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01-07-2010 | Original Contribution

Lack of evidence for a pathogenic role of proteasome-directed autoimmunity in dilated cardiomyopathy

Authors: Antje Voigt, Christiane Trimpert, Katrin Bartel, Karl Egerer, Ulrike Kuckelkorn, Eugen Feist, Christine Gericke, Karin Klingel, Reinhard Kandolf, Stephan B. Felix, Gert Baumann, Peter-M. Kloetzel, Karl Stangl, Alexander Staudt

Published in: Basic Research in Cardiology | Issue 4/2010

Abstract

The proteasome has been identified as a target of the humoral autoimmune response in different inflammatory disease entities including dilated cardiomyopathy (DCM). However, the role of proteasome autoantibodies (ProtAb) remains to be studied. Here, we have isolated human ProtAb by affinity-purification from the IgG fractions obtained from DCM patients, which predominantly detected the outer ring subunits α3 of the 20S proteasome. In an attempt to study the cellular effects potentially exerted by these ProtAb, simultaneous calcium and cell contractility measurements were performed in rat cardiomyocytes revealing no short-term effects upon human ProtAb exposure. Immunofluorescence staining and FACS analysis pointed towards a failure of human ProtAb to bind to the intact cell membrane, whereas human ProtAb detected 20S proteasomes in the cytoplasm and nucleus. The lack of the cell surface interaction of human ProtAb was in agreement with the failure of these autoantibodies to interfere with the cellular viability. Further, we investigated whether the removal of ProtAb by immunoadsorption (IA) resulted in functional improvement in DCM patients. IA was performed in 90 DCM patients (left ventricular ejection fraction ≤45%, ProtAb detection at baseline in 30% of these DCM patients). Improvement of LVEF was not associated with the initial detection and removal of ProtAb in DCM patients. ProtAb were reconstituted to baseline levels as soon as after 3 months post-IA/IgG treatment despite the overall improvement of LVEF in this study group. In conclusion, our data argue against a direct impact of ProtAb in the pathogenesis of DCM.

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Title: Lack of evidence for a pathogenic role of proteasome-directed autoimmunity in dilated cardiomyopathy
Authors: Antje Voigt
Christiane Trimpert
Katrin Bartel
Karl Egerer
Ulrike Kuckelkorn
Eugen Feist
Christine Gericke
Karin Klingel
Reinhard Kandolf
Stephan B. Felix
Gert Baumann
Peter-M. Kloetzel
Karl Stangl
Alexander Staudt
Publication date: 01-07-2010
Publisher: Springer-Verlag
Published in: Basic Research in Cardiology / Issue 4/2010
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-010-0096-1

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