Molecular Mechanisms of Autoimmune Heart Disease

自身免疫性心脏病的分子机制

• 批准号: 7228543
• 负责人: MYRA A LIPES
• 金额: $ 46.58万
• 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 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7228543
• 关键词: Activities of Daily Living; Adjuvant; Affect; Animal Model; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; CD4 Positive T Lymphocytes; Cardiac; Cardiac Myocytes; Cardiac Myosins; Cardiomyopathies; Celiac Disease; Cells; Cessation of life; Characteristics; Child; Class; Collaborations; Congenic Strain; Development; Diabetes Mellitus; Diagnosis; Dilated Cardiomyopathy; Disease; Epitopes; Etiology; Exhibits; Frequencies; Genes; Genotype; HLA-DQ8 antigen; Haplotypes; Heart; Heart Diseases; Heart failure; Hospitals; Human; Immunization; Immunoglobulin G; Immunologic Tests; Immunologist; Inbred NOD Mice; Infection; Insulin-Dependent Diabetes Mellitus; Interferon Type II; Interferons; Interleukin-4; Lead; Lesion; Lymphocytic Infiltrate; MHC Class II Genes; Mediating; Mediator of activation protein; Methods; Modeling; Molecular; Mus; Myocarditis; Myocardium; Myosin ATPase; Myosin Heavy Chains; Organ; Pathogenesis; Patients; Phenotype; Process; Resistance; Secondary to; Self Tolerance; Skeletal Muscle Myosins; Skeletal system; Specificity; Staging; Subgroup; Sudden Death; Susceptibility Gene; T-Lymphocyte; Thinking; Transgenic Organisms; Virus; Virus Diseases; Woman; cytokine; human disease; improved; in vivo; response; translational study; young adult

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，病因尚不清楚。我们发现，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的表达会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，破坏性的淋巴细胞浸润在心肌中，循环IgG自身抗体对抗心肌肌球蛋白重链，类似于人类心肌炎。对直接从心脏病变中分离的CD4 T细胞克隆的分析表明，与与骨骼和心脏肌球蛋白交叉反应的自身抗体相反，CD4 T细胞只识别心脏肌球蛋白，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，这与致病性Th1表型一致。该项目的具体目标是：1)利用T细胞克隆和功能探针鉴定导致心肌细胞自我耐受性丧失的肌球蛋白3蛋白的表位；2)鉴定参与疾病发病机制的主要细胞介质，并利用同源菌株确定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)探讨人类心肌炎是否是一种与HLA- dq8相关的器官特异性自身免疫性疾病，HLA分型与免疫学检测相结合是否能够检测到。这些转化研究将涉及PI和布里格姆妇女医院高级心脏病科主任，心肌炎领域的领导者Kenneth Baughman博士之间的合作。这些研究结果为了解人类心肌炎的病因打开了一扇新的窗口，并有助于改进这一严重疾病的诊断和治疗方法。

项目成果

Myocardial infarction triggers chronic cardiac autoimmunity in type 1 diabetes.

• DOI: 10.1126/scitranslmed.3003551
• 发表时间: 2012-06-13
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Gottumukkala RV;Lv H;Cornivelli L;Wagers AJ;Kwong RY;Bronson R;Stewart GC;Schulze PC;Chutkow W;Wolpert HA;Lee RT;Lipes MA
• 通讯作者: Lipes MA