系统性红斑狼疮血脑屏障损伤的动态增强磁共振检测及分子免疫机制的研究

Systemic Lupus Erythematosus (SLE) is a serious autoimmune disease that affects almost all of the organs and systems in the body. The etiologies of SLE remain unclear. The CNS involvement and neuropsychiatric symptoms (NPSLE) are usual in SLE, resulting in the poor treatment effect and prognosis. Until now, understanding of NPSLE is a big challenge for the clinical practice, due to the unknown pathologies, difficulty of early diagnosis, and absence of objective indictors. Recent studies prove the association between the damage of blood-brain barrier (BBB) and the NPSLE. The dysfunction of BBB may happen very early in the course of SLE and become the core deficit of the brain in NPSLE. Effective treatment may accompany with the recovery of BBB. However, the methods used to evaluate the damage of BBB are rare and insensitive, leading to the difficulty of early recognize and treatment decision. A newly developed technique, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), with the advantage of invasive, convenient and sensitive, has been used to the evaluation of deficit of BBB in patients with brain tumor or hemorrhage successfully. Yet there is no established methods used in SLE. Present study aims to establish a systemic technique for evaluating the deficit of BBB in SLE. Combined with other biological makers, the measurement of BBB dysfunction may help to the understanding of the molecular mechanism of BBB deficit in SLE. We also want to compare the measurement of BBB dysfunction before and after the corticosteroid treatment to understand the value of DCE-MRI in the evaluation of BBB dysfunction and recovery. Providing a new method for the clinical evaluation of BBB dysfunction and recovery in SLE, this study will have a great value in the early diagnosis and treatment decision for the brain damage of SLE.

系统性红斑狼疮（SLE）是一种病因不明的自身免疫病，中枢神经系统受累的神经精神狼疮（NPSLE）严重影响疾病疗效和预后。血脑屏障（BBB）的损伤在NPSLE中有重要作用，可能是SLE早期脑损伤的核心，而有效的治疗常伴随BBB的修复。现有BBB损伤的判断方法较少且不敏感，给NPSLE早期识别与疗效判断带来困难。新近开发的动态增强磁共振（DCE-MRI）技术具有无创、快捷、敏感性高等优势，已用于检查脑肿瘤及脑出血患者的BBB损伤，但尚未建立应用于SLE中BBB损伤的方法。本研究拟建立用DCE-MRI技术评价SLE中BBB损伤的方法；结合生物学标记和免疫因子检测，探讨BBB损伤的分子免疫机制；对有BBB损伤的患者进行治疗前后比较，了解该方法用于评价SLE中BBB损伤及修复程度的价值。研究结果将提供临床一种新的无创性评价SLE中BBB损伤的方法，对NPSLE的早期治疗及预后判断有极大应用价值。

本项目的主要目的是探索建立DCE-MRI技术检查SLE患者BBB损伤的方法，并结合其他生物学标记检测，探讨SLE中BBB损伤的分子机制；同时了解该方法用于评价SLE中BBB损伤及修复的价值。以上研究的开展将提供临床一种新的无创性评价SLE血脑屏障损害的方法，对SLE的脑损害的早期治疗及预后判断有极大应用价值。项目实施过程中选择明确诊断的SLE患者以及性别年龄匹配的正常人进行了DCE-MRI磁共振成像扫描，并收集了患者的脑脊液；通过计算ROI脑区的Ktrans值，与BBB损伤的分子指标比对，建立了用DCE-MRI评价SLE患者BBB损害的方法。通过以上研究证实了SLE患者的BBB损伤，发现SLE患者尤其NPSLE患者的Ktrans均值均明显升高，且NP患者组QAIb、IgG指数较非NP患者组明显升高，以Ktrans均值作为诊断NPSLE的敏感性为75%，特异性为63.6%。因此SLE患者，尤其是NPSLE患者存在BBB破坏，可能与神经精神症状相关，并且可能在出现明显神经精神症状前就已经存在。所建立的DCE-MRI方法可以检测到SLE患者BBB破坏，对BBB破坏的诊断与QAIb无明显差异，且特异性和敏感性较好，较QAIb等生物指标能更早的反映BBB通透性改变，有望临床推广运用。.本项目在原计划的基础上，还分析了Th1细胞因子（IL-2、TNF-α、IFN-γ），Th2细胞因子（IL-4、IL-6、IL-10）与系统性红斑狼疮临床表型特征之间的关系的分析，结果发现IL-6水平在 SLE患者中显著升高，IL-10水平与SLEDAI呈正相关， IL-6及IL-10水平在血液系统多系损害中明显升高，提示Th2细胞因子与SLE血液系统损害相关，Th2细胞因子（IL-6及IL-10）与自身抗体的生成相关；Th2细胞因子在SLE中具有协同作用，相互促进。因此以上免疫因子与表观遗传机制可能共同参与了SLE的发病机制与屏障损伤。.通过该项目运行培养了相关技术人员，研究结果已有20篇论文发表，含SCI收录8篇，共获得科技成果奖7项(云南省科学技术进步奖三等奖3项，云南省卫生科技成果奖二等奖1项及三等奖3项)。在以上研究基础上，项目负责人拓展了研究领域，于2017年获国家自然科学基金地区基金资助1项（81760296）。