Mononuclear cell secretome in autoimmune myocarditis.

Myocarditis is defined as inflammation of cardiac muscle with or without myocyte necrosis. Both infectious and non-infectious aetiologies for myocarditis are known, but the most common is virus-induced myocarditis often followed by post-infectious inflammatory cardiomyopathy. Many RNA (picorna-, orthomyxo-, paramyxo-, and flaviviruses) as well as DNA (adeno-, erythro-, herpes-, and retroviruses) viruses are capable of infecting the heart and inducing direct cytopathic injury. During the last 20 years, important new observations and insights regarding the pathophysiological mechanisms of the disease have been made by employing two murine models of myocarditis, one induced by Coxsackievirus B3 (CVB3) infection, and the other by immunization with cardiac myosin or troponin. These studies resulted in novel therapeutic interventions such as immunosuppressive and immunomodulatory treatments. However, because of the heterogeneity of clinical presentation and incomplete understanding of human immunopathology, therapeutic options are still limited. Congestive heart failure is frequently caused by virus infection that has been implicated as an important causal factor responsible for the development of dilated inflammatory cardiomyopathy (DCMi). Viral infection triggers an inflammatory process by expression of cytokines, chemokines, and abundant infiltration with T cells and macrophages, that outlasts the initial replicative phase and may lead to post-viral autoimmunity. Chronic inflammation then leads to tissue injury, endothelial dysfunction, and cardiac remodelling, resulting in deterioration of myocardial contractility and left ventricular ejection fraction (Figure 1). Therefore, the immune response, characterized by immunohistologically proven inflammatory infiltrates and viral genomes in biopsy specimens, plays a crucial role in the diagnosis as well as the outcome of DCMi. In many patients, the innate and adaptive immune response results in elimination of the viral agents followed by termination of inflammation. However, disarrangement of the immune response or molecular mimicry often triggers exposition of autoantigens followed by a chronic autoimmune disorder called inflammatory cardiomyopathy. Immunosuppressive therapy in the absence of virus together with symptomatic heart failure medication is the mainstay of clinical therapy and has been shown in prospective clinical trials to protect cardiac tissue from inflammatory injury. However, virus particles including enterovirus are often detected in cardiac tissue. Specific treatments encompass antiviral agents such as Val-/Gan-/Aciclovir (human herpes virus 6, cytomegalovirus, herpes zoster virus, herpes simplex virus), interferon-beta (entero-/adenovirus), or interferon-alpha and ribaverin (hepatitis C virus). Hoetzenecker et al. report a possible new therapeutic option for virus-negative autoimmune cardiomyopathy. They used an approach originally employed in stem cell therapy, injecting the secretome (i.e. secreted proteins) of mononuclear cells into mice with experimental autoimmune myocarditis (EAM), and were thus able to limit cardiac inflammation in this T cell-dependent model of autoimmune myocarditis (Figure 1). Experimental autoimmune myocarditis in mouse mimics certain aspects of human inflammatory cardiomyopathy. In particular the autoimmune response and chronic inflammation of the heart can be studied by immunizing susceptable mice (e.g. BALBc) with cardiac-specific a-myosin heavy chain peptides. The autoimmune inflammation characterized by mononuclear cell infiltration peaks at day 21 post-immunization. Hoetzenecker et al. injected the secretome (i.e. a cocktail of several secreted proteins from mononuclear cells) at different time points in order to suppress autoimmune inflammation since monocytes are known to inhibit CD4+ cell-dependent inflammation in this model. The immune response to pathogens or other tissue injury relies on the concerted release of cytokines and proteins with biological