Mimicry and antibody-mediated cell signaling in autoimmune myocarditis.
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 beta-adrenergic receptor (beta-AR) pathway. mAbs confirmed mimicry between CM and the beta-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 beta-AR and subsequent Ab-mediated cell signaling in the heart.
Li
Ya
Y
Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Biomedical Research Center, 975 NE 10th Street, Oklahoma City, OK 73104, USA.
Heuser
Janet S
JS
Cunningham
Luke C
LC
Kosanke
Stanley D
SD
Cunningham
Madeleine W
MW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology*; D015153:Blotting, Western; D024722:Cardiac Myosins / Q000276:immunology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D018716:Molecular Mimicry / Q000276:immunology*; D009205:Myocarditis / Q000276:immunology*; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D001324:Autoantigens; D011943:Receptors, Adrenergic, beta; D017868:Cyclic AMP-Dependent Protein Kinases; D024722:Cardiac Myosins