Autoimmunity against M₂muscarinic 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(2)R). To elucidate the role of autoimmunity against M(2)R in disease development, we induced an immune response against M(2)R by adoptive transfer into Rag2(-/-) mice of splenocytes from M(2)R(-/-) mice immunized with a recombinant M(2)R protein. T lymphocytes transiently infiltrated the heart in recipient mice followed by morphological changes in cardiomyocytes. These mice produced IgG antibodies against M(2)R, 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(2)R 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.
Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.
Akihiro
A
Yoshizawa
Shigenori
S
Nagai
Yukiko
Y
Baba
Taketo
T
Yamada
Minoru
M
Matsui
Hikaru
H
Tanaka
Shun-ichiro
S
Miyoshi
Masayuki
M
Amagai
Tsutomu
T
Yoshikawa
Keiichi
K
Fukuda
Satoshi
S
Ogawa
Shigeo
S
Koyasu
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology; D015551:Autoimmunity; D020013:Calcium Signaling / Q000276:immunology; D002311:Cardiomyopathy, Dilated / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D007074:Immunoglobulin G / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009205:Myocarditis / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000276:immunology / Q000473:pathology; D009929:Organ Size / Q000276:immunology; D051381:Rats; D017208:Rats, Wistar; D043585:Receptor, Muscarinic M2 / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
D001323:Autoantibodies; D007074:Immunoglobulin G; D043585:Receptor, Muscarinic M2