Autoimmune Determinants of Human Cardiac Myosin

点击翻译按钮获取中文摘要

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.