中枢神经系统炎性脱髓鞘疾病新型生物标记物研究

发布时间：2018-05-23 19:17

本文选题：脱髓鞘疾病趋化因子 + CXCL13　；参考：《安徽医科大学》2017年硕士论文

【摘要】：目的探讨中枢神经系统(CNS)炎性脱髓鞘疾病相关的一些新型生物标记物,包括B细胞趋化因子CXCL13、神经丝蛋白轻链(NFL)、25-羟基维生素D3[25(OH)D3]的表达特点及其与临床、影像的关系,探讨维生素D受体基因(VDR)、水通道蛋白4(AQP4)基因、Fc受体样3(Fc RL3)基因单核苷酸多态性(SNPs)突变情况,为CNS炎性脱髓鞘疾病发病机制的探索、鉴别诊断和临床转归提供依据。方法收集就诊于海军总医院神经内科的CNS炎性脱髓鞘疾病患者及正常对照(NC),收集实验组临床、影像信息及各组血清、全血和脑脊液(CSF)标本,以酶联免疫吸附实验(ELISA)方法检测血清和CSF中CXCL13水平及CSF中NFL水平,以质谱法检测血清25(OH)D3水平,以第一代基因测序方法检测VDR基因、AQP4基因和Fc RL3基因SNPs序列。结果(1)CIS组、MS组、NMOSD组血清和CSF中CXCL13水平均高于NC组(P0.05)。NMOSD组血清和CSF中CXCL13水平明显高于CIS组和MS组(P0.05),MS组CSF中CXCL13水平明显高于CIS组(P0.05)。CIS组、MS组、NMOSD组CSF中CXCL13水平分别与其EDSS评分和MRI上病灶强化相关(P0.05)。(2)CIS组、MS组、NMOSD组CSF中NFL水平均高于NC组(P0.05)。CIS组、MS组、NMOSD组组间CSF中NFL水平无显著统计学差异(P0.05)。CIS组、MS组、NMOSD组CSF中NFL水平与其EDSS评分和MRI上病灶强化相关(P0.05)。(3)CIS组、MS组、NMOSD组血清25(OH)D3水平均明显低于NC组(P0.05)。CIS组、MS组、NMOSD组组间血清25(OH)D3水平比较无显著统计学差异(P0.05)。CIS组、MS组、NMOSD组组间血清25(OH)D3水平与EDSS评分和CSF中NFL水平无明显相关(P0.05)。(4)CIS组、MS组、NMOSD组VDR基因rs2228570位点突变率明显高于NC组,且具有统计学差异(P0.05)。CIS组、NMOSD组rs7975232位点突变率明显高于NC组,且具有统计学差异(P0.05);MS组rs7975232位点突变率高于NC组,但无统计学差异(P0.05)。(5)CIS组、MS组、NMOSD组AQP4基因rs2075575、rs3763043、rs14393位点突变率分别与NC组比较均无统计学差异(P0.05);NMOSD组AQP4-Ab阳性与否对AQP4基因SNPs亦无影响(P0.05)。(6)CIS组、NMOSD组Fc RL3基因rs7528684和rs3761959位点突变率明显高于NC组,且具有统计学差异(P0.05);MS组rs7528684和rs3761959位点突变率高于NC组,但无统计学差异(P0.05)。MS组、NMOSD组rs945635位点突变率明显高于NC组,且具有统计学差异(P0.05);CIS组rs945635位点突变率高于NC组,但无统计学差异(P0.05)。结论CSF中CXCL13水平和CSF中NFL水平是预测CIS、MS和NMOSD的残障程度及疾病活动性的生物学指标。CIS、MS和NMOSD患者均存在维生素D缺乏,但其血清25(OH)D3水平与残障程度不相关。VDR基因rs7975232和rs2228570位点突变、Fc RL3基因rs7528684、rs945635和rs3761959位点突变可增加CIS、MS、NMOSD患者发病风险,但对区分CNS炎性脱髓鞘疾病的种类和判断其转归均无明显作用。AQP4基因SNPs对CIS、MS、NMOSD患者发病无明显影响。
[Abstract]:Objective to investigate the expression characteristics of neurofilament light chain protein (NFL) 25-hydroxyvitamin D _ 3 (25(OH)D3) and its relationship with clinical and imaging features, including B cell chemokine CXCL13, neurofilament protein light chain, and some novel biomarkers associated with inflammatory demyelinating disease in central nervous system (CNS). To investigate the mutations of vitamin D receptor gene (VDR), aquaporin-4 (aquaporin-4) gene, FC-like 3(Fc RL3) gene and single nucleotide polymorphisms (SNPs) in order to explore the pathogenesis of CNS inflammatory demyelinating disease and to provide evidence for differential diagnosis and clinical outcome. Methods the clinical, imaging information and serum, whole blood and cerebrospinal fluid (CSF) samples of patients with CNS inflammatory demyelinating disease and normal control group were collected from Department of Neurology, Naval General Hospital. The levels of CXCL13 in serum and CSF and NFL in CSF were detected by Elisa, 25(OH)D3 in serum were detected by mass spectrometry, and SNPs sequences of VDR and FC RL3 genes were detected by first-generation gene sequencing. Results the levels of CXCL13 in serum and CSF in MS group were higher than those in NMOSD group in NC group (P 0.05). CXCL13 in CSF group was significantly higher than that in CSF in CIS group and MS group (P 0.05). CXCL13 level in CSF in MS group was significantly higher than that in CIS group (P 0.05). The CXCL13 level in CSF in MS group was significantly higher than that in CIS group. The NFL level in CSF of MS group was higher than that of NC group P0.05 +. Cis group. There was no significant difference in NFL level between MS group and NMOSD group (P0.05). NFL level in CSF, EDSS score and enhancement of MRI in MS group were higher than those in NMOSD group (P 0.05 ~ 0. 