抗β_1肾上腺素受体自身抗体与心律失常的关系及其意义分析
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摘要
研究背景
G蛋白耦联受体(G protein-coupled receptor, GPCR)是人体内最大的膜受体蛋白家族,广泛分布于全身组织器官,其中位于心肌细胞膜上的β1肾上腺素受体(β1-adrenoceptor,β1-AR)在调节心脏功能活动中发挥着重要作用。生理情况下,β1-AR通过识别并选择性地与儿茶酚胺类物质结合,引起胞内信号转导通路激活,进而发挥心脏的正性变时、正性变力和正性变传导作用,在介导机体对心脏功能活动的神经-体液调节中发挥重要作用。近二十年来,诸多学者相继在扩张型心肌病、风湿性心脏病、Chagas病和原发性心电紊乱等心脏病中均检测到抗β1-AR细胞外第二环的自身抗体(antibodies against the second extracellular loop ofβ1-adrenoceptor,β1-AAB),提示这种自身抗体可能与多种心脏疾患的病理生理机制有关。
有研究表明:在扩心病伴发室性心律失常及传导阻滞患者的血清中检测到高水平的β1-AAB ,提示β1-AAB可能与心律失常的发生有关。但β1-AAB在其他类型心律失常患者血清中的分布情况如何尚不得而知。1990年Magnusson等的研究发现,抗β1-AR自身抗体(β1-AAB)能够专一性识别β1-AR细胞外第二环的功能表位肽段,并具有类激动剂样的正性变时效应。但是与激动剂不同的是,该自身抗体表现为对β1-AR持续的刺激效应,即具有不脱敏性。1996年Mijares等研究发现,β1-AAB能够通过cAMP依赖性的蛋白激酶途径激活心肌细胞膜上的L型Ca2+通道,进而增强钙离子内流,并且可缩短QT间期。鉴于L型Ca2+通道电流是自律细胞动作电位0期去极化、非自律细胞动作电位平台期的主要内向离子电流,那么,具有类激动剂样作用的β1-AAB是否有可能通过影响钙电流而导致心电活动异常,进而导致心律失常的发生呢?但是,证实这一推测的前提是需要阐明在心律失常患者血清中是否存在这种抗体,如果存在,那么这种自身抗体在心律失常患者中的分布特征如何,这些问题的解决将为证实β1-AAB是否参与了心律失常发生发展的病理生理过程提供第一手资料。
大量的研究已经表明,在健康机体中存在有产生自身抗体的B淋巴细胞株,但它们通常被抑制或处于低水平状态,不足以造成组织损伤或引起疾病。自身免疫在正常人体内亦屡有发生,一般起维持机体生理自稳的作用,正常人血清中含有多种针对自身抗原的自身抗体,但其效价极低,能够协助机体清除自身衰老变性的成分,故被称为生理性抗体。在某些病理状态下,自身抗体较原有的生理性抗体在效价上有大幅度增长的趋势,这些在质和量上表现异常的自身抗体,或通过攻击自身靶抗原细胞和组织,或反过来影响机体的免疫系统使其功能紊乱,进而使组织或细胞产生病理改变和功能障碍,形成自身免疫性疾病。机体免疫系统中淋巴细胞增殖是机体对抗原刺激产生免疫应答过程中的重要事件,淋巴细胞增殖结果表现为产生效应淋巴细胞,最终清除抗原,维护机体内环境稳定,而T淋巴细胞在免疫应答起始阶段起着必不可少的辅助作用。已有研究表明,具有激动剂样作用的β1-AAB是机体免疫系统功能失衡的产物,并且,T淋巴细胞膜上存在β1-AR,那么,由免疫应答产生的β1-AAB除了先前所发现的对心脏的作用外,是否还可以与T淋巴细胞膜上的相应受体结合,反过来影响机体的免疫调节功能,从而进一步影响心律失常,这些问题目前均未见报道。我们的前期研究发现,抗血管紧张素Ⅱ(AT1)受体自身抗体对大鼠脾脏T淋巴细胞具有促增殖作用。由于β1-AR与AT1受体同属于G蛋白耦联受体,且根据文献报道,T淋巴细胞上亦分布有β1-AR,因此我们推测,免疫系统可能也是β1-AAB的作用靶点之一。如果这种假设成立,β1-AAB对T淋巴细胞有何作用,对机体免疫系统的功能有无影响等问题,均有待通过实验进行一一分析。
研究目的
1.确定心律失常患者血清中是否存在β1-AAB,如果存在,分析该自身抗体在各型心律失常患者中的分布特征及其可能的临床意义。
2.观察β1-AAB对正常大鼠和心衰大鼠是否具有致心律失常作用,如果有,分析其有何特点。
3.初步探讨β1-AAB是否能够影响机体免疫系统的功能,如果能,对T淋巴细胞的增殖有何作用?
