T淋巴细胞在α1肾上腺素受体自身抗体诱导的高血压血管损伤中的作用研究

Autoimmune mechanisms play an important role in the pathogenesis of hypertension. Evidences suggested that high titers of autoantibodies against the second extracellular loop of α1-adrenergic receptor (α1-AA) were detected in sera of hypertensive patients. Additionally, long-term existence of α1-AA induced vascular injury, but the mechanisms remain unclear. Our preliminary study demonstrated that α1-AA enhanced T lymphocytes proliferation in vitro, and supernatants of T lymphocytes induced endothelial cell apoptosis, suggesting that T lymphocytes may contribute to α1-AA-induced vascular injury. In our current study, the pattern of α1-AA development was observed in SHR, then the relationship of the antibody and vascular injury, immune system disorder was analyzed. The effect of α1-AA monoclonal antibody on vascular function and moraphage in BalB/C mice and BalB/C nude mice is monitored by passive immunization model. Then, the study is designed to determine whether α1-AA monoclonal antibody can cause T lymphocytes from BalB/C mice to proliferate, or secrete cytokines, and to identify the signaling pathways that mediate T lymphocytes responses by gene transfection and RNAi technology. Finally, the cytokines closely related to hypertension induced by α1-AA are screening by cytokines antibody arrays. This study makes effort to illustrate possible contribution of T lymphocytes in hypertension induced by α1-AA at the level of the cellular, molecular and animal levels, which will provide new ideas for understanding the mechanisms involved in α1-AA-induced hypertension.

自身免疫机制在高血压发生发展中的作用不可忽视。研究发现高血压患者血清中存在α1-肾上腺素受体自身抗体(α1-AA);该抗体长期存在可诱导大鼠心血管损伤。我们前期研究发现α1-AA可引起培养T淋巴细胞增殖，其上清液导致血管内皮细胞凋亡,提示T淋巴细胞可能参与了α1-AA导致的血管内皮损伤。本研究拟观察高血压发展过程中α1-AA的产生规律与血管损伤和免疫系统紊乱(T淋巴细胞亚群数量及功能)的关系;利用T淋巴细胞缺失的BalB/C裸鼠及对照进行被动免疫,动态监测两组小鼠心血管功能和形态,判断T细胞是否参与α1-AA致血管损伤;利用RNA干扰和基因转染技术探讨α1-AA致T淋巴细胞功能改变的信号转导机制;通过细胞因子芯片技术筛查T细胞分泌的、与α1-AA致血管损伤密切相关的细胞因子,并明确该类因子在α1-AA致血管损伤中的作用。本课题拟从整体、细胞和分子水平探讨α1-AA对T淋巴细胞的作用及意义。

自身免疫机制在高血压发生发展中的作用不可忽视。研究发现高血压患者血清中存在α1-肾上腺素受体自身抗体(α1-AA);该抗体长期存在可诱导大鼠心血管损伤。我们前期研究发现α1-AA可引起培养的T淋巴细胞增殖，其上清液导致血管内皮细胞凋亡,提示T淋巴细胞可能参与了α1-AA导致的血管内皮损伤。本研究观察到高血压发展过程中伴随着血管损伤和免疫系统紊乱(T淋巴细胞亚群数量及功能)，α1-AA的水平也逐渐增加的关系;利用T淋巴细胞缺失的BalB/C裸鼠及对照进行被动免疫,动态监测两组小鼠心血管功能和形态,提示T细胞参与α1-AA致血管损伤;利用RNA干扰技术明确α1-AA通过激活α1-AR// PLC / IP3致T淋巴细胞分泌免疫功能改变;通过细胞因子芯片技术筛查明确了T细胞分泌的、与α1-AA致血管损伤密切相关的细胞因子IL-1β，在α1-AA致血管损伤中发挥关键作用，可能成为治疗α1-AA阳性的难治性高血压患者的重要靶点。