Abstract
BackgroundKawasaki disease (KD) is a systemic vasculitis of unknown etiology. The innate immune system is involved in its pathophysiology at the acute phase. We have recently established a novel murine model of KD coronary arteritis by oral administration of a synthetic microbe-associated molecular pattern (MAMP). On the hypothesis that specific MAMPs exist in KD sera, we have searched them to identify KD-specific molecules and to assess the pathogenesis.MethodsWe performed liquid chromatography-mass spectrometry (LC-MS) analysis of fractionated serum samples from 117 patients with KD and 106 controls. Microbiological and LC-MS evaluation of biofilm samples were also performed.ResultsKD samples elicited proinflammatory cytokine responses from human coronary artery endothelial cells (HCAECs). By LC-MS analysis of KD serum samples collected at 3 different periods, we detected a variety of KD-specific molecules in the lipophilic fractions that showed distinct m/z and MS/MS fragmentation patterns in each cluster. Serum KD-specific molecules showed m/z and MS/MS fragmentation patterns almost identical to those of MAMPs obtained from the biofilms formed in vitro (common MAMPs from Bacillus cereus, Yersinia pseudotuberculosis and Staphylococcus aureus) at the 1st study period, and from the biofilms formed in vivo (common MAMPs from Bacillus cereus, Bacillus subtilis/Bacillus cereus/Yersinia pseudotuberculosis and Staphylococcus aureus) at the 2nd and 3rd periods. The biofilm extracts from Bacillus cereus, Bacillus subtilis, Yersinia pseudotuberculosis and Staphylococcus aureus also induced proinflammatory cytokines by HCAECs. By the experiments with IgG affinity chromatography, some of these serum KD-specific molecules bound to IgG.ConclusionsWe herein conclude that serum KD-specific molecules were mostly derived from biofilms and possessed molecular structures common to MAMPs from Bacillus cereus, Bacillus subtilis, Yersinia pseudotuberculosis and Staphylococcus aureus. Discovery of these KD-specific molecules might offer novel insight into the diagnosis and management of KD as well as its pathogenesis.
Highlights
The etiology of Kawasaki disease (KD) remains unknown, KD has long been considered to be caused by an infectious agent, because of its characteristics of the symptoms, age distribution, seasonality, occurrence of community outbreaks and epidemic cycles
We performed liquid chromatography-mass spectrometry (LC-MS) analysis of KD sera to find out KD-specific molecules and demonstrated that serum KD-specific molecules were closely linked to microbe-associated molecular pattern (MAMP) in the biofilms
Activation of human coronary artery endothelial cells (HCAECs) by KD sera in vitro Since NOD1 ligand directly activates endothelial cells [8] and the expression of endothelial activation antigens was detected in KD skin biopsy specimens [14], HCAECs were employed for the
Summary
The etiology of Kawasaki disease (KD) remains unknown, KD has long been considered to be caused by an infectious agent, because of its characteristics of the symptoms, age distribution, seasonality, occurrence of community outbreaks and epidemic cycles. Temporal clustering and marked seasonality in KD occurrence in Japan, Hawaii and San Diego suggest a wind-borne environmental trigger for this disease [4]. We have established a novel murine model of KD coronary arteritis by oral administration of FK565, which functions as a synthetic microbe-associated molecular pattern (MAMP) and a ligand to one of the innate immune receptors, nucleotide-binding oligomerization domaincontaining protein (NOD) 1 [8]. We have recently established a novel murine model of KD coronary arteritis by oral administration of a synthetic microbe-associated molecular pattern (MAMP). On the hypothesis that specific MAMPs exist in KD sera, we have searched them to identify KD-specific molecules and to assess the pathogenesis
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