Consequences of unlocking the cardiac myosin molecule in human myocarditis and cardiomyopathies

Abstract

Myocarditis, often initiated by viral infection, may progress to autoimmune inflammatory heart disease, dilated cardiomyopathy and heart failure. Although cardiac myosin is a dominant autoantigen in animal models of myocarditis and is released from the heart during viral myocarditis, the characterization, role and significance of anti-cardiac myosin autoantibodies is poorly defined. In our study, we define the human cardiac myosin epitopes in human myocarditis and cardiomyopathies and establish a mechanism to explain how anti-cardiac myosin autoantibodies may contribute to heart disease. We show that autoantibodies to cardiac myosin in sera from myocarditis and dilated cardiomyopathies in humans targeted primarily epitopes in the S2 hinge region of cardiac myosin. In addition, anti-cardiac myosin antibodies in sera or purified IgG from myocarditis and cardiomyopathy targeted the beta-adrenergic receptor and induced antibody-mediated cAMP-dependent protein kinase A (PKA) cell signaling activity in heart cells. Antibody-mediated PKA activity in sera was abrogated by absorption with anti-human IgG. Antibody-mediated cell signaling of PKA was blocked by antigen-specific inhibition by human cardiac myosin or the beta-adrenergic receptor but not the alpha adrenergic receptor or bovine serum albumin. Propranolol, a beta blocker and inhibitor of the beta-adrenergic receptor pathway also blocked the antibody-mediated signaling of the beta-adrenergic receptor and PKA. The data suggest that IgG antibody against human cardiac myosin reacts with the beta-adrenergic receptor and triggers PKA signaling in heart cells. In-summary, we have identified a new class of crossreactive autoantibodies against human cardiac myosin and the beta-adrenergic receptor in the heart. In addition, we have defined disease specific peptide epitopes in the human cardiac myosin rod S2 region in human myocarditis and cardiomyopathy as well as a mechanistic role of autoantibody in the pathogenesis of disease.

Autoimmunity and heart diseases: pathogenesis and diagnostic criteria

“…Autoantibodies against cardiac α and β myosin heavy chain, mitochondrial antigens, adenine nucleotide translocator, cardiac β1 adrenergic receptor and M2 muscarinic receptor, anti-branched chain α-ketoacid dehydrogenase dihydrolipoyl transacylase, and other autoantigens might participate in the pathogenesis (Afanasyeva et al 2004;Li et al 2008). Immunization against cardiac myosin heavy chain or infusion of anti--myosin autoantibodies in susceptible mice have caused myocarditis (Mascaro-Blanco et al 2008;Rose 2008). Autoantibodies can cause apoptosis of cardiomyocytes or complement activation, direct cell-mediated cyotoxicity, or alter myocardial function (Afanasyeva et al 2004;Mascaro-Blanco et al 2008).…”

Molecular Mimicry

“…Mimicry between microbial pathogens and host tissues may lead to the induction of antibodies which signal cells in an autoantibody-mediated cell signalling mechanism. The most recent studies have shown that crossreactive antibodies against cardiac myosin and the b adrenergic receptor in the heart can lead to induction and activation of protein kinase A signaling (Li, Heuser et al, 2006;Mascaro-Blanco et al, 2008). The passive transfer of autoantibodies which signal myocardial cells led to sites of apoptosis in the heart (Li et al, 2006).…”

“…The passive transfer of autoantibodies which signal myocardial cells led to sites of apoptosis in the heart (Li et al, 2006). Such pathogenic signalling autoantibodies may lead to dilated cardiomyopathy in humans (Mascaro-Blanco et al, 2008).…”

Advances in monoclonal antibody application in myocarditis

“…And the pathogenesis is similar to the second stage of VMC. Mascaro-Blanco et al (2008) found a new class of cross-reactive autoantibodies against human cardiac myosin, whose epitopes can also be widely considered as the diseasespecific peptide epitopes in cardiomyopathies. In addition, they pointed out that these epitopes were found primarily in the S2 region of the cardiac myosin rod as well as a mechanistic role of autoantibody in the disease pathogenesis.…”