研究方法
1.以合成的人β1-AR细胞外第二环氨基酸肽段(197-222位)为抗原,采用SA-ELISA方法筛查106例心律失常患者、100例冠心病患者和100例正常人血清中的β1-AAB,并分析其在各型心律失常患者中的分布特征。
2.以合成的人β1-AR细胞外第二环氨基酸肽段(197-222位)为抗原主动免疫大鼠,免疫过程中定期鼠尾静脉采血,采用流式细胞测定技术检测外周血T淋巴细胞亚群CD4+/CD8+比值的变化;免疫结束后,用亲和层析法分别提纯免疫鼠血清中β1-AAB阳性和阴性的IgGs。
3.采用缩窄腹主动脉法制备心力衰竭大鼠模型,模型成功后,筛选β1-AAB阴性的模型鼠,经鼠尾静脉急性给予β1-AAB IgGs,观察该抗体对心衰大鼠、伪手术和正常大鼠心电图的影响。
4.培养肠系膜淋巴结细胞,采用CCK-8检测试剂盒,观察β1-AAB对刀豆球蛋白A(concanavalin A, Con A)刺激的T淋巴细胞增殖功能的影响。
研究结果
1.β1-AAB在心律失常患者血清中的分布呈高阳性率
在筛查的106例心律失常患者血清中,有58例呈β1-AAB阳性,其阳性率为52.8%,与正常对照组的5.0%及冠心病组的24.0%相比,有显著性差异(P<0.01)(见表1-1,1-2)。说明心律失常患者血清中这种自身抗体的阳性率高于冠心病人和正常人。
22 .β1-AAB在在在不不同类型心律失常患者血清中的分布情况
以OD值表示血清中β1-AAB的含量,对其进行分析发现,室性、房性和传导异常性心律失常患者血清中β1-AAB平均OD值分别为0.35±0.02、0.20±0.01和0.22±0.02,均高于正常对照组的OD值0.13±0.01(P<0.01);且室性心律失常组β1-AAB平均OD值与房性及传导异常性相比均有显著性差异(P<0.01)(见图1-1)。这些结果说明,β1-AAB在室性、传导异常性和房性心律失常患者中的分布均高于正常人,而且可能和室性心律失常的相关性更高。
3.主动免疫大鼠模型建立成功和β1-AAB的提纯
用β1-AR细胞外第二环的抗原肽段主动免疫大鼠后,血清β1-AAB含量在免疫4周时已明显升高,10周时达高峰(稀释度1:20时OD值为3.43±0.72,P<0.01, vs.同期对照组)(见图2-1)。提纯大鼠的抗血清,得到以β1-AAB为主的总IgGs。
4.心力衰竭大鼠模型建立成功
心衰大鼠建模后12周,心衰组左心室收缩压(LVSP)、室内压上升和下降的最大速率(±dp/dtmax)均低于伪手术组(P<0.05),而左心室舒张末压(LVEDP)则高于伪手术组(P<0.05)(见表2-1);且心衰组心脏重量与体重之比明显高于同期伪手术组(P<0.01)(见表2-2)。以上指标均说明心衰大鼠模型建立成功。
5.β1-AAB对正常大鼠和心衰大鼠心电图的影响
经鼠尾静脉急性给予β1-AAB后,在正常大鼠和心衰大鼠均监测到不同程度及不同类型的心律失常,其中以室性心律失常最为多见(见图2-2);心衰大鼠心律失常的发生频率明显高于正常大鼠(见图2-3)。
6.免疫鼠外周血T淋巴细胞亚群的改变
β1-AR抗原肽段免疫组和对照组大鼠的外周血T淋巴细胞亚型CD4+/CD8+的比值在处理24小时后即开始增加,β1-AR抗原肽段免疫组在第7天时达较高水平(3.26±0.32),随后在观察时间内呈逐渐增高趋势;而对照组的CD4+/CD8+之比在第3天时达峰值(2.72±0.47),随后逐渐降低(见表3-1)。这一结果表明与对照组相比,β1-AR抗原肽段免疫组出现明显的免疫功能亢进。
7.β1-AAB对T淋巴细胞增殖功能的影响
经CCK-8试剂盒检测结果显示,三个浓度的β1-AAB(0.01,0.1,1 mol/L)均可以促进Con A激活的T淋巴细胞增殖,并呈浓度依赖性趋势(OD值分别为0.49±0.05,0.69±0.08,0.82±0.07),该作用类似于β1-AR激动剂异丙肾上腺素的作用(见图3-1)。此外,β1-AAB的作用可被β1-AR特异性阻断剂Metoprolol和β1-AR细胞外第二环的抗原肽段所中和,而单纯Metoprolol或β1-AR抗原肽段对T淋巴细胞的增殖功能无明显影响(见图3-2)。
结论
1.在心律失常患者血清中,β1-AAB的阳性率明显高于冠心病病人和正常人,且该自身抗体可能和室性心律失常的相关性更高。
2.β1-AAB具有直接致正常大鼠和心衰大鼠心律失常的作用,并以室性心律失常最为多见。此外,本实验首次发现心衰大鼠发生心律失常的易感性明显增加,提示心衰患者血清中β1-AAB的存在可能具有更为重要的病理意义。
3.通过本研究首次证实β1-AAB可以影响机体的免疫调节功能,并促进T淋巴细胞的增殖。
Background
G protein-coupled receptor (G protein-coupled receptor, GPCR) is the largest membrane receptor protein family in the body and it is widely distributed in body tissues and organs,β1 adrenergic receptor (β1-AR)located on Myocardial cell membrane is one kind of the GPCR, it plays an important role in regulating cardiac function and activities. In physiological circumstances,β1-AR identify and selectively bind to catecholamines, then active signal transduction pathway in the cell, mediated positive chronotropic, inotropic and dromotropic effect in the heart and participate in energy metabolism of cardimyocyte.β1-AR plays a dominant role in the Nerve - humoral regulation in the function and activation of the heart. Over the past two decades, many scholars have detected antibodies against the second extracellular loop ofβ1-adrenoceptor(β1-AAB)in dilated cardiomyopathy, rheumatic heart disease, Chagas disease and primary cardiac electricity disorders disease and so on. This suggests that this autoantibody may be associated with the pathophysiology mechanisms of the cardiac disease.
