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Kawasaki disease: pathophysiology and insights from mouse models.

ABSTRACT: Kawasaki disease is an acute febrile illness and systemic vasculitis of unknown aetiology that predominantly afflicts young children, causes coronary artery aneurysms and can result in long-term cardiovascular sequelae. Kawasaki disease is the leading cause of acquired heart disease among children in the USA. Coronary artery aneurysms develop in some untreated children with Kawasaki disease, leading to ischaemic heart disease and myocardial infarction. Although intravenous immunoglobulin (IVIG) treatment reduces the risk of development of coronary artery aneurysms, some children have IVIG-resistant Kawasaki disease and are at increased risk of developing coronary artery damage. In addition, the lack of specific diagnostic tests and biomarkers for Kawasaki disease make early diagnosis and treatment challenging. The use of experimental mouse models of Kawasaki disease vasculitis has considerably improved our understanding of the pathology of the disease and helped characterize the cellular and molecular immune mechanisms contributing to cardiovascular complications, in turn leading to the development of innovative therapeutic approaches. Here, we outline the pathophysiology of Kawasaki disease and summarize and discuss the progress gained from experimental mouse models and their potential therapeutic translation to human disease.

SUBMITTER: Noval Rivas M

PROVIDER: S-EPMC7250272 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Kawasaki disease: pathophysiology and insights from mouse models.

Noval Rivas Magali M Arditi Moshe M

Nature reviews. Rheumatology 20200526 7

Kawasaki disease is an acute febrile illness and systemic vasculitis of unknown aetiology that predominantly afflicts young children, causes coronary artery aneurysms and can result in long-term cardiovascular sequelae. Kawasaki disease is the leading cause of acquired heart disease among children in the USA. Coronary artery aneurysms develop in some untreated children with Kawasaki disease, leading to ischaemic heart disease and myocardial infarction. Although intravenous immunoglobulin (IVIG) ...[more]

PMID: 32457494

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Project description:Background: Kawasaki disease (KD) is an acute self-limited vasculitis and the leading cause of acquired heart disease in children in developed countries. No etiologic agent(s) has been identified, and the processes that mediate formation of coronary artery aneurysms and abatement of fever following treatment with intravenous immunoglobulin (IVIG) remain poorly understood. Results: In an initial survey, we used DNA microarrays to examine patterns of gene expression in peripheral whole blood from 20 children with KD; each was sampled during the acute, subacute, and convalescent phases of the illness. Acute KD was characterized by increased relative abundance of gene transcripts associated with innate immune and proinflammatory responses and decreased abundance of transcripts associated with natural killer cells and CD8+ lymphocytes. There was significant temporal variation in transcript levels during the acute disease phase and stabilization thereafter. We confirmed these temporal patterns in a second cohort of 64 patients, and identified additional inter-individual differences in transcript abundance. Notably, higher levels of transcripts of the gene for carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) were associated with an increased percentage of unsegmented neutrophils, fewer days of illness, higher levels of C-reactive protein, and subsequent non-response to IVIG; this last association was confirmed by quantitative reverse transcription PCR in a third cohort of 33 patients, and was independent of day of illness. Conclusions: Acute KD is characterized by dynamic and variable gene-expression programs that highlight the importance of neutrophil activation state and apoptosis in KD pathogenesis. Our findings also support the feasibility of extracting biomarkers associated with clinical prognosis from gene-expression profiles of individuals with systemic inflammatory illnesses. Whole blood (PAXgene tubes) was obtained from 64 Kawasaki disease patients prior to treatment. RNA was amplified using the MessageAmp kit (Ambion), and reverse transcribed. Each sample was labelled with Cy5, and hybridized to a Lymphochip cDNA array along with amplified human reference RNA labelled with Cy3(Universal Human Reference RNA, Stratagene). Analysis was restricted to those array elements (LUIDs) with signal intensity/background of at least 2.5 in either channel for at least 80% of the samples, and a regression correlation of 0.6. Patterns of gene expression were correlated with clinical parameters, including subsequent response to treatment with intravenous immunoglobulin (IVIG). A disease state experiment design type is where the state of some disease such as infection, pathology, syndrome, etc is studied. Phenotype: Patient responded (R) or not (NR) to IVIG therapy. Some patients were not classified because they were treated more than 10 days after onset of fever Keywords: disease_state_design

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Kawasaki disease: pathophysiology and insights from mouse models.

Publications

Kawasaki disease: pathophysiology and insights from mouse models.

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