Analysis of T-cell receptor β-chain complementarity-determining region 3 motifs of infiltrating T cells in the inflammatory lesions from human myocarditis

心肌肌球蛋白诱导的大鼠实验性自身免疫性心肌炎(EAM)是人巨细胞心肌炎的动物模型。急性发作期后，EAM导致心肌炎后扩张性心肌病。为探讨自身免疫性心肌损伤的发病机制，我们首先分析了T细胞在心肌中的T细胞受体互补决定区3(CDR3)的结构。心肌肌球蛋白杆状蛋白免疫大鼠后，心脏浸润性T细胞CDR3基序受到抑制。心肌肌球蛋白杆状蛋白含有多个致心肌梗死表位。用人工合成的促心肌钙素免疫诱导EAM时，心脏浸润性T细胞为寡克隆性。分析病变中T细胞的CDR4基序可能是自身免疫发病机制的一个标志(循环研究83：133-140,1998)。细胞因子在自身免疫性心肌损伤的发病机制中起重要作用。IL-12通过…促进Th0T细胞向T细胞转化更多Th1功能。IL-12的信使RNA在EAM大鼠心肌中表达，观察IL-12对EAM的影响。体内应用IL-12使EMA的自然病程转变为严重而持久的形式。因此，Th1极性与EAM的发生、发展和持续有关(循环研究82：1035-1042,1998)。柯萨奇病毒和腺病毒受体(CAR)是新近发现的一种病毒，其基因已被克隆。该分子可能与心肌炎的易感性有关。我们研究了CAR在EAM大鼠心脏中的表达。CAR在新生大鼠心肌中表达，而在成年大鼠心脏中检测不到。在EAM过程中，从免疫后18d开始，心肌开始表达CAR基因。免疫组织化学显示24天后心肌组织中有CAR的表达。体外研究表明，心肌CAR的表达是由炎性细胞因子诱导的(循环研究86：275-280,2000)。心肌炎的临床表现从无症状到暴发性和致死性不同。心肌炎患者病程的预测因素尚未建立。我们研究了各种参数在急性心肌炎患者病程中的预测价值。我们在新泻县收集了人类心肌炎病例。对连续21例经组织学证实的心肌炎患者进行了分析。13例患者能在急性期存活，其余患者死亡。死亡组血压低于存活组，肺毛细血管楔压高于存活组。死亡组血清可溶性Fas和Fas配体水平显著高于存活组。SFas和Fas配体可作为预测心肌炎患者预后的血清学标志物(2000年循环102：2829-2835)。较少

Cardiac myosin-induced rat experimental autoimmune myocarditis (EAM) is an animal model of human giant cell myocarditis. After the acute fulminant phase, EAM leads to post-myocarditis dilated cardiomyopathy. Pathogenesis of autoimmune myocardial injuries was investigated using EAM.Initially, we analyzed structure of the T-cell receptor complementarity determining region 3 (CDR3) of T-cells infiltrating in myocardium. When rats were immunized with cardiac myosin rod protein, CDR3 motif of the heart infiltrating T-cells were restricted. Cardiac myosin rod protein contains several myocarditogenic epitopes. When EAM was induced by immunization with a synthetic myocarditogenic peptide, heart infiltrating T-cells were oligoclonal. Analysis of CDR4 motif of t-cells in the lesion may be a marker for autoimmune pathogenesis (Circulation Research 83 : 133-140, 1998). Cytokines play important roles in the pathogenesis of autoimmune myocardial injuries. IL-12 promotes Th0 T-cells into T-cells with … More Th1 function. Messenger RNA of IL-12 was expressed in the myocardium in EAM.Effects of IL-12 were investigated. In vivo administration of IL-12 shifted the natural course of EMA to severe and persistent form. Thus, Th1 polarity related to the onset, progression and persistence of EAM (Circulation Research 82 : 1035-1042, 1998). Coxsakievirus and adenovirus receptor (CAR) has recently been found and its gene has been cloned. This molecule may be related to susceptibility of myocarditis. We investigated expression of CAR in the rat hearts with EAM.CAR was expressed on the neonatal myocardium, but it could not be detected on the adult rat heart. During the course of EAM, mRNA of CAR was expressed on the myocardium from 18 days after immunization. Immunohistochemistry also revealed expression of CAR on the myocardium from day 24. In vitro studies demonstrated that myocardial expression of CAR was induced by inflammatory cytokines (Circulation Research 86 : 275-280, 2000).Clinical manifestation of myocarditis vary from asymptomatic to fulminant and fatal form. The predictors of the course of the disease in patients with myocarditis have not yet been established. We examined the predictive values of various parameters in the disease course of patients with acute myocarditis. We collected human cases of myocarditis in Niigata prefecture. Twenty-one consecutive patients with histology-proven myocarditis were analyzed. Thirteen patients could survive acute phase and remainder were died. The fatal group had lower blood pressure and higher pulmonary capillary wedge pressure compared with the survival group. Serum levels of soluble Fas and Fas ligand were significantly higher in the fatal group than the survival group. Soluble Fas and Fas ligand would be serological marker to predict prognosis in patients with myocarditis (Circulation 102 : 2829-2835, 2000). Less