Fc Gamma Receptors Expression and Impact on Kawasaki Disease

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). Intravenous immunoglobulin (IVIG) is the most important treatment for acute stage of KD and Fc gamma receptors is the binding site for IVIG. From our previous results, we found that T helper (Th) 2 immune reaction including eosinophil, interleukin (IL)-5 and IL-4 (Pediatr Allergy Immunol 2007, 2009) were associated with protective effect in CAL formation and intravenous immunoglobulin (IVIG) treatment response in KD. We found autoimmune associated inflammation Th17- related cytokine and mRNA expression are associated with acute and resolving KD. (Allergy 2015, SCI IF: 6.028)。Cooperation with Sinca Taiwanica, we revealed CXCL10/IP-10 is a biomarker and mediator for KD. (Circulation Research 2015, SCI IF: 11.018) 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). 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. Recently, we identification of an association between genomic hypomethylation of FCGR2A and susceptibility to KD and IVIG resistance by DNA methylation array. (Arthritis and Rheumatology 2015, SCI IF: 7.764) Anthony RM. et al. reported novel DC-SIGN-Th2 pathway initiated by an endogenous ligand, sFc, provides an intrinsic mechanism for maintaining immune homeostasis that could be manipulated to provide therapeutic benefit in autoimmune diseases and suppress inflammation.(Nature 2011) The anti-inflammation of Th2 was compatible with our findings of eosinophil and IL-4. Fc receptors also regulate innate and adaptive immunity. (Nature Immunology 2014) Thus, we hypothesize that certain Fc gamma receptors are responsible for the susceptibility and/or CAL formation in KD through regulating Th1/Th2/Th17 immune response. Based on the hypothesis above, we attempt to reach the 3 specific aims in the following 3 years below: 1. Methylation detection through pyrosequencing of Fc gamma receptors including (I, IIa, IIb, IIc, IIIa, IIIb) and flowcytometry for cell surface markers of Fc gamma receptors (CD64, CD32a, CD32b, CD32c, CD16a, CD16b) in different stage of KD. We will use previous samples from previous study (IRB: 100-2879A3) and enroll 50 new KD patients with 50 new age-marched controls each year. 2. Detection mRNA expression of Fc gamma receptors (I, IIa, IIb, IIc, IIIa, IIIb) and analysis with Th1/Th2/Th17 immune response (cytokines: IL-4, IL-5, IL-2, IFN-gamma, IL-17, and mRNA: T-bet, GATA-3, IL-17, RORrt）to study the relation between Fc gamma receptors and Th2 (anti-inflammation) with Th1/Th17 (inflammation response) in different stage of KD, CAL and IVIG treatment response. 3. To validate functional implications of different Fc gamma receptors on Th1/Th2/Th17 response. Recombination IVIG (rIVIG) only contain Fc portion will be studied and compare the effect with IVIG on in vitro KD model of CD40 expression and calcification. Clarification of the immunophathogenesis of Fc gamma receptors on Th1/Th2/Th17 expression and the impact on CAL formation of KD will provide information to prevent CAL formation, and possibly to raise strategies for treatment of KD with rIVIG.

Project ID:PC10507-0269
External Project ID:MOST105-2314-B182-050-MY3