Autoimmune Determinants of Human Cardiac Myosin

描述（由申请方提供）：心肌炎和风湿性心脏炎分别是病毒或细菌感染的后遗症，发生在病毒感染、A组链球菌感染或心肌肌球蛋白（CM）免疫接种后的人类和动物模型中。心肌炎可能是扩张型心肌病和心力衰竭的前兆。这些疾病的发病机制可能有一个共同点，部分涉及感染性病原体和宿主自身抗原CM之间的分子模拟或感染期间心肌细胞释放的针对CM的免疫应答。虽然CM可以在动物中诱导心肌炎和心瓣膜炎，但CM在人类疾病的分子发病机制中的作用尚未明确。拟议的工作的目标是定义人类CM的自身免疫反应，在人类和CM诱导的心肌炎动物模型，以了解如何细胞内分子，如肌球蛋白可以通过外源性外来抗原或内源性自身抗原的免疫模拟引起疾病。我们将研究先天免疫和适应性免疫之间的联系，以CM和使用动物模型，为人类的研究提供线索。我们将测试的假设，即自身免疫性心脏炎可能会出现由于分子模拟的影响，这可能会导致其他心脏蛋白/抗原通过先天免疫，模仿或表位扩散的参与。在目标1和目标2中，我们计划纵向评估一组心肌炎患者，以确定恢复和疾病的免疫学参数，这对未来理解和制定个性化治疗计划可能很重要。为了阐明患者的致病反应性，我们计划：1）从选定的心肌炎和心肌病患者中制备人单克隆抗体，以确定模拟性和抗体在心肌炎和心肌病发病机制中的作用：2）使用心肌炎和心肌病中的人CM的合成肽以及与疾病相关的表位，评估人T细胞应答并产生针对CM表位的T细胞克隆; 3）确定CM作为内源性配体和刺激先天性免疫的能力4）研究我们先前建立的刘易斯大鼠CM肽诱导的严重心肌炎模型的炎症性心脏病参数，包括分子模拟、细胞因子、调节性T细胞、Th 17细胞和抗体在心肌炎诱导和保护中的作用。我们的工作将提供一个更好地了解心肌炎和心肌病的动物模型中的致病性和保护性免疫机制及其与人类疾病的关系。公共卫生相关性：心肌炎和心肌病是心力衰竭的原因，占所有心脏移植的45%。心肌炎可能开始与流感样病毒性疾病或其他并发症影响心脏，并最终可能发展成心肌病与心脏扩大，心肌功能丧失，心律失常。导致该疾病的潜在自身免疫机制在人类中尚未完全建立。提出的研究将有助于我们了解疾病的免疫学基础。

DESCRIPTION (provided by applicant): Myocarditis and rheumatic carditis are sequelae of viral or bacterial infections, respectively, and occur in humans and animal models following viral infection, group A streptococcal infection, or immunization with cardiac myosin(CM). Myocarditis may be a precursor of dilated cardiomyopathy and heart failure. The pathogenesis of these diseases may have a common denominator related in part to molecular mimicry between the infectious pathogen and the host autoantigen CM or to immune responses against CM released from cardiomyocytes during infection. Although CM can induce myocarditis and valvulitis in animals, the role of CM in the molecular pathogenesis of disease in humans is not well defined. The goal of the proposed work is to define the autoimmune response to human CM in humans and in CM-induced animal models of myocarditis to understand how an intracellular molecule such as myosin can act through immunological mimicry of exogenous foreign antigens or endogenous self antigens to cause disease. We will investigate links between innate and adaptive immunity to CM and use animal models to provide clues for studies in humans. We will test the hypothesis that autoimmune carditis may arise due to the influence of molecular mimicry, which may lead to the involvement of other heart proteins/antigens through innate immunity, mimicry or epitope spreading. In aims 1 and 2, we plan to evaluate a group of myocarditis patients longitudinally where we can determine immunological parameters of recovery and disease which may be important in understanding and developing individualized treatment plans in the future. In order to decipher pathogenic reactivity in patients we plan: 1)To produce human monoclonal antibodies from selected patients with myocarditis and cardiomyopathy to determine mimicry and the role of antibody in the pathogenesis of myocarditis and cardiomyopathy; 2)To evaluate human T cell responses and to produce T cell clones to CM epitopes using synthetic peptides of human CM in carditis and cardiomyopathy and correlate epitopes with disease; 3) To determine the ability of CM to act as an endogenous ligand and stimulate innate immunity 4) To investigate our previously established Lewis rat CM peptide-induced model of severe myocarditis for parameters of inflammatory heart disease including the role of molecular mimicry, cytokines, regulatory T cells, Th17 cells and antibody in the induction of and protection against myocarditis. Our work will provide a better understanding of pathogenic and protective immune mechanisms in animal models of myocarditis and cardiomyopathy and their relationship to human disease. PUBLIC HEALTH RELEVANCE: Myocarditis and cardiomyopathy are a cause of heart failure and forty-five percent of all heart transplantations. Myocarditis may begin with a flu-like viral illness or other complications affecting the heart and eventually may develop into cardiomyopathy with heart enlargement, loss of function of the heart muscle, and cardiac arrythmias. Underlying autoimmune mechanisms that contribute to the disease are not well established in humans. Studies proposed will contribute to our understanding of the immunologic basis of the disease.