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:

Autoimmunity due to molecular mimicry as a cause of neurological disease

Nature Medicine volume 8, pages 509–513 (2002)Cite this article

Abstract

One hypothesis that couples infection with autoimmune disease is molecular mimicry. Molecular mimicry is characterized by an immune response to an environmental agent that cross-reacts with a host antigen, resulting in disease1,2. This hypothesis has been implicated in the pathogenesis of diabetes, lupus and multiple sclerosis (MS)1,2,3,4. There is limited direct evidence linking causative agents with pathogenic immune reactions in these diseases. Our study establishes a clear link between viral infection, autoimmunity and neurological disease in humans. As a model for molecular mimicry, we studied patients with human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a disease that can be indistinguishable from MS (refs. 5,6,7). HAM/TSP patients develop antibodies to neurons8. We hypothesized these antibodies would identify a central nervous system (CNS) autoantigen. Immunoglobulin G isolated from HAM/TSP patients identified heterogeneous nuclear ribonuclear protein-A1 (hnRNP-A1) as the autoantigen. Antibodies to hnRNP-A1 cross-reacted with HTLV-1-tax, the immune response to which is associated with HAM/TSP (refs. 5,9). Immunoglobulin G specifically stained human Betz cells, whose axons are preferentially damaged7. Infusion of autoantibodies in brain sections inhibited neuronal firing, indicative of their pathogenic nature. These data demonstrate the importance of molecular mimicry between an infecting agent and hnRNP-A1 in autoimmune disease of the CNS.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Specificity of HAM/TSP IgG for CNS neurons and isolation of the neuronal antigen.
Figure 2: Immunoreactivity of HAM/TSP IgG with the neuronal extract and hnRNP-A1.
Figure 3: Target specificity and biologic activity of HAM/TSP IgG.

Similar content being viewed by others

References

  1. Oldstone, M. Molecular mimicry and immune mediated disease. FASEB J. 12, 1255–1265 (1998).

    Article  CAS  Google Scholar 

  2. Albert, L.J. & Inman, R.D. Molecular mimicry and autoimmunity. New Engl. J. Med. 341, 2068–2074 (1999).

    Article  CAS  Google Scholar 

  3. Gran, B., Hemmer, B., Vergelli, M., McFarland, H. & Martin, R. Molecular mimicry and multiple sclerosis: Degenerate T-cell recognition and the induction of autoimmunity. Ann. Neurol. 45, 559–567 (1999).

    Article  CAS  Google Scholar 

  4. Fujinami, R. & Oldstone, M. Amino acid homology between the encephalitogenic site of myelin basic protein and virus: A mechanism for autoimmunity. Science 230, 1043–1045 (1985).

    Article  CAS  Google Scholar 

  5. Jacobson, S., Shida, H., McFarlin, D., Fauci, A. & Koenig, S. Circulating CD8+ cytotoxic lymphocytes specific for HTLV-1 in patients with HTLV-1 associated neurological disease. Nature 348, 245–248 (1990).

    Article  CAS  Google Scholar 

  6. Levin, M. et al. Immunopathogenesis of HTLV-1 associated neurologic disease based on a spinal cord biopsy from a patient with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). New. Engl. J. Med. 336, 839–845 (1997).

    Article  CAS  Google Scholar 

  7. Levin, M. & Jacobson, S. HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP): A chronic progressive neurologic disease associated with immunlogically mediated damage to the central nervous system. J. Neurovirol. 3, 126–140 (1997).

    Article  CAS  Google Scholar 

  8. Levin, M. et al. Neuronal molecular mimicry in immune mediated neurologic disease. Ann. Neurol. 44, 87–98 (1998).

    Article  CAS  Google Scholar 

  9. Lal, R., Giam, C., Coligan, J. & Rudolph, D. Differential immune responsiveness to the immunodominant epitopes of regulatory proteins (tax and rex) in human T-cell lymphotropic virus type I associated myelopathy. J. Infect. Dis. 169, 496–503 (1994).

    Article  CAS  Google Scholar 

  10. Kahn, R., Bertorini, T. & Levin, M. Neurologic complications of HTLV-1 infection. The Neurologist 7, 271–278 (2001).

    Article  Google Scholar 

  11. Beranova-Giorgianni, S. & Desiderio, D. Mass spectrometry of the human pituitary proteome: Identification of selected proteins. Rapid Commun. Mass Spectrom. 14, 161–167 (2000).

    Article  CAS  Google Scholar 

  12. Biamonti, G., Ghigna, C., Caporali, R. & Montecucco, C. Heterogeneous nuclear ribonucleoproteins (hnRNPs): An emerging family of autoantigens in rheumatic diseases. Clin. Exp. Rheumatol. 16, 317–326 (1998).

    CAS  PubMed  Google Scholar 

  13. Krecic, A.M. & Swanson, M.S. hnRNP complexes: Composition, structure, and function. Curr. Opin. Cell Biol. 11, 363–371 (1999).

