Abstract O.20: Deep RNA Sequencing Reveals a Transcriptional Profile of Cytotoxic T Lymphocyte Activation, Antigen Presentation, Immunoglobulin Production, and Type I Interferon Response in Kawasaki Disease Arteritis
Introduction: Subacute/chronic arteritis (SA/C) and luminal myofibroblastic proliferation are the pathologic processes that can continue in Kawasaki Disease (KD) coronary arteries after the second week of illness, when acute neutrophilic necrotizing arteritis has subsided. The specific dysregulated immune pathways in SA/C arteritis have been unknown, hampering the development of effective immunomodulatory therapies for patients not responding to intravenous gammaglobulin therapy. Controversy exists as to whether the arteritis is lymphocyte or macrophage-mediated.
Hypothesis: Based on our histopathologic studies, we hypothesized that the immune transcriptome of SA/C KD arteritis was primarily lymphocyte- rather than macrophage-mediated.
Methods: RNA was isolated from paraffin-embedded CA tissues, and samples passing quality control assays were subjected to deep RNA sequencing (101 nt paired-end reads, 40-100million reads/sample). Reads were aligned to the human genome, and HTseq used to determine read counts. DESeq was used to test for differential gene expression in CA tissues from 8 KD children (median age=7 mo, median 4 wks and all >2 weeks after onset) compared to 7 controls with normal CAs (median age=5 mo). Pathways analysis was performed using Ingenuity iReport™.
Results: 1074 differentially expressed genes were identified with >1.5-fold change and q-value <0.05. The most significantly upregulated pathways included cytotoxic CD8 T lymphocyte, dendritic cell and toll-like receptor (TLR) signaling, and antigen presentation. Immunoglobulin and type I interferon-stimulated genes were significantly upregulated. 50 immune response genes encoding secreted proteins were upregulated and are candidate biomarkers of KD arteritis.
Conclusions: The immune transcriptional profile in KD CA tissues after the second week of illness is primarily lymphocyte-mediated and compatible with an antiviral immune response. This first report of the KD CA transcriptome identifies specific dysregulated immune response pathways that can inform the development of new therapies for and biomarkers of KD vasculitis, and provides direction for future etiologic studies of this potentially fatal childhood illness.
Author Disclosures: A.H. Rowley: 2. Research Grant; Significant; NIH. K. Wylie: None. K.A. Kim: 2. Research Grant; Significant; NIH. A.J. Pink: None. R. Reindel: None. S.C. Baker: 2. Research Grant; Significant; NIH. S.T. Shulman: None. A. Yang: None. J.M. Orenstein: None. M.W. Lingen: None. G. Weinstock: None. T. Wylie: None.
- © 2015 by American Heart Association, Inc.