Abstract 13308: The Transcriptome of Kawasaki Disease Arteritis Reveals Activation of T Lymphocyte and Natural Killer Cell Function, Antigen Presentation, Immunoglobulin Production, and Interferon Response
Introduction: We recently published the new information that necrotizing arteritis, subacute/chronic vasculitis and luminal myofibroblastic proliferation are the three linked pathologic processes of Kawasaki Disease (KD) vasculopathy, which critically affects the coronary arteries (CA). The specific dysregulated immune pathways in KD CA have been unknown, and controversy exists as to whether immune dysregulation is primarily macrophage or T and B lymphocyte-driven.
Hypothesis: We hypothesized that the immune transcriptome of KD arteritis was primarily one of T and B lymphocyte rather than macrophage activation.
Methods: RNA was isolated from paraffin-embedded CA tissues. RNA samples passing quality control assays were subjected to ribosomal RNA subtraction, and Illumina HiSeq 2000 RNA sequencing (101 nt paired-end reads, 40-100million reads/sample) was performed. Reads were aligned to the human genome, and Cuffdiff used to test for differential gene expression in CA tissues from 8 KD children (median age=7 mo, median 4 wks from onset) compared to 7 controls who had normal CA pathology (median age=5 mo). Pathways analysis was performed using Ingenuity iReport™.
Results: 1057 differentially expressed transcripts were identified with >1.5-fold change and q-value <0.05. The most significantly upregulated pathways included T lymphocyte, dendritic cell and natural killer cell signaling, antigen presentation, and toll-like receptor (TLR) signaling (p values 1e-18 to 5e-05). Immunoglobulin A, G, and M genes and at least 50 type I interferon-stimulated genes were significantly upregulated. Tumor necrosis factor α (TNFα) receptor and transforming growth factor β signaling pathways were not significantly altered (p-value >0.1). 50 immune response genes encoding secreted proteins were upregulated and are candidate biomarkers of KD arteritis.
Conclusions: The host transcriptional response in target CA tissues in KD demonstrates a prominent innate and acquired immune response to antigen. Genes related to T and B lymphocyte activation were upregulated but macrophage responses were not prominent. This first report of the CA transcriptome of KD could lead to identification of new therapeutic targets and biomarkers for KD arteriopathy.
Author Disclosures: A.H. Rowley: Other; Modest; Reviewer, Up-To-Date. K. Wylie: None. A. Pink: None. R. Reindel: None. S. Baker: None. S. Shulman: None. J. Orenstein: None. E. Perlman: None. M. Lingen: None. G. Weinstock: None. T. Wylie: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.