    Article  CAS  Google Scholar 

  14. Nakielny, S. & Dreyfuss, G. Nuclear export of proteins and RNAs. Curr. Opin. Cell Biol. 9, 420–429 (1997).

    Article  CAS  Google Scholar 

  15. Shyu, A.-B. & Wilkinson, M.F. The double lives of shuttling mRNA binding proteins. Cell 102, 135–138 (2000).

    Article  CAS  Google Scholar 

  16. Kamma, H., Portman, D.S. & Dreyfuss, G. Cell type-specific expression of hnRNP proteins. Exp. Cell Res. 221, 187–196 (1995).

    Article  CAS  Google Scholar 

  17. Lassek, A.M. The human pyramidal tract. IV. A study of the mature, myelinated fibers of the pyramid. J. Comp. Neurol. 76, 217–225 (1942).

    Article  Google Scholar 

  18. Callaway, J., Lasser-Ross, N., Stuart, N. & Ross, W. Dynamics of intracellular free calcium concentration in the presynaptic arbors of individual barnacle photoreceptors. J. Neurosci. 13, 1157–1166 (1993).

    Article  CAS  Google Scholar 

  19. Nagai, M. et al. Analysis of HTLV-1 proviral load in 202 HAM/TSP patients and 243 asymptomatic HTLV-1 carriers: High proviral load strongly predisposes to HAM/TSP. J. Neurovirol 4, 586–593 (1998).

    Article  CAS  Google Scholar 

  20. Muller, S. et al. IgG Autoantibody response in HTLV-1-infected patients. Clin. Immunol. Immunopathol. 77, 282–290 (1995).

    Article  CAS  Google Scholar 

  21. Warren, K., Catz, I. & Steinman, L. Fine specificity of the antibody response to myelin basic protein in the central nervous system in multiple sclerosis: The minimal B-cell epitope and a model of its features. Proc. Natl. Acad. Sci. USA 92, 11061–11065 (1995).

    Article  CAS  Google Scholar 

  22. Romero, I. et al. Interactions between brain endothelial cells and human T-cell leukemia virus type 1 infected lymphocytes: Mechanisms of viral entry into the central nervous system. J. Virol. 74, 6021–6030 (2000).

    Article  CAS  Google Scholar 

  23. Giraudon, P. et al. T lymphocytes activated by persistent viral infection differentially modify the expression of metalloproteinases and their endogenous inhibitors, TIMPs, in human astrocytes: Relevance of HTLV-I-induced neurologic disease. J. Immunol. 164, 2718–2727 (2000).

    Article  CAS  Google Scholar 

  24. Chen, W., Elias, R.V., Cao, W., Lerious, V. & McGinnis, J.F. Anti-recoverin antibodies cause the apoptotic death of mammalian photoreceptor cells in vitro. J. Neurosci. Res. 57, 706–718 (1999).

    Article  CAS  Google Scholar 

  25. Munro, T.P. et al. Mutational analysis of a heterogeneous nuclear ribonucleoprotein A2 response element for RNA trafficking. J. Biol. Chem. 274, 34389–34395 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank K. Troughton, E. Umstot and J. Berk for technical assistance; C. Raine for autopsy material; S. Jacobson for some of the serum samples; and B. Langton for the HTLV-1-tax monoclonal antibody obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH. This material is based upon work supported by the Office of Research and Development, Medical Research Service, Department of Veterans Affairs. This study was funded by the VA Career Development Award and NIH RO1-NS-38876 (to M.C.L.), and NIH RR 10522 and NSF-DBI-9604633 (to D.M.D.).

Author information

Authors and Affiliations

  1. Research Service, Veterans Affairs Medical Center, Memphis, Tennessee, USA

    Michael C. Levin, Karen A. Hasty & John M. Stuart

  2. Center for the Neurobiology of Brain Disease, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA

    Michael C. Levin, Sang Min Lee, Franck Kalume, Yvette Morcos & Joseph C. Callaway

  3. Departments of Neurology, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA

    Michael C. Levin, Sang Min Lee, Yvette Morcos & Dominic M. Desiderio

  4. Departments of Anatomy, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA

    Franck Kalume & Joseph C. Callaway

  5. Departments of Pathology, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA

    F. Curtis Dohan Jr

  6. Departments of Orthopedics-Campbell Clinic, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA

    Karen A. Hasty

  7. Departments of Molecular Science and The Charles B. Stout Neuroscience Mass Spectrometry Laboratory, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA

    Dominic M. Desiderio

  8. Medicine and Center of Excellence in Connective Tissue Diseases, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA

    Karen A. Hasty & John M. Stuart

  9. Department of Neurology, University of Washington, Seattle, Washington, USA

    Joseph Zunt

Authors
  1. Michael C. Levin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sang Min Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Franck Kalume
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yvette Morcos
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. F. Curtis Dohan Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Karen A. Hasty
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Joseph C. Callaway
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Joseph Zunt
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Dominic M. Desiderio
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. John M. Stuart
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael C. Levin.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Levin, M., Lee, S., Kalume, F. et al. Autoimmunity due to molecular mimicry as a cause of neurological disease. Nat Med 8, 509–513 (2002). https://doi.org/10.1038/nm0502-509

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0502-509

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