Autoantibodies in against human ventricular myosin in sera of patients with acute and chronic myocarditis

Lauer, Bernward; Padberg, Klaus; Schultheiss, Heinz‐Peter; Strauer, B. E.

doi:10.1016/0735-1097(94)90513-4

Cited by 87 publications

(35 citation statements)

References 27 publications

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“…In addition, mice produced cardiac myosinspecific IgG antibodies and spontaneous response to cardiac myosin. Anti cardiac-myosin antibodies to cardiac-myosin have been reported in myocarditis patients [22,23]. Thus the present data suggest a role of T and B cell in pathogenesis of myocarditis, which is in agreement with previous findings [12,24,25].…”

Section: Discussionsupporting

confidence: 93%

Spontaneous myocarditis mimicking human disease occurs in the presence of an appropriate MHC and non-MHC background in transgenic mice

Taneja

Behrens

Cooper

et al. 2007

Journal of Molecular and Cellular Cardiology

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Most individuals have viral infections at some point in their life, however, only few develop autoreactivity to cardiac myosin following infection resulting in myocarditis suggesting a genetic predisposition. Most mouse models of myocarditis are induced by viral infection or by immunization with cardiac myosin. We generated HLA-DR3.Aβo and HLA-DQ8.Aβo transgenic mice in NOD and HLA-DQ8.Aβo in B10 background to study spontaneous autoimmunity. A high mortality was observed in NOD.DQ8 female mice 16 weeks or older. Echocardiography showed marked systolic dysfunction. Histopathology of various organs revealed an enlarged heart with mononuclear infiltrate consisting of CD4 and Mac-1+ cells and myocyte necrosis. The autoimmunity was associated with the presence of spontaneous autoreactive T cells and antibodies to cardiac myosin. Serologically, mice were negative for all known mouse viruses. NOD.DR3.Aβo, the transgene negative littermates, NOD, and B10.DQ8 Aβo mice had no gross or microscopic cardiac pathology. Spontaneous cellular and humoral response to cardiac myosin suggest that NOD.DQ8 may harbor autoreative cells that can lead to spontaneous myocarditis and dilated cardiomyopathy. HLA-DQ8 is required for predisposition to the spontaneous autoreactivity while NOD background influences onset and progression of disease. This model of myocarditis occurs predominantly in female mice and may provide insight into the pathogenesis of heart disease in women.

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Section: Discussionsupporting

confidence: 93%

Spontaneous myocarditis mimicking human disease occurs in the presence of an appropriate MHC and non-MHC background in transgenic mice

Taneja

Behrens

Cooper

et al. 2007

Journal of Molecular and Cellular Cardiology

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“…Reactivity was not detectable in other tissues such as liver or kidney, but a ϳ200-kDa protein was seen in skeletal muscle that corresponded to skeletal muscle myosin (data not shown). This cross-reactivity was not unexpected, because the ␣-cardiac and ␤-skeletal muscle myosin H chain isoforms in rodents are highly (Ͼ97%) homologous (32); similar cardiac and skeletal muscle Ab cross-reactivity is also seen in human myocarditis (33). These findings sharply contrasted with the cardiac specificity of this autoimmune disease process, because autoimmune infiltrates developed in the heart (Fig.…”

Section: Resultscontrasting

confidence: 50%

A Spontaneous Model for Autoimmune Myocarditis Using the Human MHC Molecule HLA-DQ8

Taylor

Havari

McInerney

et al. 2004

The Journal of Immunology

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Genome-wide analyses have shown that the MHC class II region is the principal locus that confers susceptibility to a number of human autoimmune diseases. Due to the high degree of linkage disequilibrium across the MHC, it has been difficult to dissect the contribution of individual genes to disease susceptibility. As a result, intensive efforts have been made to generate mice transgenic for human class II molecules as models of autoimmune disease. However, in every case, additional manipulations—such as immunization with Ag in adjuvant, expression of immunostimulants on target tissues, or coexpression of TCR transgenes—have been required to induce disease. In this study, we show that expression of the human HLA-DQ8 (DQA1*0301/DQB1*0302) molecule alone in three lines of transgenic nonobese diabetic murine class II-deficient (mII−/−) mice results in the spontaneous development of autoimmune myocarditis. The disease shares key features of human myocarditis and was characterized by lymphocytic infiltrates in the myocardium and cardiac myocyte destruction, circulating IgG autoantibodies against cardiac myosin heavy chain, and premature death due to heart failure. We demonstrate that myocarditis could be transferred into healthy HLA-DQ8+RAG-1−/−mII−/− nonobese diabetic recipients with lymphocytes, but not sera. It has been widely thought that autoimmune myocarditis is of infectious etiology, with the immune responses arising secondary to cardiac damage from pathogens. These studies provide direct experimental evidence that spontaneous autoimmune myocarditis can occur in the absence of infection and that expression of HLA-DQ8 confers susceptibility to this organ-specific autoimmune disease.

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“…Circulating cardiac autoantibodies to CM and other heart-specific autoantigens are markers of autoimmunity in human myocarditis (11,12,(32)(33)(34)(35)(36). In mice, deposition of CM-reactive Abs in the myocardium was detected after immunization with CM (26).…”

Section: Discussionmentioning

confidence: 99%

Mimicry and Antibody-Mediated Cell Signaling in Autoimmune Myocarditis

Wang

Heuser

Cunningham

et al. 2006

The Journal of Immunology

137

143

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The mechanisms by which autoantibodies against cardiac myosin (CM) may lead to heart dysfunction is unknown. We show that autoantibodies to CM in anti-CM sera and mAbs derived from experimental autoimmune myocarditis targeted the heart cell surface and induced Ab-mediated cAMP-dependent protein kinase A activity. Ab-mediated cell signaling of protein kinase A was blocked by CM, anti-IgG, or by specific inhibitors of the β-adrenergic receptor (β-AR) pathway. mAbs confirmed mimicry between CM and the β-AR. Passive transfer of purified Ab (IgG) from CM-immunized rats resulted in IgG deposition and apoptosis in the heart, leading to a cardiomyopathic heart disease phenotype in recipients. Our novel findings link anti-CM Ab with the β-AR and subsequent Ab-mediated cell signaling in the heart.

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Autoantibodies in against human ventricular myosin in sera of patients with acute and chronic myocarditis

Cited by 87 publications

References 27 publications

Spontaneous myocarditis mimicking human disease occurs in the presence of an appropriate MHC and non-MHC background in transgenic mice

Spontaneous myocarditis mimicking human disease occurs in the presence of an appropriate MHC and non-MHC background in transgenic mice

A Spontaneous Model for Autoimmune Myocarditis Using the Human MHC Molecule HLA-DQ8

Mimicry and Antibody-Mediated Cell Signaling in Autoimmune Myocarditis

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