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The enteric nervous system is a potential autoimmune target in multiple sclerosis

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Abstract

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) in young adults that has serious negative socioeconomic effects. In addition to symptoms caused by CNS pathology, the majority of MS patients frequently exhibit gastrointestinal dysfunction, which was previously either explained by the presence of spinal cord lesions or not directly linked to the autoimmune etiology of the disease. Here, we studied the enteric nervous system (ENS) in a B cell- and antibody-dependent mouse model of MS by immunohistochemistry and electron microscopy at different stages of the disease. ENS degeneration was evident prior to the development of CNS lesions and the onset of neurological deficits in mice. The pathology was antibody mediated and caused a significant decrease in gastrointestinal motility, which was associated with ENS gliosis and neuronal loss. We identified autoantibodies against four potential target antigens derived from enteric glia and/or neurons by immunoprecipitation and mass spectrometry. Antibodies against three of the target antigens were also present in the plasma of MS patients as confirmed by ELISA. The analysis of human colon resectates provided evidence of gliosis and ENS degeneration in MS patients compared to non-MS controls. For the first time, this study establishes a pathomechanistic link between the well-established autoimmune attack on the CNS and ENS pathology in MS, which might provide a paradigm shift in our current understanding of the immunopathogenesis of the disease with broad diagnostic and therapeutic implications.

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Acknowledgements

We are grateful to Alla Ganscher, Eleonora Maier, Brigitte Treffny, Nicole Wagner, Michael Rodi and Andrea Schampel for technical support und Michael Christof for help with the figure design. We thank Logopharm GmbH for target antigen identification. We would like to thank Bertal H. Aktas for providing the elF3D plasmid.

Funding

Stefanie Kuerten was supported by the Deutsche Forschungsgemeinschaft (DFG; Grants KU2760/2-1 and KU2760/4-1). Claus-Jürgen Scholz was supported by the Interdisziplinäres Zentrum für Klinische Forschung (IZKF; Grant Z-6).

Author information

Authors and Affiliations

  1. Department of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany

    Marie Wunsch, Oktay Göcer, Süleyman Ergün & Stefanie Kuerten

  2. Institute of Anatomy and Cell Biology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany

    Samir Jabari, Michael Enders & Stefanie Kuerten

  3. Institute of Physiology, University of Würzburg, Würzburg, Germany

    Barbara Voussen & Andreas Friebe

  4. Department of Medicine, Emory University, Atlanta, GA, USA

    Shanthi Srinivasan

  5. Institute of Anatomy, Christian-Albrechts University of Kiel, Kiel, Germany

    François Cossais, Thilo Wedel & Martina Boettner

  6. Department of Anatomy and Cell Biology, University Hospital Cologne, Cologne, Germany

    Anna Schwarz, Linda Weyer & Klaus Addicks

  7. Department of Neurology, University Hospital Cologne, Cologne, Germany

    Michael Schroeter

  8. Department of Neurology, Caritas-Krankenhaus Bad Mergentheim, Bad Mergentheim, Germany

    Mathias Maeurer

  9. Department of Pathology, Caritas-Krankenhaus Bad Mergentheim, Bad Mergentheim, Germany

    Matthias Woenckhaus

  10. Deutsches Rheuma-Forschungszentrum, Charité-Universitätsmedizin Berlin, Berlin, Germany

    Karolin Pollok

  11. Department of Neuropathology, Charité-Universitätsmedizin Berlin, Berlin, Germany

    Helena Radbruch

  12. Department of Neurology, University Hospital Münster, Münster, Germany

    Luisa Klotz

  13. Core Unit Systems Medicine, University of Würzburg, Würzburg, Germany

    Claus-Jürgen Scholz

  14. LIMES Institute, University of Bonn, Bonn, Germany

    Claus-Jürgen Scholz

  15. Institute of Tissue Engineering and Regenerative Medicine, University of Würzburg, Würzburg, Germany

    Joachim Nickel

  16. Cellular Technology Limited, Shaker Heights, OH, USA

    Paul V. Lehmann

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  1. Marie Wunsch
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Corresponding author

Correspondence to Stefanie Kuerten.

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The authors declare no conflict of interest with respect to the study and data presented in this paper.

Ethical standards

The institutional review boards of the Universities of Würzburg and Erlangen-Nürnberg approved the study of human gut resectates (Files 81/14 and 2550). All animal experiments were approved by the ‘Regierung von Unterfranken’ (Files 114/13 and 91/14).

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Wunsch, M., Jabari, S., Voussen, B. et al. The enteric nervous system is a potential autoimmune target in multiple sclerosis. Acta Neuropathol 134, 281–295 (2017). https://doi.org/10.1007/s00401-017-1742-6

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