Activation of T Lymphocytes as a Novel Mechanism in Beta1-Adrenergic Receptor Autoantibody-Induced Cardiac Remodeling
Activation of T Lymphocytes as a Novel Mechanism in Beta1-Adrenergic Receptor Autoantibody-Induced Cardiac Remodeling
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DOI：
10.1007/s10557-019-06856-2
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发表时间：
2019-04-01
影响因子：
3.4
通讯作者：
Fu, Michael
中科院分区：
文献类型：
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作者：
Du, Yunhui;Li, Xiao;Fu, Michael
背景许多研究报道心力衰竭患者血清中抗（1）-肾上腺素能受体（1）-AA（一种具有（1）-肾上腺素能活性的儿茶酚胺样物质）第二环细胞外抗体滴度显著升高。尽管有证据表明这种自身抗体可能改变T细胞增殖和分泌，但T淋巴细胞在（1）-AA诱导的心力衰竭中的作用仍不清楚。方法和结果（1）用杂交瘤技术制备的抗（1）-AA单克隆抗体（（1）-AAmAb）分别接种野生型小鼠和T淋巴细胞缺陷裸鼠，观察12周。体外培养心力衰竭患者的T淋巴细胞和新生心肌细胞。采用小鼠蛋白抗体芯片分析来检测负责（1）-AAmAb诱导的心力衰竭的细胞因子。与野生型小鼠相比，T淋巴细胞缺乏小鼠防止心脏功能恶化，减轻不良重塑，并改善心肌细胞凋亡和纤维化。如蛋白质阵列所示，在（1）-AAmAb处理后，与野生型相比，裸组中白细胞介素（IL）-6的血清水平显著降低。体外机制研究表明，（1）-AAmAb刺激的T淋巴细胞培养上清对心肌细胞造成直接损伤，（1）-AAmAb促进心力衰竭患者T淋巴细胞增殖，增加IL-6的释放。IL-6特异性siRNA抑制了心肌细胞凋亡，提示IL-6可能是T淋巴细胞释放的一种关键细胞因子，参与了（1）-AAmAb诱导的心脏重构。
BackgroundNumerous studies have reported significantly elevated titers of serum autoantibody against the second extracellular loop of (1)-adrenoceptor ((1)-AA), a catecholamine-like substance with (1)-adrenergic activity, in patients with heart failure. Although evidence demonstrates that this autoantibody may alter T cell proliferation and secretion, the role of T lymphocytes in heart failure induced by (1)-AA remains unclear. The current study was designed to determine whether T cell disorder contributes to heart failure induced by (1)-AA.Methods and Results(1)-AA monoclonal antibodies ((1)-AAmAb) produced using the hybridoma technique were administered in wild-type mice or T lymphocyte deficiency nudes for 12weeks. T lymphocytes from heart failure patients and neonatal cardiomyocytes were utilized in vitro. Mouse protein antibody array analysis was employed to detect the cytokines responsible for (1)-AAmAb-induced heart failure. Compared to wild-type mice, T lymphocyte deficiency mice prevented cardiac function from getting worse, attenuated adverse remodeling, and ameliorated cardiomyocyte apoptosis and fibrosis. As shown by protein array, the serum level of interleukin (IL)-6 was significantly lower in the nude group as compared to wild-type after (1)-AAmAb treatment. Mechanistic studies in vitro demonstrated that T lymphocyte culture supernatants stimulated by (1)-AAmAb caused direct damage in the cardiomyocytes, and (1)-AAmAb promoted proliferation of T lymphocytes isolated from patients with heart failure and increased IL-6 release. IL-6-specific siRNA virtually abolished cardiomyocyte apoptosis, suggesting that IL-6 may be a key cytokine released by T lymphocytes and responsible for (1)-AAmAb-induced cardiac remodeling.ConclusionsCollectively, we demonstrate that (1)-AAmAb-induced cardiac remodeling via mediating T lymphocyte disorder and releasing a variety of IL-6.