Molecular Mechanisms of Autoimmune Heart Disease

自身免疫性心脏病的分子机制

• 批准号: 7074056
• 负责人: MYRA A LIPES
• 金额: $ 46.67万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-15 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7074056
• 关键词: MHC class II antigen; NOD mouse; T cell receptor; T lymphocyte; autoimmune disorder; cardiac myocytes; clinical research; disease /disorder etiology; enzyme linked immunosorbent assay; flow cytometry; genetic regulation; genotype; helper T lymphocyte; high performance liquid chromatography; histocompatibility typing; human subject; immune tolerance /unresponsiveness; immunologic assay /test; insulin dependent diabetes mellitus; laboratory mouse; molecular pathology; molecular shape; myocarditis; pathologic process; protein structure; western blottings

DESCRIPTION (provided by applicant): Autoimmune myocarditis is a major cause of sudden death in children and young adults. Although widely thought to be of infectious etiology, in the majority of cases the cause of disease is unknown. We have discovered that expression of the human HLA class II molecule, HLA-DQ8, in nonobese diabetic mice that lack endogenous murine class II genes results in the spontaneous development of autoimmune myocarditis. Disease was characterized by premature death due to heart failure, destructive lymphocytic infiltrates in the myocardium, and circulating IgG autantibodies against cardiac myosin heavy chain, similar to human myocarditis. Analysis of CD4 T cell clones isolated directly from the heart lesions reveals that, in contrast to the autoantibodies that cross-react with skeletal and cardiac myosin, the CD4 T cells recognize only cardiac myosin, consistent with the cardiac-specificity of this autoimmune disease process. These clones produce large amounts of interferon-gamma, but not IL-4, consistent with a pathogenic Th1 phenotype. The specific aims of this project are: 1) to use the T cell clones a functional probes to identify the epitopes of the myosin 3rotein that are reponsible for the loss of self-tolerance to cardiac myocytes, 2) to identify the primary cellular mediators involved in the pathogenesis of disease and to use congenic strains to determine whether type 1 diabetes and autoimmune myocarditis are controlled by common 'autoimmunity genes', 3) to investigate whether myocarditis in humans is an organ-specific autoimmune disease associated with HLA-DQ8 and whether it can be detected with a combination of HLA typing and immunological testing. These translational studies will involve a collaboration between the PI and Dr. Kenneth Baughman, Director of the Advanced Heart Disease Division at Brigham and Women's Hospital and a leader in the field of myocarditis. The results of these studies could open a new window into the etiology of human myocarditis and lead to improved methods to diagnose and treat this serious disease.

描述（由申请人提供）：自身免疫性心肌炎是儿童和年轻人猝死的主要原因。虽然被广泛认为是感染性病因，但在大多数情况下，疾病的原因是未知的。我们已经发现，在缺乏内源性鼠II类基因的非肥胖糖尿病小鼠中，人类HLA II类分子HLA-DQ 8的表达导致自身免疫性心肌炎的自发发展。疾病的特征是由于心力衰竭导致的过早死亡、心肌中的破坏性淋巴细胞浸润和针对心肌肌球蛋白重链的循环IgG自身抗体，类似于人类心肌炎。对直接从心脏病变中分离的CD 4 T细胞克隆的分析表明，与与骨骼肌和心肌肌球蛋白交叉反应的自身抗体相反，CD 4 T细胞仅识别心肌肌球蛋白，这与这种自身免疫性疾病过程的心脏特异性一致。这些克隆产生大量的干扰素-γ，但不产生IL-4，与致病性Th 1表型一致。该项目的具体目标是：1）使用T细胞克隆作为功能探针来鉴定与心肌细胞自身耐受性丧失有关的肌球蛋白3蛋白的表位，2）鉴定参与疾病发病机制的主要细胞介质，并使用同源菌株来确定1型糖尿病和自身免疫性心肌炎是否由共同的“自身免疫基因”控制，3）研究人类心肌炎是否是与HLA-DQ 8相关的器官特异性自身免疫性疾病，以及是否可以通过HLA分型和免疫学检测相结合来检测。这些转化研究将涉及PI与Brigham and Women's Hospital高级心脏病部主任Kenneth Baughman博士以及心肌炎领域的领导者之间的合作。这些研究的结果可能为人类心肌炎的病因学打开一个新的窗口，并导致诊断和治疗这种严重疾病的方法得到改进。