Skip to main content

Thank you for visiting nature.com. 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.

  • Article
  • Published:

Myelin-specific T cells also recognize neuronal autoantigen in a transgenic mouse model of multiple sclerosis

Nature Medicine volume 15, pages 626–632 (2009)Cite this article

Abstract

We describe here the paradoxical development of spontaneous experimental autoimmune encephalomyelitis (EAE) in transgenic mice expressing a myelin oligodendrocyte glycoprotein (MOG)-specific T cell antigen receptor (TCR) in the absence of MOG. We report that in Mog-deficient mice (Mog−/−), the autoimmune response by transgenic T cells is redirected to a neuronal cytoskeletal self antigen, neurofilament-M (NF-M). Although components of radically different protein classes, the cross-reacting major histocompatibility complex I-Ab–restricted epitope sequences of MOG35–55 and NF-M18–30 share essential TCR contact positions. This pattern of cross-reaction is not specific to the transgenic TCR but is also commonly seen in MOG35–55–I-Ab–reactive T cells. We propose that in the C57BL/6 mouse, MOG and NF-M response components add up to overcome the general resistance of this strain to experimental induction of autoimmunity. Similar cumulative responses against more than one autoantigen may have a role in spontaneously developing human autoimmune diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Paradoxical development of spontaneous EAE in MOG-specific 2D2 TCR–transgenic mice in two different Mog-deficient strains.
Figure 2: MOG-specific T cells respond to myelin from Mog−/− mice.
Figure 3: Fractionation of CNS proteins from Mog−/−, WT and Nefm−/− mice.
Figure 4: Identification of a protein that cross-reacts with MOG-specific 2D2–transgenic T cells.
Figure 5: NF-M reacts specifically with 2D2-transgenic T cells.
Figure 6: In vitro and in vivo cross-reactivity between NF-M– and MOG-specific T cells.

Similar content being viewed by others

References

  1. Goebels, N. et al. Repertoire dynamics of autoreactive T cells in multiple sclerosis patients and healthy subjects. Epitope spreading versus clonal persistence. Brain 123, 508–518 (2000).

    Article  Google Scholar 

  2. Wekerle, H. Breaking ignorance: the case of the brain. in Current Concepts in Autoimmunity and Chronic Inflammation (eds. Radbruch, A. & Lipsky, P.E.) 25–50 (Springer, Berlin, 2006).

    Chapter  Google Scholar 

  3. 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).

    Article  CAS  Google Scholar 

  4. Litzenburger, T. et al. B lymphocytes producing demyelinating autoantibodies: development and function in gene-targeted transgenic mice. J. Exp. Med. 188, 169–180 (1998).

    Article  CAS  Google Scholar 

  5. Delarasse, C. et al. Myelin/oligodendrocyte glycoprotein–deficient (MOG-deficient) mice reveal lack of immune tolerance to MOG in wild-type mice. J. Clin. Invest. 112, 544–553 (2003).

    Article  CAS  Google Scholar 

  6. Krishnamoorthy, G., Lassmann, H., Wekerle, H. & Holz, A. Spontaneous opticospinal encephalomyelitis in a double-transgenic mouse model of autoimmune T cell/B cell cooperation. J. Clin. Invest. 116, 2385–2392 (2006).

    Article  CAS  Google Scholar 

  7. Bettelli, E., Baeten, D., Jäger, A., Sobel, R.A. & Kuchroo, V.K. Myelin oligodendrocyte glycoprotein-specific T and B cells cooperate to induce a Devic-like disease in mice. J. Clin. Invest. 116, 2393–2402 (2006).

    Article  CAS  Google Scholar 

  8. 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 

  9. Norton, W.T. & Poduslo, S.E. Myelination in rat brain changes in myelin composition during maturation. J. Neurochem. 21, 759–773 (1973).

    Article  CAS  Google Scholar 

  10. Chantry, A., Gregson, N.A. & Glynn, P. A novel metalloproteinase associated with brain myelin membranes. Isolation and characterization. J. Biol. Chem. 264, 21603–21607 (1989).

