FCGR2A基因多态性通过TLRs-NFκB信号通路介导川崎病IVIG抵抗的分子机制研究

丙种球蛋白（IVIG）无反应型川崎病（KD）表现为患儿对首剂IVIG治疗不敏感，其血浆中C反应蛋白（CRP）水平异常增高。Fcγ受体IIa（FcγR IIa，FCGR2A）是CRP分布在人单核细胞表面的主要受体，其编码基因rs1801274位点单核苷酸多态性A/G决定FcγR IIa与IgG及CRP结合的强弱，当此位点为A时，与IgG高亲和力而与CRP低亲和力结合；为G时则相反。本课题组参加的一项GWAS研究证实FCGR2A基因rs1801274位点与KD患儿冠状动脉病变发生有关。目前研究显示Toll样受体（TLRs）在KD患儿体内高度表达，TLRs的异常激活对炎症性疾病的发生起着关键性作用。本研究拟用分子及细胞生物学方法检测FCGR2A基因rs1801274位点多态性导致其和CRP及IgG结合能力失衡与TLRs-NFκB异常激活的关系，阐明高水平CRP介导IVIG无反应型KD的机制。

Intravenous immunoglobulin-nonresponsive Kawasaki disease (KD) is characterized by insensitivity to the first dose of intravenous immunoglobulin (IVIG) and abnormal elevation of plasma C-reactive protein (CRP). Fc gamma receptor IIa (Fc gamma RIIa, FCGR2A) is the main receptor of CRP on the surface of human monocytes, which encodes single nucleotide polymorphism at rs1801274 locus resulted in high binding ability of FcγRIIa to CRP and low ability of IG. Our GWAS study in 2011 confirmed that single nucleotide polymorphism at rs1801274 locus of FCGR2A gene was associated with coronary artery lesion with KD. At present, clinical studies have found that Toll-like receptors (TLRs) are highly expressed in KD patients. Aberrant activation of TLRs may result in unrestricted inflammatory responses, which play a pivotal role in the development of inflammatory diseases. This study aimed to explore the relationship between the polymorphism of rs1801274 locus of FCGR2A gene imbalanced binds to CRP and IG and the abnormal activation of TLRs-NFκB in peripheral blood mononuclear cells of KD patients, human monocyte line (THP-1) and animal models by molecular and cellular techniques, and to elucidate the molecular mechanism of IVIG-nonresponsive KD mediated by high-level CRP, which lays a foundation for finding therapeutic targets of IVIG-nonresponsive KD.