Hui-Yuen Joyce S, Duong Trang T, Yeung Rae S M
Cancer Research Program, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, Ontario, Canada.
J Immunol. 2006 May 15;176(10):6294-301. doi: 10.4049/jimmunol.176.10.6294.
Kawasaki disease is the most common cause of multisystem vasculitis in childhood. The resultant coronary artery lesions make Kawasaki disease the leading cause of acquired heart disease in children in the developed world. TNF-alpha is a pleiotropic inflammatory cytokine elevated during the acute phase of Kawasaki disease. In this study, we report rapid production of TNF-alpha in the peripheral immune system after disease induction in a murine model of Kawasaki disease. This immune response becomes site directed, with migration to the coronary arteries dependent on TNF-alpha-mediated events. Production of TNF-alpha in the heart is coincident with the presence of inflammatory infiltrate at the coronary arteries, which persists during development of aneurysms. More importantly, inflammation and elastin breakdown in the coronary vessels are completely eliminated in the absence of TNF-alpha effector functions. Mice treated with the TNF-alpha-blocking agent etanercept, as well as TNFRI knockout mice, are resistant to development of both coronary arteritis and coronary aneurysm formation. Taken together, TNF-alpha is necessary for the development of coronary artery lesions in an animal model of Kawasaki disease. These findings have important implications for potential new therapeutic interventions in children with Kawasaki disease.
川崎病是儿童多系统血管炎最常见的病因。由此导致的冠状动脉病变使川崎病成为发达国家儿童后天性心脏病的主要病因。肿瘤坏死因子-α（TNF-α）是一种多效性炎症细胞因子，在川崎病急性期升高。在本研究中，我们报告了在川崎病小鼠模型中疾病诱导后外周免疫系统中TNF-α的快速产生。这种免疫反应具有部位特异性，向冠状动脉的迁移依赖于TNF-α介导的事件。心脏中TNF-α的产生与冠状动脉处炎症浸润的存在同时发生，这种炎症浸润在动脉瘤形成过程中持续存在。更重要的是，在没有TNF-α效应功能的情况下，冠状动脉血管中的炎症和弹性蛋白分解完全消除。用TNF-α阻断剂依那西普治疗的小鼠以及TNFRI基因敲除小鼠对冠状动脉炎和冠状动脉瘤形成均具有抗性。综上所述，TNF-α是川崎病动物模型中冠状动脉病变发展所必需的。这些发现对川崎病患儿潜在的新治疗干预具有重要意义。
