ABSTRACT
BACKGROUND: Kawasaki disease (KD) is widely viewed as an acute arteritis. However, our pathologic studies show that chronic coronary arteritis can persist long after disease onset and is closely linked with arterial stenosis. Transcriptome profiling of acute KD arteritis tissues revealed upregulation of T lymphocyte, type I interferon, and allograft inflammatory factor-1 (AIF1) genes. We determined whether these immune responses persist in chronic KD arteritis, and we investigated the role of AIF1 in these responses. METHODS: Gene expression in chronic KD and childhood control arteries was determined by real-time reverse-transcriptase polymerase chain reaction, and arterial protein expression was determined by immunohistochemistry and immunofluorescence. Allograft inflammatory factor-1 small-interfering ribonucleic acid macrophage treatment was performed to investigate the role of AIF1 in macrophage and T lymphocyte activation. RESULTS: Allograft inflammatory factor-1 protein was highly expressed in stenotic KD arteries and colocalized with the macrophage marker CD68. T lymphocyte and interferon pathway genes were significantly upregulated in chronic KD coronary artery tissues. Alpha interferon-induced macrophage expression of CD80 and major histocompatibility complex class II was dependent on AIF1, and macrophage expression of AIF1 was required for antigen-specific T lymphocyte activation. CONCLUSIONS: Allograft inflammatory factor-1, originally identified in posttransplant arterial stenosis, is markedly upregulated in KD stenotic arterial tissues. T lymphocyte and type I interferon responses persist in chronic KD arteritis. Allograft inflammatory factor-1 may play multiple roles linking type I interferon response, macrophage activation, and antigen-specific T lymphocyte activation. These results suggest the likely importance of lymphocyte-myeloid cell cross-talk in the pathogenesis of KD arteritis and can inform selection of new immunotherapies for clinical trials in high-risk KD children.
Subject(s)
Arteritis/immunology , DNA-Binding Proteins/metabolism , Interferons/metabolism , Macrophage Activation , Mucocutaneous Lymph Node Syndrome/immunology , T-Lymphocytes/immunology , Adolescent , Antigens, CD/genetics , Antigens, CD/metabolism , Antigens, Differentiation, T-Lymphocyte/genetics , Antigens, Differentiation, T-Lymphocyte/metabolism , Apoptosis/genetics , Arteritis/metabolism , B7-1 Antigen/genetics , B7-1 Antigen/metabolism , CD8-Positive T-Lymphocytes , Calcium-Binding Proteins , Chicago , Child , Child, Preschool , Coronary Vessels/pathology , DNA-Binding Proteins/genetics , Female , Fibrinogen , Fluorescent Antibody Technique , Gene Expression , Humans , Immunohistochemistry , Infant , Infant, Newborn , Intercellular Signaling Peptides and Proteins/genetics , Interferons/genetics , Lectins, C-Type/genetics , Lectins, C-Type/metabolism , Macrophages/metabolism , Male , Microfilament Proteins , Mucocutaneous Lymph Node Syndrome/genetics , Mucocutaneous Lymph Node Syndrome/metabolism , Mucocutaneous Lymph Node Syndrome/pathology , Receptors, Interferon/genetics , Young AdultABSTRACT
BACKGROUND: Kawasaki Disease (KD) can cause potentially life-threatening coronary arteritis in young children, and has a likely infectious etiology. Transcriptome profiling is a powerful approach to investigate gene expression in diseased tissues. RNA sequencing of KD coronary arteries could elucidate the etiology and the host response, with the potential to improve KD diagnosis and/or treatment. METHODS: Deep RNA sequencing was performed on KD (n = 8) and childhood control (n = 7) coronary artery tissues, revealing 1074 differentially expressed mRNAs. Non-human RNA sequences were subjected to a microbial discovery bioinformatics platform, and microbial sequences were analyzed by Metastats for association with KD. RESULTS: T lymphocyte activation, antigen presentation, immunoglobulin production, and type I interferon response were significantly upregulated in KD arteritis, while the tumor necrosis factor α pathway was not differentially expressed. Transcripts from known infectious agents were not specifically associated with KD coronary arteritis. CONCLUSIONS: The immune transcriptional profile in KD coronary artery tissues has features of an antiviral immune response such as activated cytotoxic T lymphocyte and type I interferon-induced gene upregulation. These results provide new insights into the pathogenesis of KD arteritis that can guide selection of new immunomodulatory therapies for high-risk KD patients, and provide direction for future etiologic studies.
