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.

  • Review Article
  • Published:

Transcriptional analysis of targets in multiple sclerosis

Key Points

  • Large-scale analysis of the messenger RNA transcripts that are expressed in diseased tissues can enable new components of pathways resulting in autoimmunity to be identified.

  • Large-scale sequencing can be carried out using robotic sequences of libraries, or using oligonucleotide microarrays.

  • The identification of new targets that are involved in the pathogenesis of multiple sclerosis (MS) is discussed.

  • Osteopontin is an important transcript found in MS lesions, and it modulates T helper 1 (TH1)-cell-mediated autoimmunity.

  • Leptin is found in MS lesions and it modulates the TH1–TH2 balance.

  • Statins not only lower cholesterol, but are also found in MS lesions and influence TH1-cell-mediated autoimmunity.

  • Several molecules that are involved in allergic responses, including histamine, also modulate autoimmunity.

Abstract

Large-scale analyses of messenger RNA transcripts and autoantibody responses, taken from the actual sites of disease, provide us with an unprecedented view of the complexity of autoimmunity. Despite an appreciation of the large number of pathways and pathological processes that are involved in these diseases, a few practical targets and several new strategies have emerged from these studies. This review focuses on multiple sclerosis and on the approaches that are being used to identify new targets that might be manipulated to control this disease.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: The inflammatory phase of multiple sclerosis.
Figure 2: Large-scale analysis of gene transcription from MS lesions.
Figure 3: The neurodegenerative phase of multiple sclerosis.
Figure 4: The intricate interplay between leptin, corticotropin-releasing factor and the melanocortins in the regulation of TH1 immunity.
Figure 5: The 'reverse proteomic' approach.

Similar content being viewed by others

References

  1. Chabas, D. et al. The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 294, 1731–1735 (2001). This study describes the sequencing of messenger RNA transcripts found in the brain using robotics. The biological role of osteopontin (OPN), one of the sequences that are found in the brain of patients with multiple sclerosis (MS), is described.

    Article  CAS  Google Scholar 

  2. Lock, C. et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nature Med. 8, 500–508 (2002). This paper shows how oligonucleotide microarrays are used to assess mRNA transcripts in acute and chronic MS lesions. The biological roles of some of these transcripts, including those encoding G-CSF and Fcε receptor, are shown.

    Article  CAS  Google Scholar 

  3. Robinson, W. H. et al. Antigen arrays for multiplex characterization of autoantibody responses. Nature Med. 8, 295–301 (2002).

    Article  CAS  Google Scholar 

  4. Steinman, L. Multiple sclerosis: a two stage disease. Nature Immunol. 2, 762–765 (2001).

    Article  CAS  Google Scholar 

  5. Steinman, L. Autoimmune disease. Sci. Am. 269, 106–114 (1993).

    Article  CAS  Google Scholar 

  6. Steinman, L., Martin, R., Bernard, C. C. A., Conlon, P. & Oksenberg, J. R. Multiple sclerosis: deeper understanding of its pathogenesis reveals new targets for therapy. Annu. Rev. Neurosci. 25, 491–505 (2002).

    Article  CAS  Google Scholar 

  7. Dyment, D. & Ebers, G. An array of sunshine in multiple sclerosis. N. Engl. J. Med. 247, 1445–1447 (2002). This paper reviews the promise of microarray technologies to discover new targets in MS.

    Article  Google Scholar 

  8. Schadt, E. E., Li, C., Su, C. & Wong, W. H. Analyzing high-density oligonucleotide gene expression array data. J. Cell Biochem. 80, 192–202 (2000).

    Article  CAS  Google Scholar 

  9. Tusher, V. G., Tibshirani, R. & Chu, G. Significance analysis of microarrays applied to the ionizing radiation response. Proc. Natl Acad. Sci. USA 98, 5116–5121 (2001).

    Article  CAS  Google Scholar 

  10. Whitney, L. W. et al. Analysis of gene expression in multiple sclerosis lesions using cDNA microarrays. Ann. Neurol. 46, 425–428 (1999).

    Article  CAS  Google Scholar 

  11. Mycko, M. P., Papoian, R., Boschert, U., Raine, C. S. & Selmaj, K. W. cDNA microarray analysis in multiple sclerosis lesions: detection of genes associated with disease activity. Brain 126, 1048–1057 (2003).

    Article  Google Scholar 

  12. Whitney, L. W., Ludwin, S. K., McFarland, H. F. & Biddison, W. E. Microarray analysis of gene expression in multiple sclerosis and EAE identifies 5-lipoxygenase as a component of inflammatory lesions. J. Neuroimmunol. 121, 40–48 (2001).

    Article  CAS  Google Scholar 

  13. Ibrahim, S. M. et al. Gene expression profiling of the nervous system in murine experimental autoimmune encephalomyelitis. Brain 124, 1927–1938 (2001).

