Comprehensive search for genes associated with susceptibility to subacute sclerosing panencephalitis in Asia.

亚急性硬化性全脑炎(SSPE)是一种进行性和致命性的神经系统疾病，没有既定的治疗方法。SSPE流行于一些麻疹疫苗覆盖率较低的亚洲国家。由于麻疹病毒引起SSPE的确切机制尚不清楚，充分阐明其发病机制和病理生理学对于制定有效的治疗策略是至关重要的。在本项目中，我们根据已知的发病机制和DNA微阵列分析数据，对SSPE的新易感基因进行了全面的寻找。高密度寡核苷酸芯片和随后的定量逆转录聚合酶链式反应显示，颗粒溶素在SSPE患者中表达降低，在麻疹患者中表达升高，提示颗粒溶素可能在宿主对MV的防御中发挥作用，并可能参与SSPE的发病或病理生理。我们证明了…的功能多态更多的MXA、白介素4和干扰素调节因子1基因与日本人SSPE的发生有关。然而，对菲律宾SSPE患者和对照组的相同分析未能揭示这些基因与SSPE之间的关联。作为SSPE易感的新候选基因，共分析了12个编码双链RNA识别分子、共刺激分子及相关分子的基因的27个多态性。在日本和菲律宾，PD-1与SSPE的发生有关，而TLR-3仅在日本显示出相同的相关性。对脑室内应用利巴韦林治疗SSPE患者的分析表明，将脑脊液利巴韦林浓度维持在最佳水平对于清除中枢神经系统中的SSPE病毒并减少治疗期间的不良事件至关重要。IL-6、IL-4、IL-2、干扰素-γ、、肿瘤坏死因子-α、、IL-10、、和血脑屏障相关分子MMP9、TIMP-1参与了SSPE的病理炎症过程。较少

Subacute sclerosing panencephalitis (SSPE) is a progressive and fatal neurological illness without established treatment. SSPE is prevalent in some Asian countries where coverage rate of measles vaccine is low. As the precise mechanism how measles virus causes SSPE is still unknown, full clarification of pathogenesis and pathophysiology is essential to establish effective strategy to treat the illness. In this project, we performed a comprehensive search for novel susceptibility genes of SSPE based on the known pathogenesis and data on DNA microarray analysis. High-density oligonucleotide microarray and subsequent quantitative reverse transcriptase polymerase chain reaction demonstrated that the mRNA levels of granulysin were decreased in SSPE patients and were increased in measles patients, suggesting that granulysin might play a role in the host defense against MV and possibly be involved in the pathogenesis or pathophysiology of SSPE. We demonstrated that functional polymorphisms of … More MxA, interleukin (IL)-4 and interferon regulatory factor-1 (IRF-1) genes are associated with the development of SSPE in Japanese. However, the same analysis on Filipino SSPE patients and controls failed to reveal the association between these genes and SSPE. As novel candidate genes for susceptibility to SSPE, a total of 27 polymorphisms of 12 genes encoding molecules involved in double-strand RNA recognition, costimulatory molecules and related molecules were analyzed. PD-1 was associated with the development of SSPE in both Japanese and Filipino, while TLR-3 showed same association only in Japanese.Analyses of patients treated with intraventricular administration of ribavirin which has been developed as a novel treatment for SSPE showed that it is crucial to maintain CSF ribavirin concentration at optimum level to eradicate SSPE virus from CNS and reduce the adverse events during the treatment.Immunological aspect of the pathophysiology of SSPE was analyzed in terms of serum and CSF cytokines. IL-6、 IL-4、 IL-2、 interferon-γ、 TNF-α、 IL-10、 sTNFR1 and two molecules associated with blood brain barrier, MMP-9 and TIMP-1 were associated with the pathological inflammatory process of SSPE.. Less