Impact of IL2RA variants on the coronary artery lesions of Kawasaki disease

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

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
StatusFinished
Effective start/end date01/07/1330/06/14

Keywords

  • Kawasaki disease
  • IL2RA
  • coronary artery lesions
  • Th1/Th2

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