In 1990, Magnusson et al. discovered that: anti-β1-AR autoantibody (β1-AAB)is able to recognize the functional epitope peptide of the second extracellular loop of theβ1-AR, and it exhibited the agonist-like effect such as positive chronotropic effect. However, there is still some difference to agonist: the stimulation effect of the autoantibody to theβ1-AR receptor is sustained, which showed no desensitization. In 1996, Mijares et al. found thatβ1-AAB can active L-type calcium channel in the membrane of cardimyocytes through cAMP-dependent protein kinase pathway, then enhanced calcium influx and shortened the QT interval. In view of L-type Ca2+ channel current is the main inward currents of the action potential plateau of non-self-regulatory cells and 0 phase depolarization of the self-regulatory, whetherβ1-AAB which has the agonist-like effect is associated with the abnormal electrical activity of heart, then further associated with the occurrence of arrhythmia remains unknown However, in order to confirm this speculation, whether such antibodies existed in sera of patients with arrhythmias should be clarified. Furthermore, clarify whether such autoantibodies are associated with arrhythmia. First-hand information should be provided for conforming thatβ1-AAB is involved in the pathophysiological process of occurrence and development of arrhythmia.
Studies have shown that B-lymphocytes, which can produce autoantibodies, existed in healthy organism, and they are usually suppressed or in a low lever status, therefore, they can’t induce tissue damage or induce disease. Autoimmunity also often happens in normal human, and the general function is to maintain the physiological homeostasis. In sera from normal human there are a variety of autoantibodies against self-antigen, but the titer is very low, just can assist the body to clear aging self-composition. Therefore, it is known as physiological antibodies. In some pathological conditions, there is a more significant increasing trend of autoantibodies titer than the original physiological antibodies. The autoantibodies which are abnormal in quality and quantity attack self cells and tissues which have target antigen or in turn affect and destroy the immune system, thus produce the pathological changes and dysfunction, then form the autoimmune disease. In immune system, proliferation of lymphocytes is an important event in the immune response to the stimulation of antigen, and results in producing effector lymphocytes. Finally clear the antigen and maintain the internal environment stabilization. In the start-up phase of immune response, T lymphocytes play an essential supplementary role. In addition, there isβ1-AR on the membrane of T lymphocytes. Except the function to the heart ofβ1-AAB which was previously found. Therefore, whetherβ1-AAB can bind to the corresponding receptor on membrane of T lymphocyte, and further affect the immune regulatory function, thereby affect the arrhythmia needs to be further investigated.
Our preliminary study has found that antibody against AT1R could promote proliferation of T lymphocytes from rats’spleen. For bothβ1-AR and AT1 receptor are G protein-coupled receptors, andβ1-AR also distributed on T lymphocytes according to previous reports. So we speculate that the immune system may also be one of the targets ofβ1-AAB. If so, what’s the function ofβ1-AAB to T lymphocytes? And whether it can affect the function of immune system? All these questions have to be analyzed one by one through experiments.
Objective
1. To investigate whether there isβ1-AAB in the sera of arrhythmia patients, and if so, to determine the distribution characteristics ofβ1-AAB in various types of arrhythmia patients and its possible clinical significances.
2. To observe whetherβ1-AAB can induce the occurrence of arrhythmia in normal rats or heart failure rats, and if so, what are their characteristics?
3. To preliminaryly study whetherβ1-AAB can influence the function of immune system, if so, what is the effect ofβ1-AAB on the proliferation of T lymphocytes?
Methods
1. The synthesized peptides of the second extracellular loop ofβ1-AR (197-222 amino acids) were used as antigen to detectβ1-AAB in the sera of 106 cases arrhythmia patients, 100 cases coronary heart disease patients and 100 cases healthy people by SA-ELISA technology, and analyze the distribution characteristics ofβ1-AAB in various types of arrhythmia patients.
2. The synthesized peptides corresponding to the second extracellular loop ofβ1-AR (197-222 amino acids) were used as antigen to immunize rats. During the immunization course we collected the peripheral blood from tail vein to detect the ratios of CD4+ and CD8+ T lymphocytes by flow cytometry technology. By the end of immunization, the positive and negative IgGs of seraβ1-AAB were purified respectively by affinity chromatography.
