AUTOIMMUNE DETERMINANTS OF HUMAN CARDIAC MYOSIN

描述(摘自研究人员摘要)：心肌炎是一种 人类病毒或细菌感染的后遗症，易发于 柯萨奇病毒感染或免疫后的动物品系 心肌肌球蛋白。在某些情况下，心肌炎可能是由于分子 感染性病原体与宿主心脏自身抗原之间的拟态 肌球蛋白。心肌炎可能是由于宿主暴露在模仿环境中引起的 可能打破对心肌肌球蛋白耐受性的表位。虽然心动 肌球蛋白是已知的可引起动物心肌炎的自身抗原， 人类疾病发病的分子基础仍然存在 未知。此外，在人类身上很少有研究确定 定义疾病的免疫学表位。拟议工作的目标是 目的是确定动物对人心肌肌球蛋白的自身免疫反应 心肌炎模型和人类心肌炎模型，并测试 假设疾病中的抗肌球蛋白抗体和T细胞是 与病毒或细菌表位发生交叉反应。出于这些原因， 调查人员选择探索以下对象：1)生产 人抗肌球蛋白单抗(MAb)在慢性阻塞性肺疾病中的应用 心肌炎及单抗与人心肌肌球蛋白反应性的研究 及其片段和合成肽、链球菌M蛋白和 柯萨奇病毒蛋白和多肽，并研究单抗的细胞毒性 抗心肌细胞培养；2)研究T细胞对心肌细胞的反应 心肌炎患者对人心肌肌球蛋白、片段和合成的研究 多肽、链球菌M蛋白和柯萨奇病毒多肽，包括 人心肌肌球蛋白反应性T细胞克隆的产生；3)a)确定 心脏特异性浸润性T细胞/系/克隆的特异性 心肌炎动物模型(Lewis大鼠、A/J和MRL小鼠)的心脏。 T细胞株/克隆将被测试对人类基因片段的反应性 心肌肌球蛋白、链球菌M蛋白和柯萨奇病毒蛋白以及 并将与人类T细胞的特异性进行比较 心肌炎的反应，b)研究肌球蛋白致病多肽， 柯萨奇病毒或链球菌M蛋白来确定它们的能力 对柯萨奇病毒或肌球蛋白引起的心肌炎产生耐受性。

DESCRIPTION (Adapted from Investigator's abstract): Myocarditis is a sequela of viral or bacterial infections in humans and occurs in susceptible animal strains following coxsackievirus infection or immunization with cardiac myosin. In some instances, myocarditis may be due to molecular mimicry between an infectious pathogen and the host autoantigen cardiac myosin. Myocarditis may result from exposure of the host to mimicking epitopes which may break tolerance against cardiac myosin. Although cardiac myosin is the known autoantigen which can induce myocarditis in animals, the molecular basis of the pathogenesis of the disease in humans remains unknown. In addition, there are few studies in humans which identify the immunological epitopes defining the disease. The goal of the proposed work is to define the autoimmune response to human cardiac myosin in animal models of myocarditis and in humans with myocarditis and to test the hypothesis that the anti-myosin antibodies and T-cells in the disease are crossreactive with viral or bacterial epitopes. For these reasons, the investigators have chosen to explore the following objects: 1) To produce human anti-myosin monoclonal antibodies (Mabs) from patients with myocarditis and investigate the Mabs reactivity with human cardiac myosin and its fragments and synthetic peptides, streptococcal M protein and coxsackieviral proteins and peptides, and to investigate mAb cytotoxicity against heart cells in culture; 2) To investigate the T-cell response in myocarditis patients to human cardiac myosin, fragments and synthetic peptides, streptococcal M Protein and coxsackieviral peptides, including production of human cardiac myosin response T-cell clones; 3)a) To determine the specificity of the heart specific infiltrating T-cells/lines/clones from hearts in animals models (Lewis rats and A/J and MRL mice) of myocarditis. T-cell lines/clones will be tested for responsiveness to fragments of human cardiac myosin, streptococcal M protein, and coxsackieviral proteins and peptides and will be compared with the specificities of the human T-cell response in myocarditis, b) to study pathogenic peptides of myosin, coxsackievirus or streptococcal M protein to determine their ability to produce tolerance against coxsackieviral or myosin-induced myocarditis.