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ResearchIn-Press PreviewNeuroscience Open Access | 10.1172/jci.insight.169135

Eculizumab treatment alters the proteometabolome beyond the inhibiton of complement

Christopher Nelke,1 Christina B. Schroeter,1 Frauke Stascheit,2 Niklas Huntemann,1 Marc Pawlitzki,1 Alice G. Willison,1 Saskia Räuber,1 Nico Melzer,1 Ute Distler,3 Stefan Tenzer,4 Kai Stühler,5 Andreas Roos,6 Andreas Meisel,7 Sven G. Meuth,1 and Tobias Ruck1

1Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

2Department of Neurology, Charité – Universitätsmedizin Berlin, Berlin, Germany

3Luxembourg Clinical Proteomics Center, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Luxembourg

4Institute of Immunology, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany

5Molecular Proteomics Laboratory, Heinrich Heine University, Düsseldorf, Germany

6Department of Neuropediatrics, University of Duisburg-Essen, Essen, Germany

7Neuroscience Clinical Research Center, Charité – Universitätsmedizin Berlin, berlin, Germany

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1Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

2Department of Neurology, Charité – Universitätsmedizin Berlin, Berlin, Germany

3Luxembourg Clinical Proteomics Center, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Luxembourg

4Institute of Immunology, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany

5Molecular Proteomics Laboratory, Heinrich Heine University, Düsseldorf, Germany

6Department of Neuropediatrics, University of Duisburg-Essen, Essen, Germany

7Neuroscience Clinical Research Center, Charité – Universitätsmedizin Berlin, berlin, Germany

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1Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

2Department of Neurology, Charité – Universitätsmedizin Berlin, Berlin, Germany

3Luxembourg Clinical Proteomics Center, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Luxembourg

4Institute of Immunology, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany

5Molecular Proteomics Laboratory, Heinrich Heine University, Düsseldorf, Germany

6Department of Neuropediatrics, University of Duisburg-Essen, Essen, Germany

7Neuroscience Clinical Research Center, Charité – Universitätsmedizin Berlin, berlin, Germany

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1Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

2Department of Neurology, Charité – Universitätsmedizin Berlin, Berlin, Germany

3Luxembourg Clinical Proteomics Center, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Luxembourg

4Institute of Immunology, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany

5Molecular Proteomics Laboratory, Heinrich Heine University, Düsseldorf, Germany

6Department of Neuropediatrics, University of Duisburg-Essen, Essen, Germany

7Neuroscience Clinical Research Center, Charité – Universitätsmedizin Berlin, berlin, Germany

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1Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

2Department of Neurology, Charité – Universitätsmedizin Berlin, Berlin, Germany

3Luxembourg Clinical Proteomics Center, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Luxembourg

4Institute of Immunology, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany

5Molecular Proteomics Laboratory, Heinrich Heine University, Düsseldorf, Germany

6Department of Neuropediatrics, University of Duisburg-Essen, Essen, Germany

7Neuroscience Clinical Research Center, Charité – Universitätsmedizin Berlin, berlin, Germany

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1Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

2Department of Neurology, Charité – Universitätsmedizin Berlin, Berlin, Germany

3Luxembourg Clinical Proteomics Center, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Luxembourg

4Institute of Immunology, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany

5Molecular Proteomics Laboratory, Heinrich Heine University, Düsseldorf, Germany

6Department of Neuropediatrics, University of Duisburg-Essen, Essen, Germany

7Neuroscience Clinical Research Center, Charité – Universitätsmedizin Berlin, berlin, Germany

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1Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

2Department of Neurology, Charité – Universitätsmedizin Berlin, Berlin, Germany

3Luxembourg Clinical Proteomics Center, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Luxembourg

4Institute of Immunology, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany

5Molecular Proteomics Laboratory, Heinrich Heine University, Düsseldorf, Germany

6Department of Neuropediatrics, University of Duisburg-Essen, Essen, Germany

7Neuroscience Clinical Research Center, Charité – Universitätsmedizin Berlin, berlin, Germany

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1Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

2Department of Neurology, Charité – Universitätsmedizin Berlin, Berlin, Germany

3Luxembourg Clinical Proteomics Center, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Luxembourg

4Institute of Immunology, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany

5Molecular Proteomics Laboratory, Heinrich Heine University, Düsseldorf, Germany

6Department of Neuropediatrics, University of Duisburg-Essen, Essen, Germany

7Neuroscience Clinical Research Center, Charité – Universitätsmedizin Berlin, berlin, Germany

Find articles by Melzer, N. in: JCI | PubMed | Google Scholar

1Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

2Department of Neurology, Charité – Universitätsmedizin Berlin, Berlin, Germany

3Luxembourg Clinical Proteomics Center, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Luxembourg

4Institute of Immunology, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany

5Molecular Proteomics Laboratory, Heinrich Heine University, Düsseldorf, Germany

6Department of Neuropediatrics, University of Duisburg-Essen, Essen, Germany

7Neuroscience Clinical Research Center, Charité – Universitätsmedizin Berlin, berlin, Germany