3. The heart failure models of rats were established by constricting the abdominal aorta. After the models formation, theβ1-AAB negative rats were selected by SA-ELISA technology, and were injected acutely withβ1-AAB through tail vein. Then we observed the effects ofβ1-AAB on ECG in heart failure rats, sham rats and healthy rats.
4. In cultured lymphocytes from mesenteric lymph nodes, we observed the effects ofβ1-AAB positive IgGs on T lymphocytes proliferation induced by Con A by CCK-8 Detection Kit.
Results
1. The high positive rate ofβ1-AAB in the sera of patients with arrhythmias.
In 106 cases of patients with arrhythmia, 58 cases were positive forβ1-AAB, so the positive rate was 52.8%, which was significantly higher than that in the normal subjects (5.0%) or in coronary heart disease groups (24.0%), (P<0.01) (see Table 1-1,1-2). This result indicates the positive rate ofβ1-AAB in patients with arrhythmia is higher than that in patients of coronary heart disease patients or normal subjects.
2. The distribution characteristics ofβ1-AAB in the sera of patients with different types of arrhythmia.
By analyzing the contents ofβ1-AAB based on the sera OD values, we found in patients with ventricular arrhythmia, atrial arrhythmia and conduction abnormalities arrhythmia, the OD values were 0.35±0.02,0.20±0.01 and 0.22±0.02 respectively which were all higher than that of the normal control group (0.13±0.01, P<0.01). In addition, compared with the atrial arrhythmia and conduction abnormalities arrhythmia, the OD values of ventricular arrhythmia were significantly different (P<0.01) (see Figure 1-1). These results indicate that the distribution ofβ1-AAB is higher in patients of arrhythmia than that in the normal controls, and maybeβ1-AAB is more relevant with ventricular arrhythmias.
3. Establishment of the active immunization rats models and purification ofβ1-AAB.
After active immunization with antigen peptides of the second extracellular loop ofβ1-AR in rats, theβ1-AAB contents in sera increased significantly at 4 weeks, and reached the peak at 10 weeks (at 1:20 dilution the OD value was 3.43±0.72, P<0.01, vs. the control group at the same period) (see Figure 2-1). The anti-serum of rats was purified to obtainβ1-AAB IgGs.
4. Heart failure models of rats were successfully established.
After the heart failure models were set up for 12 weeks, the left ventricular systolic pressure (LVSP) and the maximum rate of ventricular pressure rise and fall (±dp / dtmax) were lower in the heart failure group than that in the sham group (P<0.05), while the end-diastolic pressure of left ventricular (LVEDP) was higher than that in the sham group (P<0.05) (see Table 2-1). The ratios of heart weight and body weight in the heart failure group was significantly higher than that in the sham group at the same period (P<0.01) (see table 2-2). These results above indicated that the rat models of heart failure were established successfully.
5. The effects ofβ1-AAB on ECG of normal rats and heart failure rats
Whenβ1-AAB IgGs were infused from the tail vein of rats acutely, varying degrees and different types of arrhythmia were monitored in the normal rats and heart failure rats. and the ventricular arrhythmia was one of the most common (see Figure 2-2). In addition, the frequency of arrhythmia in the heart failure group was significantly higher than that in the normal rats (see Figure 2-3).
6. Changes of T lymphocyte subtypes in the peripheral blood of immunized rats
The ratios of CD4+ and CD8+ T lymphocyte began to increase in theβ1-AR antigen peptide immunization group and control group after treatment for 24 hours. And it reached a higher level in theβ1-AR antigen peptide immunization group at the 7th day (3.26±0.32), then increased gradually during the study period. However, the ratios of CD4+ and CD8+ T lymphocyte achieved peak at the third day (2.72±0.47), then decreased gradually (see Table 3-1). These results indicate that there is the emergence of significant immune hyperfunction in theβ1-AR antigen peptide immunization group compared with the control group.
7. The effects ofβ1-AAB on T lymphocytes proliferation
The results detected by CCK-8 kits showed that three concentrations ofβ1-AAB (0.01, 0.1, 1 mol/L) promoted proliferation of T lymphocytes induced by Con A in a dose-dependent manner (OD values were 0.49±0.05, 0.69±0.08, 0.82±0.07), which was similar to the role ofβ1-AR agonist isoprenaline (see Figure 3-1). In addition, the effects ofβ1-AAB could be neutralized by theβ1-AR-specific blockers Metoprolol or the antigen peptides corresponding to the second extracellular loop ofβ1-AR, but simple Metoprolol orβ1-AR antigen peptides had no significant effect on proliferation of T lymphocytes (see Figure 3-2).
Conclusions
1. In the sera of patients with arrhythmia, the positive rate ofβ1-AAB was significantly higher than that of patients with coronary heart disease and healthy subjects, and theβ1-AAB might be more relevant with ventricular arrhythmias.
2.β1-AAB had a direct-induced arrhythmia effects in normal rats and heart failure rats, and the ventricular arrhythmia was most common. In addition, the susceptibility to arrhythmia increased markedly in heart failure rats, indicating that the existence of high level ofβ1-AA in sera of patients with heart failure may have more considerable pathophysiologic significance.
3.β1-AAB were reported for the first time to promote the proliferation of T lymphocytes by activating ofβ1-AR, and affect the immune regulation function of the organism.
