抗BMPR2相关受体自身抗体参与系统性红斑狼疮相关肺动脉高压发病的分子机制研究

Systemic lupus erythematosus (SLE) is autoantibodies derived autoimmune disease. Pulmonary arterial hypertension (PAH) is one of the most important organ involvement of SLE, characterized by the dysfunction of endothelial cells, which results in the elevated pulmonary arterial pressure and right ventricular failure. SLE associated PAH (SLE-PAH) has a high mortality, however, current therapies cannot directly improve the pathogenesis of PAH, leading the progression of disease and even death. It has been shown that the dysfunction of bone morphogenetic protein receptor type 2 (BMPR2) signaling pathway is involved in the pathogenesis of PAH. Nevertheless, the mechanism of SLE-PAH has not been well studied. According to the preliminary experiment, autoantibodies against BMPR2 related receptors were identified in the serum of patients with SLE-PAH, suggesting that the autoantibodies may bind to the receptor and inhibit the downstream signaling, which finally leads to PAH. Thus, the aim of this study is to study the function of autoantibodies in the pathogenesis of SLE-PAH in both endothelial cell model and animal model. The cell model will be used to identify the effect of anti-BMPR2 related receptors on BMPR2 signaling pathway and the function of endothelial cells. The animal model will be used to identify the effect of the antibody on the hemodynamics of pulmonary circulation and the pathology change of lung tissue. In conclusion, this study will provide experimental evidence on the pathogenesis of SLE-PAH and the investigation of new therapeutic target and biomarkers.

系统性红斑狼疮（SLE）是一种自身抗体介导的免疫性疾病。肺动脉高压（PAH）是SLE一种重要临床分型，病理上因内皮细胞损伤，导致肺动脉压力升高，最终导致右心衰竭。SLE-PAH预后不良，现有药物无法从根本上逆转其病理过程。研究表明，骨形成蛋白受体-2（BMPR2）信号通路失活，参与PAH发病。但针对SLE-PAH的发病机制研究鲜有报道。本课题预实验发现，SLE-PAH患者血清中存在BMPR2相关受体的自身抗体，该抗体可能影响BMPR2通路信号调节，最终导致该病发生。基于上述假设，本研究的目的是探讨抗BMPR2受体自身抗体参与SLE-PAH发病的机制，拟①通过细胞模型研究抗BMPR2受体自身抗体对于BMPR2信号及内皮细胞功能影响；②通过动物模型研究抗BMPR2受体抗体对于肺循环血流动力学及肺组织病理学影响。本研究探索SLE-PAH发病机制，为寻找新的治疗靶点及新型血清生物标志物提供依据。

系统性红斑狼疮(SLE)是一种自身抗体介导的免疫性疾病。肺动脉高压(PAH)是SLE一种重要临床分型，病理上因内皮细胞损伤，导致肺动脉压力升高，最终导致右心衰竭。SLE-PAH预后不良，现有药物无法从根本上逆转其病理过程。研究表明，骨形成蛋白受体-2(BMPR2)信号通路失活，参与PAH发病。但针对SLE-PAH的发病机制研究鲜有报道。本研究在项目执行期内，按照研究计划，逐步完成抗BMPR2相关受体自身抗体参与系统性红斑狼疮相关肺动脉高压发病的分子机制研究。结果表明，SLE-PAH患者血清中抗BMPR2相关受体自身抗体水平显著高于SLE非PAH患者及健康对照。抗BMPR2相关受体自身抗体与SLE-PAH患者相关临床表型（基线年龄、疾病活动度、抗RNP抗体）相关。聚类分析结果表明，基于抗BMPR2相关受体自身抗体结合患者临床表型，可将SLE-PAH患者进一步分为两类，第一类（抗BMPR2相关受体自身抗体阳性组）较第二类患者（抗BMPR2相关受体自身抗体阴性组），SLE系统受累及血清学活动水平较低。但第一组患者的临床预后较第二组患者更差。分子机制研究结果表明，抗ALK1抗体可以下调BMP9介导的BMP信号功能，进一步影响肺血管内皮细胞渗透及凋亡功能。雷帕霉素可能在因抗ALK1抗体导致的肺血管内皮细胞功能异常方面，具有治疗意义。本研究结果初步表明抗BMPR2自身抗体可能在SLE-PAH发病具有重要作用，因而可能成为未来新药的潜在靶点，同时在疾病预测、诊断、治疗效果评估、预后方面成为新型生物标志物。