Project Details
Abstract
Kawasaki disease (KD) is a systemic vasculitis of unknown etiology that primarily affects
children under 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. At
present, high dose of intravenous immunoglobulin (IVIG) with aspirin is the standard
treatment for KD.
Recently, we showed that persistent monocytosis after IVIG treatment will promote the
CAL formation in KD. The monocytosis implies the augment action of innate immunity in
the acute phase of KD. In contrast, we also found that, eosinophilia after IVIG treatment
was associated with the intravenous immunoglobulin treatment failure. (Pediatr Allergy
Immunol 2007, SCI IF:2.67, rank: 11/94). Further analysis showed that eosinophilia and
interleukin-5 were associated with the protection of CAL formation in KD. (Pediatr Allergy
Immunol 2009) The eosinophilia/IL-5 elevation in KD may represent a prominent Th2
reaction. We also reported that immune regulatory gene (CTLA-4) associated with CAL
formation in KD. (J Clinic Immunol 2010, SCI IF:3.58)
Recently, we use 384 customized SNPs chip array and found the gene-gene interaction
between IL2RA- HCG8(rs2517893) had significant association with CAL formation in KD
under MDR analysis.
IL2RA, also known as CD25, is expressed on the regulatory T cells, which play an
important role in the control of immune responses, and involvement in type I diabetes and
rheumatoid arthritis. Our preliminary study found that single nucleotide polymorphism
(SNPs) of IL-2 receptor alpha (IL2RA, rs3118470, a functional locus) plays important role
on the CAL formation of KD. Thus, we hypothesize that IL2RA is responsible for the CAL
formation of KD through variant CD25/sCD25 expression and regulating Th1/Th2 immune
response. Based on the hypothesis above, we attempt to reach the 3 specific aims in the
following 3 years below:
1. To explore the association of variant SNPs IL2RA with the CAL formation of KD. We have
provided initial evidence that sequence variants (rs3118470) of IL2RA gene was associated
with the CAL formation of KD. Further studies will recruit more samples from another
cohort (VGH-KS) to confirm the impact of IL2RA on the pathogenesis of KD with and
without coronary artery lesions via CD25/sCD25 and Th1/Th2 immune response.
2. To validate functional implications of different IL2RA polymorphisms. To clarify that KD
patient with variant IL2RA SNPs revealed altered homeostasis of Th1/Th2 immune
response and CAL formation of KD. Further studies will explore the whether variants of
IL2RA affect the CD4+CD25/sCD25 and subsequent skewed Th1/Th2 immune response
under PHA or Lactobacillus casei cell wall extraction (LCWE) stimulation in the
mononuclear cells from KD patients with and without CAL.
3. To prove that variant SNPs of IL2RA are associated with different CD25/sCD25 and
skewed Th1/Th2 response as seen in KD patients with CAL. Further studies will use our
well established KD animal model with C57BL/6 and IL2RA knockout mice with
intraperitoneal injected with LCWE. Studies will explore the important role of IL2RA
knockout in the immunopathogenesis of KD with CAL formation and the Th1/Th2 immune
response.
Clarification of the immunophathogenesis of IL2RA on CD25/sCD25 and Th1/Th2 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:PC10202-0222
External Project ID:NSC100-2314-B182-061-MY3
External Project ID:NSC100-2314-B182-061-MY3
Status | Finished |
---|---|
Effective start/end date | 01/07/13 → 30/06/14 |
Keywords
- Kawasaki disease
- IL2RA
- coronary artery lesions
- Th1/Th2
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