G蛋白耦联受体(G protein-coupled receptor, GPCR)是人体内最大的膜受体蛋白家族,广泛分布于全身组织器官,其中位于心肌细胞膜上的β1肾上腺素受体(β1-adrenoceptor,β1-AR)在调节心脏功能活动中发挥着重要作用。生理情况下,β1-AR通过识别并选择性地与儿茶酚胺类物质结合,引起胞内信号转导通路激活,进而发挥心脏的正性变时、正性变力和正性变传导作用,在介导机体对心脏功能活动的神经-体液调节中发挥重要作用。近二十年来,诸多学者相继在扩张型心肌病、风湿性心脏病、Chagas病和原发性心电紊乱等心脏病中均检测到抗β1-AR细胞外第二环的自身抗体(antibodies against the second extracellular loop ofβ1-adrenoceptor,β1-AAB),提示这种自身抗体可能与多种心脏疾患的病理生理机制有关。
有研究表明:在扩心病伴发室性心律失常及传导阻滞患者的血清中检测到高水平的β1-AAB ,提示β1-AAB可能与心律失常的发生有关。但β1-AAB在其他类型心律失常患者血清中的分布情况如何尚不得而知。1990年Magnusson等的研究发现,抗β1-AR自身抗体(β1-AAB)能够专一性识别β1-AR细胞外第二环的功能表位肽段,并具有类激动剂样的正性变时效应。但是与激动剂不同的是,该自身抗体表现为对β1-AR持续的刺激效应,即具有不脱敏性。1996年Mijares等研究发现,β1-AAB能够通过cAMP依赖性的蛋白激酶途径激活心肌细胞膜上的L型Ca2+通道,进而增强钙离子内流,并且可缩短QT间期。鉴于L型Ca2+通道电流是自律细胞动作电位0期去极化、非自律细胞动作电位平台期的主要内向离子电流,那么,具有类激动剂样作用的β1-AAB是否有可能通过影响钙电流而导致心电活动异常,进而导致心律失常的发生呢?但是,证实这一推测的前提是需要阐明在心律失常患者血清中是否存在这种抗体,如果存在,那么这种自身抗体在心律失常患者中的分布特征如何,这些问题的解决将为证实β1-AAB是否参与了心律失常发生发展的病理生理过程提供第一手资料。
大量的研究已经表明,在健康机体中存在有产生自身抗体的B淋巴细胞株,但它们通常被抑制或处于低水平状态,不足以造成组织损伤或引起疾病。自身免疫在正常人体内亦屡有发生,一般起维持机体生理自稳的作用,正常人血清中含有多种针对自身抗原的自身抗体,但其效价极低,能够协助机体清除自身衰老变性的成分,故被称为生理性抗体。在某些病理状态下,自身抗体较原有的生理性抗体在效价上有大幅度增长的趋势,这些在质和量上表现异常的自身抗体,或通过攻击自身靶抗原细胞和组织,或反过来影响机体的免疫系统使其功能紊乱,进而使组织或细胞产生病理改变和功能障碍,形成自身免疫性疾病。机体免疫系统中淋巴细胞增殖是机体对抗原刺激产生免疫应答过程中的重要事件,淋巴细胞增殖结果表现为产生效应淋巴细胞,最终清除抗原,维护机体内环境稳定,而T淋巴细胞在免疫应答起始阶段起着必不可少的辅助作用。已有研究表明,具有激动剂样作用的β1-AAB是机体免疫系统功能失衡的产物,并且,T淋巴细胞膜上存在β1-AR,那么,由免疫应答产生的β1-AAB除了先前所发现的对心脏的作用外,是否还可以与T淋巴细胞膜上的相应受体结合,反过来影响机体的免疫调节功能,从而进一步影响心律失常,这些问题目前均未见报道。我们的前期研究发现,抗血管紧张素Ⅱ(AT1)受体自身抗体对大鼠脾脏T淋巴细胞具有促增殖作用。由于β1-AR与AT1受体同属于G蛋白耦联受体,且根据文献报道,T淋巴细胞上亦分布有β1-AR,因此我们推测,免疫系统可能也是β1-AAB的作用靶点之一。如果这种假设成立,β1-AAB对T淋巴细胞有何作用,对机体免疫系统的功能有无影响等问题,均有待通过实验进行一一分析。
研究目的
1.确定心律失常患者血清中是否存在β1-AAB,如果存在,分析该自身抗体在各型心律失常患者中的分布特征及其可能的临床意义。
2.观察β1-AAB对正常大鼠和心衰大鼠是否具有致心律失常作用,如果有,分析其有何特点。
3.初步探讨β1-AAB是否能够影响机体免疫系统的功能,如果能,对T淋巴细胞的增殖有何作用?
