2024, SSRN
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Research LettersS100A12 (EN-RAGE) in monitoring Kawasaki disease

Summary

Cell

J Biol Chem

Research Letters
S100A12 (EN-RAGE) in monitoring Kawasaki disease