Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Primary oligodendrocyte death does not elicit anti-CNS immunity


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. 1

    Compston, A. & Coles, A. Multiple sclerosis. Lancet 372, 1502–1517 (2008).

    CAS  Article  Google Scholar 

  2. 2

    Lassmann, H., Bruck, W. & Lucchinetti, C.F. The immunopathology of multiple sclerosis: an overview. Brain Pathol. 17, 210–218 (2007).

    Article  Google Scholar 

  3. 3

    Lucchinetti, C.F., Bruck, W. & Lassmann, H. Evidence for pathogenic heterogeneity in multiple sclerosis. Ann. Neurol. 56, 308 (2004).

    Article  Google Scholar 

  4. 4

    Barnett, M.H. & Prineas, J.W. Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann. Neurol. 55, 458–468 (2004).

    Article  Google Scholar 

  5. 5

    Barnett, M.H. & Sutton, I. The pathology of multiple sclerosis: a paradigm shift. Curr. Opin. Neurol. 19, 242–247 (2006).

    Article  Google Scholar 

  6. 6

    Filippi, M., Rocca, M.A., Martino, G., Horsfield, M.A. & Comi, G. Magnetization transfer changes in the normal appearing white matter precede the appearance of enhancing lesions in patients with multiple sclerosis. Ann. Neurol. 43, 809–814 (1998).

    CAS  Article  Google Scholar 

  7. 7

    Narayana, P.A., Doyle, T.J., Lai, D. & Wolinsky, J.S. Serial proton magnetic resonance spectroscopic imaging, contrast-enhanced magnetic resonance imaging, and quantitative lesion volumetry in multiple sclerosis. Ann. Neurol. 43, 56–71 (1998).

    CAS  Article  Google Scholar 

  8. 8

    Kassmann, C.M. et al. Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes. Nat. Genet. 39, 969–976 (2007).

    CAS  Article  Google Scholar 

  9. 9

    Ip, C.W. et al. Immune cells contribute to myelin degeneration and axonopathic changes in mice overexpressing proteolipid protein in oligodendrocytes. J. Neurosci. 26, 8206–8216 (2006).

    CAS  Article  Google Scholar 

  10. 10

    Buch, T. et al. A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration. Nat. Methods 2, 419–426 (2005).

    CAS  Article  Google Scholar 

  11. 11

    Hövelmeyer, N. et al. Apoptosis of oligodendrocytes via Fas and TNF-R1 is a key event in the induction of experimental autoimmune encephalomyelitis. J. Immunol. 175, 5875–5884 (2005).

    Article  Google Scholar 

  12. 12

    Traka, M. et al. A genetic mouse model of adult-onset, pervasive central nervous system demyelination with robust remyelination. Brain 133, 3017–3029 (2010).

    Article  Google Scholar 

  13. 13

    Pohl, H.B. et al. Genetically induced adult oligodendrocyte cell death is associated with poor myelin clearance, reduced remyelination, and axonal damage. J. Neurosci. 31, 1069–1080 (2011).

    CAS  Article  Google Scholar 

  14. 14

    van Zwam, M. et al. Surgical excision of CNS-draining lymph nodes reduces relapse severity in chronic-relapsing experimental autoimmune encephalomyelitis. J. Pathol. 217, 543–551 (2009).

    Article  Google Scholar 

  15. 15

    de Vos, A.F. et al. Transfer of central nervous system autoantigens and presentation in secondary lymphoid organs. J. Immunol. 169, 5415–5423 (2002).

    CAS  Article  Google Scholar 

  16. 16

    Fabriek, B.O. et al. In vivo detection of myelin proteins in cervical lymph nodes of MS patients using ultrasound-guided fine-needle aspiration cytology. J. Neuroimmunol. 161, 190–194 (2005).

    CAS  Article  Google Scholar 

  17. 17

    Bettelli, E. et al. Myelin oligodendrocyte glycoprotein-specific T cell receptor transgenic mice develop spontaneous autoimmune optic neuritis. J. Exp. Med. 197, 1073–1081 (2003).