研究方法
1.以合成的人β1-AR细胞外第二环氨基酸肽段(197-222位)为抗原,采用SA-ELISA方法筛查106例心律失常患者、100例冠心病患者和100例正常人血清中的β1-AAB,并分析其在各型心律失常患者中的分布特征。
2.以合成的人β1-AR细胞外第二环氨基酸肽段(197-222位)为抗原主动免疫大鼠,免疫过程中定期鼠尾静脉采血,采用流式细胞测定技术检测外周血T淋巴细胞亚群CD4+/CD8+比值的变化;免疫结束后,用亲和层析法分别提纯免疫鼠血清中β1-AAB阳性和阴性的IgGs。
3.采用缩窄腹主动脉法制备心力衰竭大鼠模型,模型成功后,筛选β1-AAB阴性的模型鼠,经鼠尾静脉急性给予β1-AAB IgGs,观察该抗体对心衰大鼠、伪手术和正常大鼠心电图的影响。
4.培养肠系膜淋巴结细胞,采用CCK-8检测试剂盒,观察β1-AAB对刀豆球蛋白A(concanavalin A, Con A)刺激的T淋巴细胞增殖功能的影响。
研究结果
1.β1-AAB在心律失常患者血清中的分布呈高阳性率
在筛查的106例心律失常患者血清中,有58例呈β1-AAB阳性,其阳性率为52.8%,与正常对照组的5.0%及冠心病组的24.0%相比,有显著性差异(P<0.01)(见表1-1,1-2)。说明心律失常患者血清中这种自身抗体的阳性率高于冠心病人和正常人。
22 .β1-AAB在在在不不同类型心律失常患者血清中的分布情况
以OD值表示血清中β1-AAB的含量,对其进行分析发现,室性、房性和传导异常性心律失常患者血清中β1-AAB平均OD值分别为0.35±0.02、0.20±0.01和0.22±0.02,均高于正常对照组的OD值0.13±0.01(P<0.01);且室性心律失常组β1-AAB平均OD值与房性及传导异常性相比均有显著性差异(P<0.01)(见图1-1)。这些结果说明,β1-AAB在室性、传导异常性和房性心律失常患者中的分布均高于正常人,而且可能和室性心律失常的相关性更高。
3.主动免疫大鼠模型建立成功和β1-AAB的提纯
用β1-AR细胞外第二环的抗原肽段主动免疫大鼠后,血清β1-AAB含量在免疫4周时已明显升高,10周时达高峰(稀释度1:20时OD值为3.43±0.72,P<0.01, vs.同期对照组)(见图2-1)。提纯大鼠的抗血清,得到以β1-AAB为主的总IgGs。
4.心力衰竭大鼠模型建立成功
心衰大鼠建模后12周,心衰组左心室收缩压(LVSP)、室内压上升和下降的最大速率(±dp/dtmax)均低于伪手术组(P<0.05),而左心室舒张末压(LVEDP)则高于伪手术组(P<0.05)(见表2-1);且心衰组心脏重量与体重之比明显高于同期伪手术组(P<0.01)(见表2-2)。以上指标均说明心衰大鼠模型建立成功。
5.β1-AAB对正常大鼠和心衰大鼠心电图的影响
经鼠尾静脉急性给予β1-AAB后,在正常大鼠和心衰大鼠均监测到不同程度及不同类型的心律失常,其中以室性心律失常最为多见(见图2-2);心衰大鼠心律失常的发生频率明显高于正常大鼠(见图2-3)。
6.免疫鼠外周血T淋巴细胞亚群的改变
β1-AR抗原肽段免疫组和对照组大鼠的外周血T淋巴细胞亚型CD4+/CD8+的比值在处理24小时后即开始增加,β1-AR抗原肽段免疫组在第7天时达较高水平(3.26±0.32),随后在观察时间内呈逐渐增高趋势;而对照组的CD4+/CD8+之比在第3天时达峰值(2.72±0.47),随后逐渐降低(见表3-1)。这一结果表明与对照组相比,β1-AR抗原肽段免疫组出现明显的免疫功能亢进。
7.β1-AAB对T淋巴细胞增殖功能的影响
经CCK-8试剂盒检测结果显示,三个浓度的β1-AAB(0.01,0.1,1 mol/L)均可以促进Con A激活的T淋巴细胞增殖,并呈浓度依赖性趋势(OD值分别为0.49±0.05,0.69±0.08,0.82±0.07),该作用类似于β1-AR激动剂异丙肾上腺素的作用(见图3-1)。此外,β1-AAB的作用可被β1-AR特异性阻断剂Metoprolol和β1-AR细胞外第二环的抗原肽段所中和,而单纯Metoprolol或β1-AR抗原肽段对T淋巴细胞的增殖功能无明显影响(见图3-2)。
结论
1.在心律失常患者血清中,β1-AAB的阳性率明显高于冠心病病人和正常人,且该自身抗体可能和室性心律失常的相关性更高。
2.β1-AAB具有直接致正常大鼠和心衰大鼠心律失常的作用,并以室性心律失常最为多见。此外,本实验首次发现心衰大鼠发生心律失常的易感性明显增加,提示心衰患者血清中β1-AAB的存在可能具有更为重要的病理意义。
3.通过本研究首次证实β1-AAB可以影响机体的免疫调节功能,并促进T淋巴细胞的增殖。
Background
G protein-coupled receptor (G protein-coupled receptor, GPCR) is the largest membrane receptor protein family in the body and it is widely distributed in body tissues and organs,β1 adrenergic receptor (β1-AR)located on Myocardial cell membrane is one kind of the GPCR, it plays an important role in regulating cardiac function and activities. In physiological circumstances,β1-AR identify and selectively bind to catecholamines, then active signal transduction pathway in the cell, mediated positive chronotropic, inotropic and dromotropic effect in the heart and participate in energy metabolism of cardimyocyte.β1-AR plays a dominant role in the Nerve - humoral regulation in the function and activation of the heart. Over the past two decades, many scholars have detected antibodies against the second extracellular loop ofβ1-adrenoceptor(β1-AAB)in dilated cardiomyopathy, rheumatic heart disease, Chagas disease and primary cardiac electricity disorders disease and so on. This suggests that this autoantibody may be associated with the pathophysiology mechanisms of the cardiac disease.