    CAS  PubMed  Google Scholar 

  11. Petersen, T.R. et al. Characterization of MHC- and TCR-binding residues of the myelin oligodendrocyte glycoprotein 38–51 peptide. Eur. J. Immunol. 34, 165–173 (2004).

    Article  CAS  Google Scholar 

  12. Ben-Nun, A. et al. Anatomy of T cell autoimmunity to myelin oligodendrocyte glycoprotein (MOG): prime role of MOG44F in selection and control of MOG-reactive T cells in H-2b mice. Eur. J. Immunol. 36, 478–493 (2006).

    Article  CAS  Google Scholar 

  13. Mendel, I., Kerlero de Rosbo, N. & Ben-Nun, A. A myelin oligodendrocyte glycoprotein peptide induces typical chronic experimental autoimmune encephalomyelitis in H-2b mice: fine specificity and T cell receptor Vβ expression of encephalitogenic T cells. Eur. J. Immunol. 25, 1951–1959 (1995).

    Article  CAS  Google Scholar 

  14. Wucherpfennig, K.W. & Strominger, J.L. Molecular mimicry in T cell–mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell 80, 695–705 (1995).

    Article  CAS  Google Scholar 

  15. Kelly, B.M., Gillespie, C.S., Sherman, D.L. & Brophy, P.J. Schwann cells of the myelin-forming phenotype express neurofilament protein NF-M. J. Cell Biol. 118, 397–410 (1992).

    Article  CAS  Google Scholar 

  16. Huizinga, R. et al. Immunization with neurofilament light protein induces spastic paresis and axonal degeneration in Biozzi ABH mice. J. Neuropathol. Exp. Neurol. 66, 295–304 (2007).

    Article  CAS  Google Scholar 

  17. Bartos, A. et al. Elevated intrathecal antibodies against the medium neurofilament subunit in multiple sclerosis. J. Neurol. 254, 20–25 (2007).

    Article  Google Scholar 

  18. Berger, T. et al. Experimental autoimmune encephalomyelitis: the antigen specificity of T-lymphocytes determines the topography of lesions in the central and peripheral nervous system. Lab. Invest. 76, 355–364 (1997).

    CAS  PubMed  Google Scholar 

  19. Kojima, K. et al. Experimental autoimmune panencephalitis and uveoretinitis in the Lewis rat transferred by T lymphocytes specific for the S100β molecule, a calcium binding protein of astroglia. J. Exp. Med. 180, 817–829 (1994).

    Article  CAS  Google Scholar 

  20. Abromson-Leeman, S. et al. T cell responses to myelin basic protein in experimental autoimmune encephalomyelitis-resistant BALB/c mice. J. Neuroimmunol. 45, 89–101 (1993).

    Article  CAS  Google Scholar 

  21. Stefferl, A. et al. Butyrophilin, a milk protein, modulates the encephalitogenic T cell response to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis. J. Immunol. 165, 2859–2865 (2000).

    Article  CAS  Google Scholar 

  22. Jacomy, H., Zhu, Q.Z., Couillard-Despres, S., Beaulieu, J.M. & Julien, J.P. Disruption of type IV intermediate filament network in mice lacking the neurofilament medium and heavy subunits. J. Neurochem. 73, 972–984 (1999).

    Article  CAS  Google Scholar 

  23. Amor, S. et al. Identification of epitopes of myelin oligodendrocyte glycoprotein for the induction of experimental allergic encephalomyelitis in SJL and Biozzi AB/H mice. J. Immunol. 153, 4349–4356 (1994).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

MogCre/Cre, Nefm−/−, 2D2 and Mog−/− mice were generously provided by A. Waisman (Johannes Gutenberg University of Mainz), J.-P. Julien (Laval University), V.K. Kuchroo (Harvard Medical School) and D. Pham-Dinh (INSERM UMR 546). We thank F. Lottspeich for granting us permission to use his mass spectrometer. We thank L. Penner and I. Arnold-Ammer for technical support. This project was supported by the Deutsche Forschungsgemeinschaft (Sonderforschungsbereiche (SFB) 571, Projects A1 and B6) and the Max Planck Society. H.S.D. is supported by a PhD fellowship (Portuguese Fundação para a Ciência ea Tecnologia (FCT) program SFRH/BD/15885/2005). Part of the study (conducted by H.W., R.L. and H.L.) was funded by the EU Project Neuropromise (PL 018637), and A.B.-N. was supported by the Israel Science Foundation and the National Multiple Sclerosis Society of New York (RG3195B8/2). A.B.-N. is an Alexander von Humboldt Prize Awardee.

