RESUMO
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.
Assuntos
Arterite/imunologia , Proteínas de Ligação a DNA/metabolismo , Interferons/metabolismo , Ativação de Macrófagos , Síndrome de Linfonodos Mucocutâneos/imunologia , Linfócitos T/imunologia , Adolescente , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/metabolismo , Apoptose/genética , Arterite/metabolismo , Antígeno B7-1/genética , Antígeno B7-1/metabolismo , Linfócitos T CD8-Positivos , Proteínas de Ligação ao Cálcio , Chicago , Criança , Pré-Escolar , Vasos Coronários/patologia , Proteínas de Ligação a DNA/genética , Feminino , Fibrinogênio , Imunofluorescência , Expressão Gênica , Humanos , Imuno-Histoquímica , Lactente , Recém-Nascido , Peptídeos e Proteínas de Sinalização Intercelular/genética , Interferons/genética , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Macrófagos/metabolismo , Masculino , Proteínas dos Microfilamentos , Síndrome de Linfonodos Mucocutâneos/genética , Síndrome de Linfonodos Mucocutâneos/metabolismo , Síndrome de Linfonodos Mucocutâneos/patologia , Receptores de Interferon/genética , Adulto JovemRESUMO
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.
Assuntos
Arterite/etiologia , Doença da Artéria Coronariana/etiologia , Síndrome de Linfonodos Mucocutâneos/complicações , Transcriptoma , Apresentação de Antígeno/imunologia , Arterite/diagnóstico , Biomarcadores , Estudos de Casos e Controles , Análise por Conglomerados , Biologia Computacional/métodos , Doença da Artéria Coronariana/diagnóstico , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Fatores Reguladores de Interferon/genética , Interferon Tipo I/metabolismo , Metabolismo dos Lipídeos/genética , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Síndrome de Linfonodos Mucocutâneos/terapia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Receptores de Reconhecimento de Padrão/genética , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
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.
