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Primary oligodendrocyte death does not elicit anti-CNS immunity

Nature Neuroscience volume 15, pages 543–550 (2012)Cite this article

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Abstract

Anti-myelin immunity is commonly thought to drive multiple sclerosis, yet the initial trigger of this autoreactivity remains elusive. One of the proposed factors for initiating this disease is the primary death of oligodendrocytes. To specifically test such oligodendrocyte death as a trigger for anti-CNS immunity, we inducibly killed oligodendrocytes in an in vivo mouse model. Strong microglia-macrophage activation followed oligodendrocyte death, and myelin components in draining lymph nodes made CNS antigens available to lymphocytes. However, even conditions favoring autoimmunity—bystander activation, removal of regulatory T cells, presence of myelin-reactive T cells and application of demyelinating antibodies—did not result in the development of CNS inflammation after oligodendrocyte death. In addition, this lack of reactivity was not mediated by enhanced myelin-specific tolerance. Thus, in contrast with previously reported impairments of oligodendrocyte physiology, diffuse oligodendrocyte death alone or in conjunction with immune activation does not trigger anti-CNS immunity.

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Figure 1: DTx-treated oDTR mice show ODC death and demyelination.
Figure 2: DTx-induced ODC death leads to sparse neuronal degeneration, recruitment of ODC progenitor and remyelination.
Figure 3: Rare activation of T cells following myelin antigen leakage.
Figure 4: Activation of microglia-macrophages, but no inflammation following ODC death.
Figure 5: Chronicity, demyelinating antibodies or immune activation do not induce autoimmunity following ODC death.
Figure 6: ODC death does not result in increased tolerance toward myelin.

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Acknowledgements

We are grateful for technical support to V. Wörtmann, A. Apladas, M. Perkovic, the Zentrum für Mikroskopie und Bildanalyse, T. Bruggmann, J. Huppert and K. Fischer, as well as the mouse facility teams in Zürich and Mainz. We thank J.D. Laman and I. Parvanova for help with manuscript preparation. This work was supported by COST action BM603 NEURINFNET (B.B., T.B., G.L. and I.B.), by Deutsche Forschungsgemeinschaft (DFG) grants 1600/3-1 and SFB/TR 52, and the German Ministry for Education and Research (Consortium UNDERSTANDMS/German Competence Network of Multiple Sclerosis) to A.W., by the DFG grant FOR1336 to I.B. and A.W., by a grant from the Bonizzi-Theler foundation to T.B., by the State Secretariat for Education and Research of Switzerland to T.B. and B.B., by the Schweizerische Nationalfonds (SNF) to T.B. (CRSI33_125073) and B.B., the National Center of Competence in Research (NCCR-Neuro) to B.B., the Swiss Multiple Sclerosis Society to T.B., and by DFG grants SFB TR43 and Exc 25 and the US National Institutes of Health (National Institute of Neurological Disorders and Stroke R01 NS046006) to F.L.H.

Author information

Author notes

  1. Giuseppe Locatelli, Simone Wörtge and Thorsten Buch: These authors contributed equally to this work.

  2. Ari Waisman and Burkhard Becher: These authors jointly directed this work.

Authors and Affiliations

  1. Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland

    Giuseppe Locatelli, Thorsten Buch, Bettina Sobottka, Claudia Bühlmann & Burkhard Becher

  2. Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg, University of Mainz, Mainz, Germany

    Simone Wörtge, Friederike Frommer, Khalad Karram & Ari Waisman

  3. Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Germany

    Thorsten Buch

  4. Institute of Pathology, Campus Mitte, Charité – Universitätsmedizin Berlin, Germany

    Barbara Ingold

  5. Institute of Anatomy, University of Leipzig, Leipzig, Germany

    Martin Krüger & Ingo Bechmann

  6. Department of Neuropathology, Campus Mitte, Charité – Universitätsmedizin Berlin, Germany

    Frank L Heppner

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Contributions

T.B., B.B. and A.W. conceived the experimental system. G.L., T.B., S.W., B.I., M.K., K.K., C.B., I.B., B.S. and F.F. carried out the experiments and analyzed the data. T.B., F.L.H., A.W. and B.B. supervised the work. G.L. and T.B. co-wrote the manuscript.

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Correspondence to Simone Wörtge or Thorsten Buch.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4 (PDF 476 kb)

Supplementary Video 1

Clinical manifestation of ataxia and tremor during motor tests following ODC death. oDTR mice were treated with DTx. The movie shows the starting phase of the clinical disease 5 weeks p.a.. Mice showed progressive ataxia which manifested itself as inability to place paws correctly during the grid walking. Also, strong tremor could be observed (score 2 in our 0–3 scale). (MOV 1116 kb)

Supplementary Video 2

Progression of clinical disease leads to strong kyphosis and dystonia. oDTR mice were treated with DTx. The movie shows the progression of the clinical disease at around 6 weeks p.a.. Mice showed kyphosis, dystonia of hind limbs, inability to maintain balanced position. (MOV 211 kb)

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Locatelli, G., Wörtge, S., Buch, T. et al. Primary oligodendrocyte death does not elicit anti-CNS immunity. Nat Neurosci 15, 543–550 (2012). https://doi.org/10.1038/nn.3062

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