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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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.
The authors declare no competing financial interests.
Supplementary Figures 1–4 (PDF 476 kb)
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)
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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