Find articles by Distler, U. in: JCI | PubMed | Google Scholar |

1Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

2Department of Neurology, Charité – Universitätsmedizin Berlin, Berlin, Germany

3Luxembourg Clinical Proteomics Center, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Luxembourg

4Institute of Immunology, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany

5Molecular Proteomics Laboratory, Heinrich Heine University, Düsseldorf, Germany

6Department of Neuropediatrics, University of Duisburg-Essen, Essen, Germany

7Neuroscience Clinical Research Center, Charité – Universitätsmedizin Berlin, berlin, Germany

Find articles by Tenzer, S. in: JCI | PubMed | Google Scholar |

1Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

2Department of Neurology, Charité – Universitätsmedizin Berlin, Berlin, Germany

3Luxembourg Clinical Proteomics Center, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Luxembourg

4Institute of Immunology, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany

5Molecular Proteomics Laboratory, Heinrich Heine University, Düsseldorf, Germany

6Department of Neuropediatrics, University of Duisburg-Essen, Essen, Germany

7Neuroscience Clinical Research Center, Charité – Universitätsmedizin Berlin, berlin, Germany

Find articles by Stühler, K. in: JCI | PubMed | Google Scholar

1Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

2Department of Neurology, Charité – Universitätsmedizin Berlin, Berlin, Germany

3Luxembourg Clinical Proteomics Center, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Luxembourg

4Institute of Immunology, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany

5Molecular Proteomics Laboratory, Heinrich Heine University, Düsseldorf, Germany

6Department of Neuropediatrics, University of Duisburg-Essen, Essen, Germany

7Neuroscience Clinical Research Center, Charité – Universitätsmedizin Berlin, berlin, Germany

Find articles by Roos, A. in: JCI | PubMed | Google Scholar

1Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

2Department of Neurology, Charité – Universitätsmedizin Berlin, Berlin, Germany

3Luxembourg Clinical Proteomics Center, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Luxembourg

4Institute of Immunology, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany

5Molecular Proteomics Laboratory, Heinrich Heine University, Düsseldorf, Germany

6Department of Neuropediatrics, University of Duisburg-Essen, Essen, Germany

7Neuroscience Clinical Research Center, Charité – Universitätsmedizin Berlin, berlin, Germany

Find articles by Meisel, A. in: JCI | PubMed | Google Scholar |

1Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

2Department of Neurology, Charité – Universitätsmedizin Berlin, Berlin, Germany

3Luxembourg Clinical Proteomics Center, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Luxembourg

4Institute of Immunology, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany

5Molecular Proteomics Laboratory, Heinrich Heine University, Düsseldorf, Germany

6Department of Neuropediatrics, University of Duisburg-Essen, Essen, Germany

7Neuroscience Clinical Research Center, Charité – Universitätsmedizin Berlin, berlin, Germany

Find articles by Meuth, S. in: JCI | PubMed | Google Scholar |

1Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

2Department of Neurology, Charité – Universitätsmedizin Berlin, Berlin, Germany

3Luxembourg Clinical Proteomics Center, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Luxembourg

4Institute of Immunology, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany

5Molecular Proteomics Laboratory, Heinrich Heine University, Düsseldorf, Germany

6Department of Neuropediatrics, University of Duisburg-Essen, Essen, Germany

7Neuroscience Clinical Research Center, Charité – Universitätsmedizin Berlin, berlin, Germany

Find articles by Ruck, T. in: JCI | PubMed | Google Scholar |

Published May 25, 2023 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.169135.
Copyright © 2023, Nelke et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published May 25, 2023 - Version history
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Abstract

Therapeutic strategies targeting complement have revolutionized the treatment of myasthenia gravis (MG). However, a deeper understanding of complement modulation in the human system is required to improve treatment responses and identify “off-target effects” shaping long-term outcomes. For this purpose, we studied a cohort of MG patients treated with either eculizumab (n = 10) or azathioprine (n = 10) as well as treatment-naïve (n = 10) patients using a combined proteomics and metabolomics approach. This strategy confirmed known effects of eculizumab on the terminal complement cascade. Beyond that, eculizumab modulated the serum proteometabolome as distinct pathways were altered in eculizumab-treated patients including the oxidative stress response, mitogen-activated protein kinase signaling and lipid metabolism with particular emphasis on arachidonic acid signaling. We detected reduced levels of arachidonate 5-lipoxygenase (ALOX5) and leukotriene A4 (LTA4) in eculizumab-treated patients. Mechanistically, ligation of the C5a receptor (C5aR) is needed for ALOX5 metabolism and generation of downstream leukotrienes. As eculizumab prevents cleavage of C5 into C5a, decreased engagement of C5aR may inhibit ALOX5-mediated synthesis of pro-inflammatory leukotrienes. These findings indicate distinct “off-target effects” induced by eculizumab, illuminating potential mechanisms of action that may be harnessed to improve treatment outcomes.

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  • Version 1 (May 25, 2023): In-Press Preview
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