Autoimmunity against M ₂ muscarinic acetylcholine receptor induces myocarditis and leads to a dilated cardiomyopathy-like phenotype

Patients with dilated cardiomyopathy (DCM) often have autoantibodies against cardiac antigens including the M ₂ muscarinic acetylcholine receptor (M ₂R). To elucidate the role of autoimmunity against M ₂R in disease development, we induced an immune response against M ₂R by adoptive transfer into Rag2 ^-/- mice of splenocytes from M ₂R ^-/- mice immunized with a recombinant M ₂R protein. T lymphocytes transiently infiltrated the heart in recipient mice followed by morphological changes in cardiomyocytes. These mice produced IgG antibodies against M ₂R, which bound to cardiomyocytes in vivo and decreased the amplitude of calcium signals in isolated rat cardiomyocytes in vitro. Recipient mice showed increased heart weights associated with increased intraventricular diameter, decreased systolic function, and increased action potential duration, which are characteristics of DCM. Our results suggest that myocarditis and DCM associated with the presence of anti-M ₂R antibodies are autoimmune diseases with a risk of progressing to the terminal stage. Our mouse model will be useful in the analysis of the molecular mechanisms of disease progression and the development of new therapies for DCM.