Kawasaki Disease (KD) is a potentially fatal vasculitis of young childhood. Although the initial presenting symptoms of fever, exanthem, enanthem, conjunctival injection, extremity changes, and adenopathy are self-limiting, our recent seminal pathologic study of autopsy or surgical arterial tissues from 41 KD patients demonstrated subacute/chronic vasculitis persisting for months to years after the onset in these patients with severe coronary artery disease. Chronic KD vasculitis was not recognized in early pathologic studies of KD, and children with persistent coronary artery aneurysms do not receive additional immunomodulatory therapies after the acute febrile phase of illness. We hypothesize that prolonged immune activation contributes to persistent coronary arteritis in KD patients, and that markers of immune activation can be detected in the sera of KD children with persistent coronary artery aneurysms. In preliminary studies, we demonstrated upregulation of more than 20 immune response genes by real-time RT-PCR analyses of coronary artery tissues from 7 KD patients with persistent aneurysms (5mo-16 yrs after the onset) and 7 childhood controls. In other preliminary studies, we performed transcriptome analysis of 8 KD and 7 childhood control coronary arteries and identified 1057 dysregulated genes (q-value &lt;0.05 and >1.5 fold change). These dysregulated genes included ~50 immune response genes that are upregulated in KD vascular tissues and encode extracellular proteins that are candidate serum biomarkers of chronic KD vasculitis. In a subsequent pilot study, we tested sera from 6 KD children with persistent (3-8 years after onset) coronary artery aneurysms and from 6 childhood controls for levels of 15 of these 50 proteins and identified 5 candidate serum markers of persistent KD vasculitis. In this exploratory proposal, we will: 1) Identify molecular pathways dysregulated in chronic KD vasculitis tissues, and 2) Identify serum immune biomarkers of chronic KD vasculitis. The results of these studies will provide important insights into the molecular immunopathogenesis of chronic KD vasculitis, and enable development of a panel of serum biomarkers of chronic KD vasculitis that can be tested in larger multicenter patient cohorts. Such non-invasive markers could enable identification and monitoring of KD patients with chronic vasculitis for participation in future multicenter collaborative trials of immunomodulatory therapies, to reduce morbidity and mortality from this serious childhood illness.
|Effective start/end date||5/1/15 → 3/31/18|
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (1R21AR068041-01)