Subject(s)
Arteritis/etiology , Coronary Artery Disease/etiology , Mucocutaneous Lymph Node Syndrome/complications , Transcriptome , Antigen Presentation/immunology , Arteritis/diagnosis , Biomarkers , Case-Control Studies , Cluster Analysis , Computational Biology/methods , Coronary Artery Disease/diagnosis , Cytokines/metabolism , Dendritic Cells/immunology , Dendritic Cells/metabolism , Female , Gene Expression Profiling , Gene Expression Regulation , High-Throughput Nucleotide Sequencing , Humans , Infant , Intercellular Signaling Peptides and Proteins/metabolism , Interferon Regulatory Factors/genetics , Interferon Type I/metabolism , Lipid Metabolism/genetics , Lymphocyte Activation/genetics , Lymphocyte Activation/immunology , Macrophages/immunology , Macrophages/metabolism , Male , Mucocutaneous Lymph Node Syndrome/diagnosis , Mucocutaneous Lymph Node Syndrome/therapy , Neutrophils/immunology , Neutrophils/metabolism , Receptors, Pattern Recognition/genetics , Signal Transduction , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolismABSTRACT
We hypothesized that cardiovascular miRNAs might be diagnostic biomarkers for Kawasaki disease (KD). We identified dysregulated miRNAs in KD coronary arteries, and tested sera from KD patients and febrile controls for cardiovascular miRNAs using 2 methods. We did not identify cardiovascular miRNAs diagnostic for KD; our results may help guide future studies of potential miRNA biomarkers for KD.
Subject(s)
Biomarkers/analysis , Biomarkers/blood , Coronary Vessels/pathology , MicroRNAs/analysis , MicroRNAs/blood , Mucocutaneous Lymph Node Syndrome/genetics , Mucocutaneous Lymph Node Syndrome/pathology , Child , Female , Humans , Infant , Infant, Newborn , MaleABSTRACT
Accumulation of anthropogenic litter (i.e. garbage; AL) and its ecosystem effects in marine environments are well documented. Rivers receive AL from terrestrial habitats and represent a major source of AL to marine environments, but AL is rarely studied within freshwater ecosystems. Our objectives were to 1) quantify AL density in urban freshwaters, 2) compare AL abundance among freshwater, terrestrial, and marine ecosystems, and 3) characterize the activity and composition of AL biofilms in freshwater habitats. We quantified AL from the Chicago River and Chicago's Lake Michigan shoreline, and found that AL abundance in Chicago freshwater ecosystems was comparable to previously reported data for marine and terrestrial ecosystems, although AL density and composition differed among habitats. To assess microbial interactions with AL, we incubated AL and natural substrates in 3 freshwater ecosystems, quantified biofilm metabolism as gross primary production (GPP) and community respiration (CR), and characterized biofilm bacterial community composition via high-throughput sequencing of 16S rRNA genes. The main driver of biofilm community composition was incubation location (e.g., river vs pond), but there were some significant differences in biofilm composition and metabolism among substrates. For example, biofilms on organic substrates (cardboard and leaves) had lower GPP than hard substrates (glass, plastic, aluminum and tiles). In addition, bacterial communities on organic substrates were distinct in composition from those on hard substrates, with higher relative abundances of bacteria associated with cellulose decomposition. Finally, we used our results to develop a conceptual diagram designed to unite the study of AL in terrestrial and freshwater environments with the well-established field of marine debris research. We suggest this broad perspective will be useful for future studies which synthesize AL sources, ecosystem effects, and fate across multiple ecosystem types, and will benefit management and reduction of global AL accumulations.