Author information

Author notes

  1. Florian C Kurschus

    Present address: Present address: I. Medizinische Klinik und Poliklinik, Johannes Gutenberg Universität, Mainz, Germany.,

  2. Klaus Dornmair, Florian C Kurschus and Roland S Liblau: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neuroimmunology, Max Planck Institute of Neurobiology, Martinsried, Germany

    Gurumoorthy Krishnamoorthy, Helena S Domingues, Klaus Dornmair, Florian C Kurschus & Hartmut Wekerle

  2. Institut National de la Santé et de la Recherche Médicale, Unité 563, Université Toulouse III, Paul-Sabatier, Toulouse, France

    Amit Saxena, Lennart T Mars & Roland S Liblau

  3. PhD Program in Experimental Biology and Biomedicine, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

    Helena S Domingues

  4. Institute of Clinical Neuroimmunology, University Hospital Grosshadern, Ludwig-Maximilians University, Munich, Germany

    Reinhard Mentele & Klaus Dornmair

  5. Department for Protein Analytics, Max Planck Institute of Biochemistry, Martinsried, Germany

    Reinhard Mentele

  6. Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel

    Avraham Ben-Nun

  7. Center for Brain Research, Medical University of Vienna, Vienna, Austria

    Hans Lassmann

Authors
  1. Gurumoorthy Krishnamoorthy
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Amit Saxena
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Lennart T Mars
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Helena S Domingues
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Reinhard Mentele
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Avraham Ben-Nun
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Hans Lassmann
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Klaus Dornmair
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Florian C Kurschus
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Roland S Liblau
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Hartmut Wekerle
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

G.K. performed most of the experiments. G.K. and H.W. designed the study and wrote the manuscript with input from co-authors. A.S., L.T.M. and R.S.L. contributed EAE and T cell data. K.D. supervised protein purification and mass spectrometry and performed in silico searches. R.M. performed mass spectrometry. H.S.D. assisted in EAE experiments. A.B.-N. performed T cell line transfer EAE experiments. H.L. performed and interpreted histology. F.C.K. designed experiments and performed protein purification.

Corresponding author

Correspondence to Hartmut Wekerle.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–13, Supplementary Tables 1 and 2 and Supplementary Methods (PDF 1029 kb)

Supplementary Video 1

Healthy 2D2 mouse. (MOV 2391 kb)

Supplementary Video 2

2D2 mouse with hind limb clasping phenotype. (MOV 2152 kb)

Supplementary Video 3

2D2 mouse with hind limb hyperextension (spasticity). (MOV 3284 kb)

Supplementary Video 4

Healthy 2D2 × Mog−/− mouse. (MOV 4442 kb)

Supplementary Video 5

2D2 × Mog−/− mouse with hind limb clasping. (MOV 3968 kb)

Supplementary Video 6

2D2 × Mog−/− mouse with hind limb clasping and hyperextension (spasticity). (MOV 3087 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Krishnamoorthy, G., Saxena, A., Mars, L. et al. Myelin-specific T cells also recognize neuronal autoantigen in a transgenic mouse model of multiple sclerosis. Nat Med 15, 626–632 (2009). https://doi.org/10.1038/nm.1975

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.1975

This article is cited by

Search

Advanced search

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
pFad - Phonifier reborn

Pfad - The Proxy pFad of © 2024 Garber Painting. All rights reserved.

Note: This service is not intended for secure transactions such as banking, social media, email, or purchasing. Use at your own risk. We assume no liability whatsoever for broken pages.


Alternative Proxies:

Alternative Proxy

pFad Proxy

pFad v3 Proxy

pFad v4 Proxy