Autoimmune Determinants of Human Cardiac Myosin

人心肌肌球蛋白的自身免疫决定因素

• 批准号: 6749549
• 负责人: MADELEINE W. CUNNINGHAM
• 金额: $ 29.1万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6749549
• 关键词: Coxsackievirus; MHC class I antigen; MHC class II antigen; RNase protection assay; Streptococcus; T lymphocyte; autoantibody; autoimmune disorder; bacterial antigens; clinical research; cross immunity; cytokine; flow cytometry; human subject; immune tolerance /unresponsiveness; laboratory rat; microarray technology; myocarditis; myosins; pathologic process; patient oriented research; tissue /cell culture; virus antigen

DESCRIPTION (provided by applicant): Myocarditis and rheumatic carditis are sequelae of viral and bacterial infections, respectively, and occur in humans and animal models following coxsackievirus infection, group A streptococcal infection, or immunization with cardiac myosin. The pathogenesis of these diseases may be due to molecular mimicry between the infectious pathogen and the host autoantigen cardiac myosin. Although cardiac myosin can induce myocarditis in animals, the molecular pathogenesis of the disease in humans is unclear. In addition, there are few studies in humans, which define the immunological parameters of disease. The goal of the proposed work is to define the parameters of the autoimmune response to human cardiac myosin in humans and in a cardiac myosin-induced rat model of myocarditis and valvulitis. We will test the hypothesis that molecular mimicry and the influence of the cytokine environment leads to development of disease. We plan: 1)To produce and investigate human T cell clones from myocarditis patients which are crossreactive with human cardiac myosin, streptococcal M protein and coxsackievirus and their peptides; to determine cytokine responses of human T cell clones as well as HLA class I and II restriction of responses and cell surface antigens by FACS analysis 2)To evaluate expression of genes by crossreactive CD4+/- and CD8+ T cell clones and by normal and myocarditis patient peripheral blood CD4+ and CD8+ lymphocytes in response to stimulation with myosin, M protein and coxsackievirus or their peptides by DNA array analysis, cytokine production, and to study the cell surface markers on T lymphocytes by FACS analysis 3) To investigate a Lewis rat cardiac S2 peptide-induced model of severe myocarditis for parameters of inflammatory heart disease including the role of molecular mimicry and cytokines in susceptible, resistant, and tolerized rat strains (Lewis and BB/DR), to determine the epitope specificity of the heart specific infiltrating T cells from hearts in the Lewis rat model and to determine cytokine expression in hearts using the RNase protection assay for TH1/TH2 cytokines and expression of a large group of genes using DNA arrays. We will establish a tolerance model to investigate the downregulation of myosin specific I cells, antibodies and cytokines in disease.

描述（由申请人提供）：心肌炎和风湿性心炎是 病毒和细菌感染的后遗症，并发生在人类中 和Coxsackievirus感染后的动物模型，A组链球菌 感染或心脏肌球蛋白免疫。这些的发病机理 疾病可能是由于感染性病原体和 宿主自身心脏肌球蛋白。虽然心脏肌球蛋白可以诱导 动物心肌炎，人类疾病的分子发病机理是 不清楚。此外，人类几乎没有研究，这些研究定义了 疾病的免疫学参数。拟议工作的目标是定义 自身免疫反应对人类心脏肌球蛋白的反应参数， 在心脏肌球蛋白引起的心肌炎和瓣膜炎的大鼠模型中。我们将 检验分子模仿和细胞因子的影响的假设 环境导致疾病的发展。我们计划：1）生产和 调查来自心肌炎患者的人类T细胞克隆 与人类心脏肌球蛋白，链球菌M蛋白和 Coxsackievievirus及其肽；确定人类的细胞因子反应 细胞克隆以及HLA I类和II的响应限制和细胞的限制 FACS分析表面抗原2）评估基因表达 交叉反应性CD4 +/-和CD8+ T细胞克隆以及正常和心肌炎 患者外周血CD4+和CD8+淋巴细胞响应刺激 与肌球蛋白，M蛋白和Coxsackievivirus或它们的肽通过DNA阵列 分析，细胞因子产生并研究T上的细胞表面标记 FACS分析的淋巴细胞3）研究刘易斯大鼠心脏S2 肽诱导的严重心肌炎模型用于炎症参数 心脏病，包括分子模仿和细胞因子在 敏感，抗性和耐受的大鼠菌株（刘易斯和bb/dr）， 确定心脏特异性浸润T细胞的表位特异性 从刘易斯大鼠模型中的心脏中心确定细胞因子的表达 心脏使用Th1/Th2细胞因子的RNase保护测定法和表达 使用DNA阵列的大量基因。我们将建立一个容忍模型 研究肌球蛋白特异性I细胞，抗体和 疾病中的细胞因子。