Autoimmune Determinants of Human Cardiac Myosin

描述（由申请人提供）：心肌炎和风湿性心肌炎分别是病毒或细菌感染的后遗症，发生在病毒感染、A组链球菌感染或接种心肌球蛋白（CM）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先兆。这些疾病的发病机制可能有一个共同点，部分与感染性病原体和宿主自身抗原CM之间的分子模仿有关，或者与感染期间心肌细胞释放的针对CM的免疫反应有关。虽然CM可以在动物中诱发心肌炎和瓣膜炎，但CM在人类疾病的分子发病机制中的作用尚不明确。本研究的目标是在人类和CM诱导的心肌炎动物模型中定义对CM的自身免疫反应，以了解细胞内分子（如肌球蛋白）如何通过外源性外来抗原或内源性自身抗原的免疫模仿作用而引起疾病。我们将研究先天性免疫和适应性免疫对CM之间的联系，并使用动物模型为人类研究提供线索。我们将检验这一假设，即自身免疫性心肌炎可能是由于分子模仿的影响而产生的，这可能导致其他心脏蛋白/抗原通过先天免疫、模仿或表位扩散参与。在目标1和目标2中，我们计划纵向评估一组心肌炎患者，我们可以确定康复和疾病的免疫参数，这可能对未来理解和制定个性化治疗计划很重要。为了了解患者的致病反应性，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，以确定抗体在心肌炎和心肌病发病机制中的相似性和作用；2)评价人T细胞对CM表位的反应，利用合成的人CM在心肌病中的肽产生T细胞克隆，并将表位与疾病联系起来；3)确定CM作为内源性配体和刺激先天免疫的能力4)研究我们已建立的Lewis大鼠CM肽诱导的重症心肌炎模型，探讨炎症性心脏病的参数，包括分子模拟、细胞因子、调节性T细胞、Th17细胞和抗体在心肌炎诱导和保护中的作用。我们的工作将更好地了解心肌炎和心肌病动物模型的致病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%。心肌炎可能以流感样病毒性疾病或其他影响心脏的并发症开始，最终可能发展为心肌病，伴有心脏增大、心肌功能丧失和心律失常。导致该疾病的潜在自身免疫机制在人类中尚未很好地确定。提出的研究将有助于我们了解该疾病的免疫学基础。

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.