In 1990, Magnusson et al. discovered that: anti-β1-AR autoantibody (β1-AAB)is able to recognize the functional epitope peptide of the second extracellular loop of theβ1-AR, and it exhibited the agonist-like effect such as positive chronotropic effect. However, there is still some difference to agonist: the stimulation effect of the autoantibody to theβ1-AR receptor is sustained, which showed no desensitization. In 1996, Mijares et al. found thatβ1-AAB can active L-type calcium channel in the membrane of cardimyocytes through cAMP-dependent protein kinase pathway, then enhanced calcium influx and shortened the QT interval. In view of L-type Ca2+ channel current is the main inward currents of the action potential plateau of non-self-regulatory cells and 0 phase depolarization of the self-regulatory, whetherβ1-AAB which has the agonist-like effect is associated with the abnormal electrical activity of heart, then further associated with the occurrence of arrhythmia remains unknown However, in order to confirm this speculation, whether such antibodies existed in sera of patients with arrhythmias should be clarified. Furthermore, clarify whether such autoantibodies are associated with arrhythmia. First-hand information should be provided for conforming thatβ1-AAB is involved in the pathophysiological process of occurrence and development of arrhythmia.
Studies have shown that B-lymphocytes, which can produce autoantibodies, existed in healthy organism, and they are usually suppressed or in a low lever status, therefore, they can’t induce tissue damage or induce disease. Autoimmunity also often happens in normal human, and the general function is to maintain the physiological homeostasis. In sera from normal human there are a variety of autoantibodies against self-antigen, but the titer is very low, just can assist the body to clear aging self-composition. Therefore, it is known as physiological antibodies. In some pathological conditions, there is a more significant increasing trend of autoantibodies titer than the original physiological antibodies. The autoantibodies which are abnormal in quality and quantity attack self cells and tissues which have target antigen or in turn affect and destroy the immune system, thus produce the pathological changes and dysfunction, then form the autoimmune disease. In immune system, proliferation of lymphocytes is an important event in the immune response to the stimulation of antigen, and results in producing effector lymphocytes. Finally clear the antigen and maintain the internal environment stabilization. In the start-up phase of immune response, T lymphocytes play an essential supplementary role. In addition, there isβ1-AR on the membrane of T lymphocytes. Except the function to the heart ofβ1-AAB which was previously found. Therefore, whetherβ1-AAB can bind to the corresponding receptor on membrane of T lymphocyte, and further affect the immune regulatory function, thereby affect the arrhythmia needs to be further investigated.
Our preliminary study has found that antibody against AT1R could promote proliferation of T lymphocytes from rats’spleen. For bothβ1-AR and AT1 receptor are G protein-coupled receptors, andβ1-AR also distributed on T lymphocytes according to previous reports. So we speculate that the immune system may also be one of the targets ofβ1-AAB. If so, what’s the function ofβ1-AAB to T lymphocytes? And whether it can affect the function of immune system? All these questions have to be analyzed one by one through experiments.
Objective
1. To investigate whether there isβ1-AAB in the sera of arrhythmia patients, and if so, to determine the distribution characteristics ofβ1-AAB in various types of arrhythmia patients and its possible clinical significances.
2. To observe whetherβ1-AAB can induce the occurrence of arrhythmia in normal rats or heart failure rats, and if so, what are their characteristics?
3. To preliminaryly study whetherβ1-AAB can influence the function of immune system, if so, what is the effect ofβ1-AAB on the proliferation of T lymphocytes?
Methods
1. The synthesized peptides of the second extracellular loop ofβ1-AR (197-222 amino acids) were used as antigen to detectβ1-AAB in the sera of 106 cases arrhythmia patients, 100 cases coronary heart disease patients and 100 cases healthy people by SA-ELISA technology, and analyze the distribution characteristics ofβ1-AAB in various types of arrhythmia patients.
2. The synthesized peptides corresponding to the second extracellular loop ofβ1-AR (197-222 amino acids) were used as antigen to immunize rats. During the immunization course we collected the peripheral blood from tail vein to detect the ratios of CD4+ and CD8+ T lymphocytes by flow cytometry technology. By the end of immunization, the positive and negative IgGs of seraβ1-AAB were purified respectively by affinity chromatography.
3. The heart failure models of rats were established by constricting the abdominal aorta. After the models formation, theβ1-AAB negative rats were selected by SA-ELISA technology, and were injected acutely withβ1-AAB through tail vein. Then we observed the effects ofβ1-AAB on ECG in heart failure rats, sham rats and healthy rats.