    CAS  Article  Google Scholar 

  18. 18

    Frommer, F. et al. Tolerance without clonal expansion: self-antigen-expressing B cells program self-reactive T cells for future deletion. J. Immunol. 181, 5748–5759 (2008).

    CAS  Article  Google Scholar 

  19. 19

    Elgueta, R. et al. Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol. Rev. 229, 152–172 (2009).

    CAS  Article  Google Scholar 

  20. 20

    Ransohoff, R.M. & Perry, V.H. Microglial physiology: unique stimuli, specialized responses. Annu. Rev. Immunol. 27, 119–145 (2009).

    CAS  Article  Google Scholar 

  21. 21

    Carson, M.J. Microglia as liaisons between the immune and central nervous systems: functional implications for multiple sclerosis. Glia 40, 218–231 (2002).

    Article  Google Scholar 

  22. 22

    Becher, B. & Antel, J.P. Comparison of phenotypic and functional properties of immediately ex vivo and cultured human adult microglia. Glia 18, 1–10 (1996).

    CAS  Article  Google Scholar 

  23. 23

    Link, H. & Muller, R. Immunoglobulins in multiple sclerosis and infections of the nervous system. Arch. Neurol. 25, 326–344 (1971).

    CAS  Article  Google Scholar 

  24. 24

    Herndon, R.M. & Kasckow, J. Electron microscopic studies of cerebrospinal fluid sediment in demyelinating disease. Ann. Neurol. 4, 515–523 (1978).

    CAS  Article  Google Scholar 

  25. 25

    Prineas, J.W. & Wright, R.G. Macrophages, lymphocytes, and plasma cells in the perivascular compartment in chronic multiple sclerosis. Lab. Invest. 38, 409–421 (1978).

    CAS  PubMed  Google Scholar 

  26. 26

    Urich, E., Gutcher, I., Prinz, M. & Becher, B. Autoantibody-mediated demyelination depends on complement activation, but not activatory Fc-receptors. Proc. Natl. Acad. Sci. USA 103, 18697–18702 (2006).

    CAS  Article  Google Scholar 

  27. 27

    Gallucci, S. & Matzinger, P. Danger signals: SOS to the immune system. Curr. Opin. Immunol. 13, 114–119 (2001).

    CAS  Article  Google Scholar 

  28. 28

    Mueller, D.L. Mechanisms maintaining peripheral tolerance. Nat. Immunol. 11, 21–27 (2010).

    CAS  Article  Google Scholar 

  29. 29

    Sakaguchi, S. et al. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol. Rev. 212, 8–27 (2006).

    CAS  Article  Google Scholar 

  30. 30

    Honjo, T., Nishizuka, Y., Kato, I. & Hayaishi, O. Adenosine diphosphate ribosylation of aminoacyl transferase II and inhibition of protein synthesis by diphtheria toxin. J. Biol. Chem. 246, 4251–4260 (1971).

    CAS  PubMed  Google Scholar 

  31. 31

    Emerson, M.R., Biswas, S. & Le Vine, S.M. Cuprizone and piperonyl butoxide, proposed inhibitors of T-cell function, attenuate experimental allergic encephalomyelitis in SJL mice. J. Neuroimmunol. 119, 205–213 (2001).

    CAS  Article  Google Scholar 

  32. 32

    Zatta, P. et al. Copper and zinc dismetabolism in the mouse brain upon chronic cuprizone treatment. Cell. Mol. Life Sci. 62, 1502–1513 (2005).

    CAS  Article  Google Scholar 

  33. 33

    Elloso, M.M., Phiel, K., Henderson, R.A., Harris, H.A. & Adelman, S.J. Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands. J. Endocrinol. 185, 243–252 (2005).

    CAS  Article  Google Scholar 

  34. 34

    Chernoff, G.F. Shiverer: an autosomal recessive mutant mouse with myelin deficiency. J. Hered. 72, 128 (1981).

    CAS  Article  Google Scholar 

  35. 35

    Wang, H., Zhan, Y., Xu, L., Feuerstein, G.Z. & Wang, X. Use of suppression subtractive hybridization for differential gene expression in stroke: discovery of CD44 gene expression and localization in permanent focal stroke in rats. Stroke 32, 1020–1027 (2001).

