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Mimicry and Antibody-Mediated Cell Signaling in Autoimmune Myocarditis¹

Ya Li^*,, Janet S. Heuser^*, Luke C. Cunningham^*, Stanley D. Kosanke^* and Madeleine W. Cunningham^2,*

^* Department of Microbiology and Immunology, and Pathology, University of Oklahoma Health Sciences Center, Biomedical Research Center, Oklahoma City, OK 73104; and Department of Microbiology and Immunology, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI 48109

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 -adrenergic receptor (-AR) pathway. mAbs confirmed mimicry between CM and the -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 -AR and subsequent Ab-mediated cell signaling in the heart.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Heart, Lung, and Blood Institute (HL56267) and the American Heart Association. M.W.C. is the recipient of an National Heart, Lung, and Blood Institute Merit Award (HL35280), and Y.L. is the recipient of an American Heart Association Predoctoral Fellowship.

² Address correspondence and reprint requests to Dr. Madeleine W. Cunningham, Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Biomedical Research Center, Room 217, 975 NE 10th Street, Oklahoma City, OK 73104. E-mail address: madeleine-cunningham{at}ouhsc.edu

³ Abbreviations used in this paper: DCM, dilated cardiomyopathy; CM, cardiac myosin; -AR, -adrenergic receptor; PKA, protein kinase A; r2-AR, recombinant 2-AR; EAM, experimental autoimmune myocarditis; PLB, phosphorylated phospholamban.

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