The immune system in viral myocarditis: maintaining the balance.

Dilated cardiomyopathy, one of the leading causes of heart failure in the United States, is a multifactorial disease that includes both hereditary and acquired forms.1 In patients, it has been shown that dilated cardiomyopathy can be a sequela of viral myocarditis.2 Although many different infectious agents have been attributed as the cause of viral myocarditis, enteroviruses, in particular Coxsackie B viruses, are consistently among the most common.2 The concept that enteroviruses contribute to the pathogenesis of a subset of human dilated cardiomyopathy has been strengthened by the detection of enteroviral genome in the hearts of patients with dilated cardiomyopathy. Since the first description by Bowles et al in 1986,3 many articles have addressed this issue (reviewed in Baboonian et al4). Although the results of individual studies vary, the data overall indicate that enteroviral genome is present in the heart of 15% to 25% of patients with dilated cardiomyopathy.4 Analogous to many other viral illnesses, both direct viral injury and the immune response of the host play an important role in the pathogenesis of viral heart disease. Furthermore, results from experiments in murine models of viral myocarditis indicate that although the immune response has an important protective role, it may also have deleterious effects on the host. The balance between these protective and deleterious effects may ultimately determine the course of disease after enteroviral infection. The direct viral effects have been demonstrated in culture and in vivo. In cultured cardiomyocytes, infection with Coxsackievirus B3 (CVB3) induces a direct cytopathic effect and cell death.5 In mice, transgenic expression of CVB3 genomes in the heart is sufficient to induce dilated cardiomyopathy.6 Both effects occurred independently of an immune response and demonstrate that coxsackieviral proteins can principally cause myocyte damage and heart disease. In this regard, a molecular pathogenic mechanism has been proposed that involves dystrophin, a cytoskeletal protein that causes dilated cardiomyopathy when genetically defective. Coxsackieviral protease 2A proteolytically cleaves and functionally impairs dystrophin during CVB3 infection.7 In an immunocompetent host, the immune response elicited by viral proteins recognized as foreign limits viral replication and, in many cases, finally clears the virus from the host. These antiviral immune properties are highlighted by experiments using immunocompromised mice infected with CVB3. Mice with severe combined immunodeficiency and mice treated with the immunosuppressive agent FK506 demonstrate enhanced myocardial damage in the absence of an effective immune response.8 In addition, knockout of the inducible nitric oxide synthase gene (NOS2) that is expressed at high levels in immune cells causes increased viral titers and myocarditis in CVB3-infected mice.9 These studies clearly show the protective aspects of mononuclear cells in murine myocarditis and the potential for direct viral mediated cardiac injury. However, the immune response may also contribute to tissue damage by inappropriately attacking cardiac myocytes. In 1974, Woodruff and Woodruff10 first demonstrated a role for T lymphocytes in the pathogenesis of murine myocarditis when they showed that depletion of T lymphocytes using antithymocyte serum or thymectomy and irradiation led to a decrease in mortality and a decrease in the inflammatory infiltrate after CVB3 infection. Subsequently, considerable research has been performed to determine the role of T-cell subtypes in the immunopathogenesis of viral myocarditis. This includes work by Huber et al11,12 that has demonstrated an important role for Th1 cell responses and the requirement for g/d T-cell activation. It has been proposed that molecular mimicry—the presence of related epitopes—exists between CVB3 and a variety of myocardial proteins. This can lead to antibodies or cytotoxic T lymphocytes originally directed against the virus to cross-react with host antigens.13 These harmful immune properties were demonstrated by transfer of mononuclear cells from mice infected with CVB3 14 or patients with myocarditis15 into genetically identical or immunodeficient mice, respectively. In addition, increased levels of cytokines, such as tumor necrosis factor (TNF)-a, may also contribute to the decrease in myocardial function associated with viral infection.16 Recently, the generation of transgenic knockout mice that lack individual components of the immune system has allowed molecular dissection of immune mechanisms that are important in the pathogenesis of viral myocarditis. In this The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Medicine, University of California, San Diego, Calif. Correspondence to Kirk U. Knowlton, MD, Department of Medicine, University of California, 9500 Gilman Dr, San Diego, CA 92093-0613C. E-mail [email protected] (Circ Res. 1999;85:559-561.) © 1999 American Heart Association, Inc.