iNOS expression and nitrotyrosine formation in the myocardium in response to inflammation is controlled by the interferon regulatory transcription factor 1.

Background: Production of NO by inducible NO synthase (iNOS) has been implicated in the pathology of spontaneous and antigen-induced autoimmune diseases, and iNOS is expressed in the myocardium of patients with heart failure. It is not clear whether inflammatory murine autoimmune heart disease, an experimental model for human postviral heart disease, is characterized by increased iNOS expression within the heart and whether iNOS and NO are essential in the pathogenesis of autoimmune myocarditis.

Methods And Results: In the murine model of cardiac myosin-induced myocarditis, we demonstrate that iNOS expression was elicited in inflammatory macrophages and in distinct cardiomyocytes.

Induction of autoimmune myocarditis in interleukin-2-deficient mice.

Background: Interleukin (IL)-2 is an important growth and survival factor for T cells and plays a crucial role in inflammation. Myosin-induced myocarditis is strictly dependent on activated T cells and is a model for postinfectious inflammatory heart disease in humans. To explore the role of IL-2 in myocarditis, we injected mice genetically deficient for IL-2 with cardiac myosin.

Low-molecular-weight tumor necrosis factor receptor p55 controls induction of autoimmune heart disease.

Background: Tumor necrosis factor-alpha (TNF-alpha) is involved in the pathogenesis of myocarditis and can bind to either tumor necrosis factor receptor (TNF-R) p55 or TNF-Rp75. However, it is not known which TNF-R mediates the specific functions of TNF in disease. To determine the role of the TNF/TNF-R system in chronic heart disease, we used a murine model of cardiac myosin-induced myocarditis that closely resembles the chronic stages of virus-induced myocarditis in humans.

Cellular and molecular mechanisms of murine autoimmune myocarditis.

Dilated cardiomyopathy is a prevalent cause of progressive heart disease and sudden death, and most patients with cardiomyopathy have a history of viral myocarditis. Coxsackie B3 (CB3) picornaviruses can be detected in as many as 50% of these patients and CB3 infections have been epidemiologically linked to chronic heart disease. Several clinical and experimental studies suggest that chronic stages of disease are mediated by an autoimmune response against heart muscle myosin.

Induction of autoimmunity in the absence of CD28 costimulation.

Ag-specific activation of T lymphocytes requires two signals, one by the TCR and a second by costimulatory molecules. In a CD4+ T helper cell-dependent experimental autoimmune myocarditis model, we provide genetic evidence that cardiac myosin-induced autoimmune myocarditis and the production of IgG auto-Abs is dependent on functional T cells and did not occur in mice lacking the tyrosine kinase p56lck or the tyrosine phosphatase CD45. By contrast, animals lacking the T cell-costimulatory molecule CD28 (CD28 -/-) developed autoimmune heart disease, although at significantly lower severity than in heterozygous littermates, and produced IgG auto-Abs depending on the concentration of the autoantigen administered.