    CAS  Article  Google Scholar 

  36. 36

    Kim, M.D., Cho, H.J. & Shin, T. Expression of osteopontin and its ligand, CD44, in the spinal cords of Lewis rats with experimental autoimmune encephalomyelitis. J. Neuroimmunol. 151, 78–84 (2004).

    CAS  Article  Google Scholar 

  37. 37

    Bédard, A., Tremblay, P., Chernomoretz, A. & Vallieres, L. Identification of genes preferentially expressed by microglia and upregulated during cuprizone-induced inflammation. Glia 55, 777–789 (2007).

    Article  Google Scholar 

  38. 38

    Remington, L.T., Babcock, A.A., Zehntner, S.P. & Owens, T. Microglial recruitment, activation and proliferation in response to primary demyelination. Am. J. Pathol. 170, 1713–1724 (2007).

    Article  Google Scholar 

  39. 39

    Hiremath, M.M., Chen, V.S., Suzuki, K., Ting, J.P. & Matsushima, G.K. MHC class II exacerbates demyelination in vivo independently of T cells. J. Neuroimmunol. 203, 23–32 (2008).

    CAS  Article  Google Scholar 

  40. 40

    Adams, C.W., Poston, R.N. & Buk, S.J. Pathology, histochemistry and immunocytochemistry of lesions in acute multiple sclerosis. J. Neurol. Sci. 92, 291–306 (1989).

    CAS  Article  Google Scholar 

  41. 41

    Maña, P. et al. Demyelination caused by the copper chelator cuprizone halts T cell–mediated autoimmune neuroinflammation. J. Neuroimmunol. 210, 13–21 (2009).

    Article  Google Scholar 

  42. 42

    Griffiths, I. et al. Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 280, 1610–1613 (1998).

    CAS  Article  Google Scholar 

  43. 43

    Yin, X. et al. Evolution of a neuroprotective function of central nervous system myelin. J. Cell Biol. 172, 469–478 (2006).

    CAS  Article  Google Scholar 

  44. 44

    Lappe-Siefke, C. et al. Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination. Nat. Genet. 33, 366–374 (2003).

    CAS  Article  Google Scholar 

  45. 45

    Berger, J. & Gartner, J. X-linked adrenoleukodystrophy: clinical, biochemical and pathogenetic aspects. Biochim. Biophys. Acta 1763, 1721–1732 (2006).

    CAS  Article  Google Scholar 

  46. 46

    Haak, S. et al. IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice. J. Clin. Invest. 119, 61–69 (2009).

    CAS  PubMed  Google Scholar 

  47. 47

    Weston, S.A. & Parish, C.R. New fluorescent dyes for lymphocyte migration studies. Analysis by flow cytometry and fluorescence microscopy. J. Immunol. Methods 133, 87–97 (1990).

    CAS  Article  Google Scholar 

  48. 48

    Becher, B., Durell, B.G. & Noelle, R.J. Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J. Clin. Invest. 110, 493–497 (2002).

    CAS  Article  Google Scholar 

  49. 49

    Förster, I. & Rajewsky, K. Expansion and functional activity of Ly-1 + B cells upon transfer of peritoneal cells into allotype-congenic, newborn mice. Eur. J. Immunol. 17, 521–528 (1987).

    Article  Google Scholar 

  50. 50

    Spergel, D.J., Kruth, U., Hanley, D.F., Sprengel, R. & Seeburg, P.H. GABA- and glutamate-activated channels in green fluorescent protein-tagged gonadotropin-releasing hormone neurons in transgenic mice. J. Neurosci. 19, 2037–2050 (1999).

    CAS  Article  Google Scholar 

Download references


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




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.

Corresponding authors

Correspondence to Simone Wörtge or Thorsten Buch.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

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)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Locatelli, G., Wörtge, S., Buch, T. et al. Primary oligodendrocyte death does not elicit anti-CNS immunity. Nat Neurosci 15, 543–550 (2012).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing