Humoral anti-proteasomal autoimmunity in dilated cardiomyopathy.
Virus-induced chronic inflammation, autoimmune processes and impaired protein quality control may be involved in the pathogenesis of dilated cardiomyopathy (DCM). The ubiquitin-proteasome system is important in the modulation of inflammatory processes and the immune response. Proteasomes were identified as targets of a humoral autoimmune response in systemic inflammatory diseases, which provoked us to investigate anti-proteasomal immunity in DCM in detail: a total of 90 DCM patients with impaired left-ventricular function (LVEF < or = 45%) were enrolled in this study. Autoimmune response to cardiac proteasomes was found to be enhanced in DCM patients, revealing the detection of predominantly alpha subunits of the 20S proteasome complex. Proteasome antibody (ProtAb) levels were found to be particularly enhanced at stages of advanced heart failure: moderately decreased LVEF and considerably increased NT-pro BNP levels were observed in DCM patients who tested positive for ProtAb (P < 0.05). A linear regression model suggested a link between the detection of cardiotropic viruses in endomyocardial biopsies and anti-proteasomal immunity (P < 0.01). Likewise, ProtAb levels were enhanced in a murine model of chronic enterovirus myocarditis. Our data also point to a potential interaction of ProtAb with the cell surface: ProtAb exerted negative inotropic effects in field-stimulated cardiomyocytes. In conclusion, humoral autoreactive anti-proteasome immune responses appear to be enhanced in DCM. Viral infection of the myocardium may be linked to the induction of anti-proteasomal immunity in DCM.
Voigt
Antje
A
Medizinische Klinik für Kardiologie und Angiologie, Charité-Universitätsmedizin Campus Mitte, Berlin, Germany.
Bartel
Katrin
K
Egerer
Karl
K
Trimpert
Christiane
C
Feist
Eugen
E
Gericke
Christine
C
Kandolf
Reinhard
R
Klingel
Karin
K
Kuckelkorn
Ulrike
U
Stangl
Karl
K
Felix
Stephan B
SB
Baumann
Gert
G
Kloetzel
Peter-M
PM
Staudt
Alexander
A
D000818:Animals; D001323:Autoantibodies / Q000378:metabolism; D015551:Autoimmunity; D002311:Cardiomyopathy, Dilated / Q000276:immunology*; D003384:Coxsackievirus Infections / Q000276:immunology; D005260:Female; D006333:Heart Failure / Q000276:immunology; D006801:Humans; D056724:Immunity, Humoral; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009205:Myocarditis / Q000276:immunology / Q000382:microbiology; D032383:Myocytes, Cardiac / Q000276:immunology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000276:immunology*; D051381:Rats
D001323:Autoantibodies; D046988:Proteasome Endopeptidase Complex