05, P < 0. 05), and there was no significant difference in NFL level between NMOSD group and MS group (P 0. 05, P 0. 05, P < 0. 05, P < 0. 05). There was no significant difference in serum 25(OH)D3 level between MS group and EDSS score and NFL level in CSF. There was no significant difference in serum 25(OH)D3 level between MS group and NMOSD group (P 0.05). There was no significant difference in serum 25(OH)D3 level between MS group and EDSS group and NFL level in CSF in MS group and in CSF group. There was no significant difference in serum 25(OH)D3 level between MS group and NC group (P 0.05, P 0.05). There was no significant difference in serum 25(OH)D3 level with EDSS score and NFL level in CSF between MS group and EDSS group in CIS group. There was no significant difference in serum 25(OH)D3 level between NMOSD group and MS group. The mutation rate of VDR rs2228570 locus in MS group was significantly higher than that in NC group. The mutation rate of rs7975232 locus in NMOSD group was significantly higher than that in NC group, and the mutation rate of rs7975232 locus in MS group was higher than that in NC group. However, there was no significant difference in the mutation rate of rs20755775, rs3763043, rs14393 in AQP4 gene between MS group and NC group. There was no significant difference between P0.05NMOSD group and NC group. There was no significant difference in AQP4-Ab positive rate of AQP4 gene SNPs between NMOSD group and NC group. The mutation rates of rs7528684 and rs3761959 locus of FC RL3 gene in NMOSD group were significantly higher than those in NC group. The mutation rate of rs7528684 and rs3761959 in MS group was higher than that in NC group, but the mutation rate of rs945635 locus in P0.05 + MS group was significantly higher than that in NC group, and the mutation rate of rs945635 locus in P0.05 + MS group was higher than that in NC group, but there was no statistical difference (P0.05). Conclusion the levels of CXCL13 in CSF and NFL in CSF are biological indexes for predicting the degree of disability and disease activity of CISMS and NMOSD. There is vitamin D deficiency in patients with CISMS and NMOSD. However, the level of serum 25(OH)D3 was not related to the degree of disability. The mutation of rs7975232 and rs2228570 locus of rs2228570 gene Fc RL3 gene rs7528684 rs945635 and rs3761959 locus increased the risk of NMOSD patients. AQP4 gene SNPs had no significant effect on the classification and prognosis of CNS inflammatory demyelinating diseases. There was no significant effect of AQP4 gene SNPs on the pathogenesis of CNS.
【学位授予单位】：安徽医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R744.5

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