A major pediatric research priority and the long-term goal of my laboratory is the identification of the etiology and pathogenesis of Kawasaki Disease (KD), the leading cause of acquired heart disease in children in developed nations. KD can result in coronary artery aneurysm (CAA) formation with resultant myocardial infarction and/or sudden death. Clinical and epidemiologic data are consistent with an infectious cause of KD, but conventional methods have not yielded the etiologic agent. We discovered that oligoclonal IgA plasma cells, CD8 T lymphocytes, and macrophages infiltrate CAA and other tissues in acute KD, indicating an antigen-driven response to an intracellular pathogen, such as a virus, with a mucosal portal of entry. We found that macrophages in CAA secrete matrix metalloproteinases and other secreted products that may result in tissue damage. In the prior funding period, we made oligoclonal KD antibodies in vitro and used them as tools to identify their target antigens. Immunohistochemistry revealed that KD synthetic antibodies detected antigen in acute KD but not control bronchial epithelium and in a subset of macrophages in acute inflamed KD tissues. In acute KD ciliated bronchial epithelium, antigen localized to distinctive perinuclear intracytoplasmic spheroids. Light microscopy using H&E, trichrome and nucleic acid stains revealed that the spheroids in ciliated bronchial epithelium were cytoplasmic inclusion bodies (CIB), and transmission electron microscopy (TEM) of these cells in 4/4 acute KD patients showed homogeneous electron-dense CIB. The CIB were most consistent with aggregates of protein and associated nucleic acid and likely derive from the KD etiologic agent. Thus, synthetic antibodies derived from IgA sequences prevalent in plasma cells infiltrating acute KD arterial wall bind to CIB in acute KD ciliated bronchial epithelium, attesting to the likely importance of the CIB in KD pathogenesis. These data support the hypothesis that the KD agent enters via the respiratory tract, infects bronchial epithelium, and travels in macrophages to targeted tissues including coronary arteries, with antigen- specific IgA plasma cells and other inflammatory cells entering the tissues to combat the pathogen and resulting in tissue damage. The presence of CIB consistent with aggregates of microbial, likely viral, proteins and nucleic acids in acute KD lung provides a structural and molecular footprint that could lead to identification of the KD etiologic agent.
The specific aims of this proposal are to 1) Identify the cell and tissue types in which CIB form in acute KD, and search these cells/tissues for microbial elements by TEM;2) identify the nucleic acid/protein contents of KD CIB;and 3), building upon our prior studies of macrophage-secreted factors that play a role in CAA formation in acute KD, determine whether dysregulation of members of the tumor necrosis factor (TNF)- and TNF-receptor superfamily contribute to KD vasculopathy. The goals of these studies are to determine whether CIB derive from the KD etiologic agent and to identify new targets for therapy of acute KD.KD is the leading cause of acquired heart disease in children in developed nations and can result in heart attacks and sudden death. Clinical and epidemiologic features point to a common infectious agent, but the cause remains unknown.
The goal of these studies is to determine whether cytoplasmic inclusion bodies in KD patient tissues derive from the KD etiologic agent, and to identify new targets for therapy of KD.
|Rowley, Anne H; Wylie, Kristine M; Kim, Kwang-Youn A et al. (2015) The transcriptional profile of coronary arteritis in Kawasaki disease. BMC Genomics 16:1076|
|Shulman, Stanford T; Rowley, Anne H (2015) Kawasaki disease: insights into pathogenesis and approaches to treatment. Nat Rev Rheumatol 11:475-82|
|Reindel, Rebecca; Kim, Kwang-Youn A; Baker, Susan C et al. (2014) Periostin is upregulated in coronary arteriopathy in Kawasaki disease and is a potential diagnostic biomarker. Pediatr Infect Dis J 33:659-61|
|Reindel, R; Bischof, J; Kim, K-Y A et al. (2014) CD84 is markedly up-regulated in Kawasaki disease arteriopathy. Clin Exp Immunol 177:203-11|
|Rowley, Anne H; Pink, Adam J; Reindel, Rebecca et al. (2014) A study of cardiovascular miRNA biomarkers for Kawasaki disease. Pediatr Infect Dis J 33:1296-9|
|Rowley, Anne H; Shulman, Stanford T (2013) Editorial commentary: missing the forest for the trees: respiratory viral assays in patients with kawasaki disease. Clin Infect Dis 56:65-6|
|Reindel, Rebecca; Baker, Susan C; Kim, Kwang-Youn et al. (2013) Integrins Ã½Ã½4 and Ã½Ã½M, collagen1A1, and matrix metalloproteinase 7 are upregulated in acute Kawasaki disease vasculopathy. Pediatr Res 73:332-6|
|Rowley, Anne H (2013) Can a systems biology approach unlock the mysteries of Kawasaki disease? Wiley Interdiscip Rev Syst Biol Med 5:221-9|
|Orenstein, Jan Marc; Shulman, Stanford T; Fox, Linda M et al. (2012) Three linked vasculopathic processes characterize Kawasaki disease: a light and transmission electron microscopic study. PLoS One 7:e38998|
|Rowley, Anne H (2011) Kawasaki disease: novel insights into etiology and genetic susceptibility. Annu Rev Med 62:69-77|
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