4. In cultured lymphocytes from mesenteric lymph nodes, we observed the effects ofβ1-AAB positive IgGs on T lymphocytes proliferation induced by Con A by CCK-8 Detection Kit.
Results
1. The high positive rate ofβ1-AAB in the sera of patients with arrhythmias.
In 106 cases of patients with arrhythmia, 58 cases were positive forβ1-AAB, so the positive rate was 52.8%, which was significantly higher than that in the normal subjects (5.0%) or in coronary heart disease groups (24.0%), (P<0.01) (see Table 1-1,1-2). This result indicates the positive rate ofβ1-AAB in patients with arrhythmia is higher than that in patients of coronary heart disease patients or normal subjects.
2. The distribution characteristics ofβ1-AAB in the sera of patients with different types of arrhythmia.
By analyzing the contents ofβ1-AAB based on the sera OD values, we found in patients with ventricular arrhythmia, atrial arrhythmia and conduction abnormalities arrhythmia, the OD values were 0.35±0.02,0.20±0.01 and 0.22±0.02 respectively which were all higher than that of the normal control group (0.13±0.01, P<0.01). In addition, compared with the atrial arrhythmia and conduction abnormalities arrhythmia, the OD values of ventricular arrhythmia were significantly different (P<0.01) (see Figure 1-1). These results indicate that the distribution ofβ1-AAB is higher in patients of arrhythmia than that in the normal controls, and maybeβ1-AAB is more relevant with ventricular arrhythmias.
3. Establishment of the active immunization rats models and purification ofβ1-AAB.
After active immunization with antigen peptides of the second extracellular loop ofβ1-AR in rats, theβ1-AAB contents in sera increased significantly at 4 weeks, and reached the peak at 10 weeks (at 1:20 dilution the OD value was 3.43±0.72, P<0.01, vs. the control group at the same period) (see Figure 2-1). The anti-serum of rats was purified to obtainβ1-AAB IgGs.
4. Heart failure models of rats were successfully established.
After the heart failure models were set up for 12 weeks, the left ventricular systolic pressure (LVSP) and the maximum rate of ventricular pressure rise and fall (±dp / dtmax) were lower in the heart failure group than that in the sham group (P<0.05), while the end-diastolic pressure of left ventricular (LVEDP) was higher than that in the sham group (P<0.05) (see Table 2-1). The ratios of heart weight and body weight in the heart failure group was significantly higher than that in the sham group at the same period (P<0.01) (see table 2-2). These results above indicated that the rat models of heart failure were established successfully.
5. The effects ofβ1-AAB on ECG of normal rats and heart failure rats
Whenβ1-AAB IgGs were infused from the tail vein of rats acutely, varying degrees and different types of arrhythmia were monitored in the normal rats and heart failure rats. and the ventricular arrhythmia was one of the most common (see Figure 2-2). In addition, the frequency of arrhythmia in the heart failure group was significantly higher than that in the normal rats (see Figure 2-3).
6. Changes of T lymphocyte subtypes in the peripheral blood of immunized rats
The ratios of CD4+ and CD8+ T lymphocyte began to increase in theβ1-AR antigen peptide immunization group and control group after treatment for 24 hours. And it reached a higher level in theβ1-AR antigen peptide immunization group at the 7th day (3.26±0.32), then increased gradually during the study period. However, the ratios of CD4+ and CD8+ T lymphocyte achieved peak at the third day (2.72±0.47), then decreased gradually (see Table 3-1). These results indicate that there is the emergence of significant immune hyperfunction in theβ1-AR antigen peptide immunization group compared with the control group.
7. The effects ofβ1-AAB on T lymphocytes proliferation
The results detected by CCK-8 kits showed that three concentrations ofβ1-AAB (0.01, 0.1, 1 mol/L) promoted proliferation of T lymphocytes induced by Con A in a dose-dependent manner (OD values were 0.49±0.05, 0.69±0.08, 0.82±0.07), which was similar to the role ofβ1-AR agonist isoprenaline (see Figure 3-1). In addition, the effects ofβ1-AAB could be neutralized by theβ1-AR-specific blockers Metoprolol or the antigen peptides corresponding to the second extracellular loop ofβ1-AR, but simple Metoprolol orβ1-AR antigen peptides had no significant effect on proliferation of T lymphocytes (see Figure 3-2).
Conclusions
1. In the sera of patients with arrhythmia, the positive rate ofβ1-AAB was significantly higher than that of patients with coronary heart disease and healthy subjects, and theβ1-AAB might be more relevant with ventricular arrhythmias.
2.β1-AAB had a direct-induced arrhythmia effects in normal rats and heart failure rats, and the ventricular arrhythmia was most common. In addition, the susceptibility to arrhythmia increased markedly in heart failure rats, indicating that the existence of high level ofβ1-AA in sera of patients with heart failure may have more considerable pathophysiologic significance.
3.β1-AAB were reported for the first time to promote the proliferation of T lymphocytes by activating ofβ1-AR, and affect the immune regulation function of the organism.
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