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

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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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Acknowledgments

This study was supported by the Deutsche Forschungsgemeinschaft SFB/TR 19: TP B3 to AV, UK, PMK; TP C2 to AS and SF; TP Z4 to KK and TP B5 to RK as well as by the Deutsche Forschungsgemeinschaft FE 470/3-1 to EF.

Conflict of interest statement

There are no financial conflicts to declare.

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Authors and Affiliations

  1. Medizinische Klinik für Kardiologie und Angiologie, Charité-Universitätsmedizin Berlin, Campus Mitte, Charitéplatz 1, 10117, Berlin, Germany

    Antje Voigt, Katrin Bartel, Gert Baumann & Karl Stangl

  2. Klinik für Innere Medizin B, Ernst-Moritz-Arndt-Universität, Greifswald, Germany

    Christiane Trimpert, Stephan B. Felix & Alexander Staudt

  3. Medizinische Klinik für Rheumatologie und Immunologie, Charité-Universitätsmedizin, Berlin, Germany

    Karl Egerer & Eugen Feist

  4. Institut für Biochemie, Charité-Universitätsmedizin, Berlin, Germany

    Ulrike Kuckelkorn & Peter-M. Kloetzel

  5. Institut für Medizinische Biometrie, Charité-Universitätsmedizin, Berlin, Germany

    Christine Gericke

  6. Molekulare Pathologie, Universität Tübingen, 72076, Tübingen, Germany

    Karin Klingel & Reinhard Kandolf

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  1. Antje Voigt
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  2. Christiane Trimpert
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  3. Katrin Bartel
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Correspondence to Antje Voigt.

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Voigt, A., Trimpert, C., Bartel, K. et al. Lack of evidence for a pathogenic role of proteasome-directed autoimmunity in dilated cardiomyopathy. Basic Res Cardiol 105, 557–567 (2010). https://doi.org/10.1007/s00395-010-0096-1

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  • DOI: https://doi.org/10.1007/s00395-010-0096-1

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