The leukocyte receptor CD69 controls the severity of cardiac insufficiency induced by myocardial inflammation

Circulation - October 05 2010

Myocarditis (inflammation of the myocardium) produces a dilated myocardiopathy that is responsible for a high percentage of cases of chronic cardiac insufficiency (CI), and is one of the leading causes of fatal CI in people under the age of 35. This disease has a variety of causes, including genetic susceptibility, infection by viruses or cardiotrophic parasites, or autoimmune responses to cardiac tissue. A clear understanding of the immunological processes that control inflammation in the myocardium is essential for the development of treatments for this disease.

The research team led by Dr. Pilar Martín Fernández at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) in Madrid, in close collaboration with the group of Dr. Francisco Sánchez-Madrid (Hospital de la Princesa-UAM-CNIC), has published an article in the leading cardiology journal Circulation (Cruz-Adalia A. et al., CD69 limits the severity of cardiomyopathy after autoimmune myocarditis). The team’s study establishes the fundamental role of the molecule CD69 in the negative regulation of cardiac inflammation and the progression  of CI in a model of autoimmune myocarditis in mice genetically deficient for CD69. Similar phenomena are very likely to occur in humans affected by myocarditis and dilated myocardiopathy. This discovery reveals the role of a new molecule important in the immunopathology of myocarditis, providing the first description of a potential target for the control of the cardiac inflammatory immune response.

Myocarditis is characterized by the infiltration of inflammatory cells to the myocardium, followed by edema, myocyte necrosis and fibrosis. This results in a permanent dysfunction of the ventricular walls, ultimately leading to CI. Many individuals with myocarditis produce autoantibodies to cardiac antigens, and treatment with immunosuppressants has been shown to improve ventricular contractile function in patients with dilated myocardiopathy. These observations suggest that post-infection autoimmune mechanisms might promote the development of the disease. Several experimental models of myocarditis have therefore been developed in order to study the mechanisms of autoimmune inflammation. One such model is experimental autoimmune myocarditis (EAM), a mouse model of post-infection myocarditis and myocardiopathy induced by specific peptides derived from cardiac myosin. These mice develop a disease mediated by CD4+ T lymphocytes. 

The new study by Pilar Martín’s group examines the role of the leukocyte receptor CD69 in the control of myocardial inflammation. The article demonstrates that CD69 negatively regulates uncontrolled infiltration of immune cells (neutrophils and macrophages) into the myocardium of mice with EAM. This action is due to the role of CD69 as a regulator of the Th17 subpopulation of lymphocytes, causal agents of the severity of inflammation. Electrocardiography analysis by implantable telemetry, conducted through collaboration with Dr. Manuel Fresno’s group (Universidad Autónoma de Madrid-CBM), revealed an increase in the number of sinus pauses in animals deficient for CD69. Echodardiography analysis of cardiac function, carried out by co-author Dr. Luis Jesús Jiménez-Borreguero (Hospital de la Princesa-Departamento de Imagen y Aterotrombosis, CNIC), showed that this results in severe defects in left ventricular contractility in the chronic phase of the disease.

The study demonstrates the central role of the leukocyte antigen CD69 as a brake on the progression of the severity of myocarditis and subsequent dilated myocardiopathy. The findings moreover establish the basis for future research to determine whether defects in CD69 expression or function influence the development of human myocardiopathies. This discovery increases understanding of the mechanisms that give rise to cardiac inflammation and subsequently to CI, unveiling the cellular and molecular basis for the development of specific therapies.