Molecular Mechanisms of Autoimmune Heart Disease

描述(申请人提供)：自身免疫性心肌炎是导致儿童和年轻人猝死的主要原因。虽然被广泛认为是传染病的病因，但在大多数病例中，病因尚不清楚。我们已经发现，在缺乏内源性小鼠II类基因的非肥胖糖尿病小鼠中，人类HLAII类分子HLA-DQ8的表达导致了自身免疫性心肌炎的自发发展。这种疾病的特征是心力衰竭导致的过早死亡，破坏性淋巴细胞在心肌中的渗透，以及循环中的抗心肌肌球蛋白重链抗体，类似于人类心肌炎。对直接从心脏病变中分离的CD4T细胞克隆的分析表明，与与骨骼肌球蛋白和心肌肌球蛋白交叉反应的自身抗体不同，CD4T细胞只识别心肌肌球蛋白，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，这与致病的Th1表型一致。该项目的具体目标是：1)使用T细胞克隆和功能探针来鉴定肌球蛋白3旋转蛋白的表位，这些表位是导致心肌细胞失去自我耐受性的原因；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受共同的‘自身免疫基因’控制；3)研究人类心肌炎是否是与HLA-DQ8相关的器官特异性自身免疫性疾病，以及是否可以结合HLA配型和免疫学检测来检测它。这些翻译研究将涉及国际心肌炎协会和肯尼斯·鲍曼博士之间的合作，肯尼斯·鲍曼博士是布里格姆妇女医院高级心脏病科主任，也是心肌炎领域的领导者。这些研究的结果可能会为人类心肌炎的病因学打开一扇新的窗口，并导致诊断和治疗这种严重疾病的改进方法。

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.