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，目前尚无成熟的治疗方法。SSPE在麻疹疫苗覆盖率较低的一些亚洲国家普遍存在。由于麻疹病毒引起SSPE的确切机制尚不清楚，因此充分阐明其发病机制和病理生理是建立有效治疗策略的必要条件。在本项目中，我们基于已知的发病机制和DNA微阵列分析数据，对SSPE的新型易感基因进行了全面的搜索。高密度寡核苷酸芯片和随后的定量逆转录酶聚合酶链反应显示，颗粒蛋白酶mRNA水平在SSPE患者中降低，而在麻疹患者中升高，提示颗粒蛋白酶可能在宿主防御MV中发挥作用，可能参与SSPE的发病机制或病理生理。结果表明，MxA、白细胞介素(IL)-4和干扰素调节因子-1 （IRF-1）基因的功能多态性与日本人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易感性的新候选基因，我们分析了编码双链RNA识别分子、共刺激分子和相关分子的12个基因的27个多态性。PD-1与日本人和菲律宾人的SSPE发生有关，而TLR-3仅与日本人的SSPE发生有关。利巴韦林是一种新的SSPE治疗方法，对脑室内给予利巴韦林治疗的患者进行分析表明，将脑脊液利巴韦林浓度维持在最佳水平对于从中枢神经系统根除SSPE病毒和减少治疗过程中的不良事件至关重要。从血清和脑脊液细胞因子的角度分析了SSPE病理生理的免疫学方面。IL-6、IL-4、IL-2、干扰素-γ、TNF-α、IL-10、sTNFR1以及与血脑屏障相关的两种分子MMP-9、TIMP-1与SSPE病理性炎症过程相关。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