TGF-β信号通路调控Treg/ Th17平衡及诱导神经梅毒免疫炎症性损伤的分子机制

Neurosyphilis can be symptomatic or asymptomatic. Symptomatic neurosyphilis may have brain parenchymal degeneration, resulting in paralytic dementia and other serious adverse outcomes, while the latter has no tissue damage, whose mechanism remains unknown. Our previous study confirmed that the lower the Treg/Th17 ratio of cerebrospinal fluid (CSF) in neurosyphilis, the more severe the CNS lesions. Moreover, our recent pre-test showed that the lower the level of TGF-β in the CSF, the higher the Treg/Th17 ratio. Accordingly we made the following assumptions: syphilis specific Treg and Th17 cells from CSF of neurosyphilis are regulated by TGF-β signaling pathway; by regulating Treg/Th17 balance, TGF-β influences the activation of microglia, thus leading to different clinical outcomes of neurosyphilis. By evaluating the level of Treg, Th17, TGF-β, IL-6, and the phosphorylation level of Smad3 in peripheral blood, CSF and tissues from various types of neurosyphilis patients, we aim to explore the molecular mechanisms of TGF-β signaling pathway in inducting Treg and Th17 cell differentiation and in regulating Treg/Th17 balance, which affects the progress of neurosyphilis. The hypothesis will be further validated in vitro and in animal experiments. This study may provide new evidence and ideas for the pathogenesis mechanism of neurosyphilis within the scope of cellular and molecular immunology.

神经梅毒可表现为有症状和无症状。有症状神经梅毒可出现脑实质退行性变，造成麻痹性痴呆等严重不良后果，而后者却无组织损伤，其机理迄今不明。我们前期研究证实，神经梅毒脑脊液（CSF）中Treg/Th17比值越低神经系统病变越重；近期预试验显示，CSF中TGF-β水平越低Treg/Th17比值越高。据此我们提出假设：神经梅毒CSF中Treg/Th17受TGF-β信号通路调控; TGF-β通过调控Treg/Th17平衡，影响小胶质细胞活化，从而影响神经梅毒不同临床结局。本研究通过检测各类神经梅毒外周血、CSF和组织中Treg、Th17、TGF和IL-6水平及Smad3的磷酸化情况，探索TGF-β信号通路在诱导Treg和Th17细胞分化、调控Treg/Th17平衡并进而影响神经梅毒发病进程的分子机制，并进一步在体外和动物实验中加以验证。这一研究可能为破解神经梅毒的细胞与分子免疫学机制提供新证据。

梅毒是由梅毒螺旋体感染引起的性传播疾病，在机体内能产生较强的免疫反应导致组织损伤，有研究报道调节性T细胞和Th17细胞在梅毒病理损伤中发挥重要的作用，而调节性T细胞和Th17细胞在神经梅毒中的作用机制尚不明确。.我们分析了431例非神经梅毒患者和100例神经梅毒患者外周血血和脑脊液中Treg的百分比和TGF-β水平，发现：与正常对照相比，二期梅毒和血清固定梅毒患者外周血中Treg的百分比和TGF-β水平均增加，并且外周血中Treg的百分比与RPR滴度呈正相关。与非神经梅毒相比，神经梅毒患者外周血中Treg的百分比增加。在神经梅毒中枢神经系统，脑脊液中白细胞数增加，以CD4+T细胞为主，但是CD4+ CD25high Treg百分比和TGF-β却降低。.用流式细胞术分析了103例神经梅毒，69例神经梅毒和70例正常对照外周血中Th17细胞百分比，用ELISA方法检测神经梅毒和非神经梅毒患者脑脊液中IL-17的水平，并且对44例神经梅毒随访一年研究IL-17在神经梅毒中枢神经系统损伤中的作用。我们的研究结果发现：与正常对照相比，神经梅毒患者外周血中Th17细胞百分比明显升高。脑脊液中IL-17水平在神经梅毒尤其是有症状神经梅毒患者中明显增高。神经梅毒中枢神经系统IL-17主要来源于CD4+T细胞（Th17），神经梅毒患者中枢神经系统IL-17水平与脑脊液中蛋白和VDRL滴度呈正相关。.我们的研究提示调节性T细胞可能在梅毒的持续性感染及中枢神经系统的损伤中发挥一定的作用。中枢神经系统Th17细胞免疫反应可能参与了神经梅毒中枢神经系统的损伤及可以作为神经梅毒临床预后的一个指标之一。