miRNA及其基因多态性与脱髓鞘性视神经炎在新疆维汉患者发病中免疫调节作用及遗传机制的研究

Demyelinating optic neuritis（DON）is one of the most common and actue optical disease and is a leading cause of vison impairing in people of the working age all over the world. It is expected that DON will have a growing impact on young populationa. Multiple mechanisms are involved in DON. But the clear and detailed pathogenesis of DON is not elucidated. There is increasing evidence that an ongoing cytokine-induced acute-phase response (sometimes called low-grade inflammation, but part of a widespread activation of the innate immune system) is closely involved in the pathogenesis of autoimmune diseases such as DON. Mammalian microRNAs (miRNAs)are small (18-25nt long),endogenous, noncoding RNA oligonucleotides. They are highly conserved during evolution and have recently emerged as potent regulators of gene expression linked to most biological function. miRNAs posttranscriptionally regulate gene expression by binding with imperfect complementarity to the sequences in the 3’ untranslated region (3’ UTR) oftarget mRNAs. miRNAs has recently been shown to have immunomodulation property. Recent studies showed that miRNA was able to skew the T cell compartment into a more anti-inflammatory and regulated state, as evidenced by inhibition of Th1 and Th17 cells and promotion of Th2 and T reg cells. In Vitro experiments showed that miRNA could promote both innate and adaptive immune responses. Studies revealed that the.development of DON depend on not only duration of demyelinating but also positive family history and individual diversities.This phenomenon may be related to various genetic polymorphisms and individuals. DON is a disease of the role of multi-gene, and therefore there is different polymorphisms in each gene. It is very important for us to accurately understand the mechanism of the difference expression of gene during the occurrence and development of DON in the early diagnosis and prevention of DON. Whether miRNA and its polymorphisms are involved in the pathogenesis in DON in Uyghur population has not been determined. This study is, therefore, designed to investigate the alteration and the possible function of miRNA its polymorphisms in Uyghur DON population.

脱髓鞘性视神经炎(demyelinating optic neuritis,DON)是主要累及视神经的中枢神经系统炎性脱髓鞘疾病，是中青年患者临床最常见的视神经病变，也是造成青壮年视力丧失的一个主要因素。DON 病因复杂，研究表明其发病与免疫反应密切相关。miRNA 是一类小分子非编码RNA，被证明在免疫反应中起重要作用，本项目以DON 为研究对象，以miRNA为切入点，探讨患者外周血中B 细胞，单核细胞及CD4+T 细胞中miRNA 表达水平的差异；探讨miRNA 对患者免疫细胞的影响及细胞因子分泌的影响，阐明miRNA 在NMO 发病过程中的免疫调节作用；在体内体外进行miRNAs 的可能靶向基因预测及验证；探讨miRNA 基因多态性与DON 的相关性。本研究将可能回答miRNA 介导的免疫反应在DON 发病过程中是否起作用及可能的作用机制，可能为DON 的防治提供新的靶点和切入点。

视神经炎（optic neuritis,ON）是现今青年人中易罹患的致盲眼病。随着十几年前APQ4-IgG的被发现和应用，进一步证实了NMO与IDON是不同的病因机制的两种疾病。近年来，在APQ4-IgG呈阴性的患者的血清中发现了MOG-IgG呈阳性，并且MOG抗体阳性和AQP4抗体阳性的视神经炎患者的临床表现及治疗预后都有差异，所以最新的国际分型为特发性脱髓鞘性视神经炎、APQ4抗体阳性的视神经炎、MOG抗体阳性的视神经炎。miRNA是一类单链RNA，目前国内外有大量研究表明视神经脊髓炎患者和多发性硬化患者全血和血清中存在有意义的差异miRNA，两者之间存在明显的表达差异。但至今国内外针对特发性视神经炎miRNA的研究基本上基于全血中的检测，且研究发现APQ4抗体阳性患者、MOG抗体阳性视神经炎患及IDON患者的脑脊液中亦存在抗体。本研究中进一步阐明miRNA在发病中的可能作用和机制，以及脑脊液中的miRNA对于两种疾病的鉴别，以达到早诊断、早治疗，甚至通过干扰和修饰miRNA达到治疗目的。与AQP-4抗体相关的ON是一种复杂免疫病理学的星形细胞病变，有大量的研究表明其发病涉及B细胞、嗜酸性粒细胞、中性粒细胞和Th17细胞。与之形成对比的是，除了自身抗体相关的机制外，关于MOG抗体介导的炎性反应相关的免疫机制并不清楚。先前的研究指出BAFF、IL-17、IL-6和CXCL13浓度的增加是诱导ON病变形成的关键因素，且已被证明与疾病的严重程度和扩大的残疾状况评分有关。鉴于新出现的致病性证据，在本研究中，我们调查和分析了AQP4+组和MOG组血清细胞因子/趋化因子水平及其相互关系，以确定是否存在某些细胞因子/趋化因子可作为MOG抗体阳性ON免疫机制的生物标志物，为进一步研究ON的发病机制及病理生理机制提供进一步参考。