Project Details
Abstract
Kawasaki disease (KD) is a systemic vasculitis of unknown etiology that primarily affects children less than 5 years of age. The incidence of coronary artery lesions (CAL) is high in untreated KD. The diagnosis criteria of KD includes fever more than 5 days as well as four of the five symptoms (bilateral non-purulent conjunctivitis, neck lymphoadenopathy, polymorphous skin rash, indurative change over extremities and oral mucosa changes). There were still no any biological markers specific for the diagnosis of KD available now. We wish to find some diagnostic markers for clinician.
From our previous results, we found that T helper (Th) 2 immune reaction including eosinophil (Pediatr Allergy Immunol 2007) and interleukin (IL)-5 (Pediatr Allergy Immunol 2009) were associated with CAL and intravenous immunoglobulin (IVIG) treatment response in KD. Th1 immune response in human and mice animal model including interferon-gamma (IFNr), IL-6 and CD40 ligand also showed significance. (PLos one 2012, Pediatrics 2003) Immune gene (CTLA-4, ITPKC) also showed significant association with susceptibility and CAL formation in KD (J Clinic Immunol 2011, Plos One 2011).
Recently, genome wide association study (GWAS) reported from different laboratory and showed immune genes including ITPKC, CD40, BLK and FCGR2A playing important role in the pathogenesis of KD and/or the formation of CAL (Nature Genetics 2008, 2011, 2012). Though lot of publication from GWAS but the clinical application of these studies still have a long distance to reach.
The influence of the environment on the epigenetic programming of adult diseases has been linked to diabetes, cardiovascular diseases, asthma, autoimmune diseases and kidney diseases. It has also been postulated that certain genes can be epigenetically modified by environmental factors thus priming individuals to develop atopy or inflammation. There are still no publications about epigenetic in KD till now. From our preliminary results, the methylation levels showed significant difference between KD and control when regarding FCGR2A. Thus, we hypothesize that epigenetic is responsible for the susceptibility and/or CAL formation in KD through regulating Th1/Th2/Th17/Treg immune response. Based on the hypothesis above, we attempt to reach the 3 specific aims in the following 3 years below:
1. Certain epigenetic programming responsible for the susceptibility and/or CAL formation in KD, through “Profiling of CpG methylation” (HumanMethylation450 BeadChip). We have enrolled more than 300 KD samples from our previous genetic studies. Different stage of KD including acute stage before IVIG treatment, acute stage after IVIG treatment and convalescence stage will enroll for analyze the methylation level changes and clinical phenotypes.
2. Validation the significant methylation results from HumanMethylation450 BeadChip assay of 1st year by pyrosequencing in different stage of KD samples. Functional validate the epigenetic changes that alter the Th1/Th2/Th17/Treg cytokines expression (IL-2, IL-4, IL-5, IFN-gamma, Th17 and TGF-beta) and mRNA expression (GATA-3, T-bet, Foxp3 and RORrt) in different stage of KD patients and association with CAL formatoin.
3. To validate functional implications of different epigenetic change. To clarify that KD patient with revealed altered Th1/Th2/Th17/Treg immune response and CAL formation of KD. Further studies will explore the different variants epigenetic change (ex. FCGR2A) regulate Th1/Th2/Th17/Treg immune response under PHA or Lactobacillus casei cell wall extraction (LCWE) stimulation in the mononuclear cells from KD patients.
Clarification of the immunophathogenesis of epigenetics on Th1/Th2/Th17/Treg expression in the CAL formation of KD will provide information to early predict KD with CAL formation, and possibly to raise strategies for preventing KD and avoiding CAL formation.
Project IDs
Project ID:PC10301-0543
External Project ID:NSC102-2314-B182-053-MY3
External Project ID:NSC102-2314-B182-053-MY3
Status | Finished |
---|---|
Effective start/end date | 01/08/14 → 31/07/15 |
Keywords
- Kawasaki disease
- epigenetics
- methylation
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