    Article  CAS  Google Scholar 

  14. Nicot, A., Ratnakar, P. V., Ron, Y., Chen, C. C. & Elkabes, S. Regulation of gene expression in experimental autoimmune encephalomyelitis indicates early neuronal dysfunction. Brain 126, 398–412 (2003).

    Article  Google Scholar 

  15. Steinman, L. Gene microarrays and experimental demyelinating disease: a tool to enhance serendipity. Brain 124, 1897–1899 (2001).

    Article  CAS  Google Scholar 

  16. Weber, G. F., Ashkar, S., Glimcher, M. J. & Cantor, H. Receptor–ligand interaction between CD44 and osteopontin (Eta-1). Science 271, 509–512 (1996).

    Article  CAS  Google Scholar 

  17. Brocke, S., Piercy, C., Steinman, L., Weissman, I. L. & Veromaa, T. Antibodies to CD44 and integrin α4, but not L-selectin, prevent CNS inflammation and experimental encephalomyelitis by blocking secondary leukocyte recruitment. Proc. Natl Acad. Sci. USA 96, 6896–6901 (1999).

    Article  CAS  Google Scholar 

  18. Jansson, M., Panoutsakapoulou, V., Baker, J., Klein, L. & Cantor, H. Attenuated EAE in Eta-1/osteopontin deficient mice. J. Immunol. 168, 2096–2099 (2002).

    Article  CAS  Google Scholar 

  19. Cua, D. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744–748 (2003). This paper contends that IL-23 is paramount in the cytokine cascade in experimental autoimmune encephalomyelitis (EAE).

    Article  CAS  Google Scholar 

  20. Caillier, S. et al. Osteopontin polymorphisms and disease course in MS. Genes Immun. 4, 312–316 (2003).

    Article  CAS  Google Scholar 

  21. Niino, M., Kikuchi, S., Fukazawa, T., Yabe, I. & Tashiro, K. Genetic polymorphisms of osteopontin in association with multiple sclerosis in Japanese patients. J. Neuroimmunol. 136, 125–129 (2003).

    Article  CAS  Google Scholar 

  22. Vogt, M. et al. Elevated osteopontin levels are associated with disease activity in relapsing–remitting MS patients. Ann. Neurol. (in the press).

  23. Karpuj, M. V. et al. Prolonged survival and decreased abnormal movements in transgenic model of Huntington's disease, with administration of cystamine, a transglutaminase inhibitor. Nature Med. 8, 143–149 (2002).

    Article  CAS  Google Scholar 

  24. Graber, K. D., Fontoura, P., Hermans, G., Steinman, L. & Prince, D. A. mRNA changes in epileptogenic and nonepileptogenic undercut rat neocortex. Epilepsia 43, 21 (2002).

    Google Scholar 

  25. Blom, T., Franzen, A., Heinegard, D. & Holmdahl, R. Comment on “The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease”. Science 299, 1845 (2003).

    Article  CAS  Google Scholar 

  26. Steinman, L. et al. Response to comment on “The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease”. Science 299, 1845 (2003).

    Article  CAS  Google Scholar 

  27. Lyons, J. A., Ramsbottom, M. J. & Cross, A. H. Critical role of antigen-specific antibody in experimental autoimmune encephalomyelitis induced by recombinant myelin oligodendrocyte glycoprotein. Eur. J. Immunol. 32, 1905–1913 (2002).

    Article  CAS  Google Scholar 

  28. Lyons, J. A., San, M., Happ, M. P. & Cross, A. H. B cells are critical to induction of experimental allergic encephalomyelitis by protein but not by a short encephalitogenic peptide. Eur. J. Immunol. 29, 3432–3439 (1999).

    Article  CAS  Google Scholar 

  29. Steinman, L. Some misconceptions about understanding autoimmunity through experiments with knockouts. J. Exp. Med. 185, 2039–2041 (1997).

    Article  CAS  Google Scholar 

  30. Steinman, L., Rosenbaum, J. T., Sriram, S. & McDevitt, H. O. In vivo effects of antibodies to immune response gene products: prevention of experimental allergic encephalomyelitis. Proc. Natl Acad. Sci. USA 78, 7111–7114 (1981).

    Article  CAS  Google Scholar 

  31. Kwak, B., Mulhaupt, F., Myit, S. & Mach, F. Statins as a newly recognized type of immunomodulator. Nature Med. 6, 1399–1402 (2000).

    Article  CAS  Google Scholar 

  32. Bottazo, G. F., Pujol-Borrell, R., Hanufusa, T. & Feldmann, M. Role of aberrant HLA-DR expression and antigen presentation in induction of endocrine autoimmunity. Lancet 12, 1115–1119 (1983).

    Article  Google Scholar 

  33. Waldor, M., Sriram, S., McDevitt, H. O. & Steinman, L. In vivo therapy with monoclonal anti-I-A antibody suppresses immune response to acetylcholine receptor. Proc. Natl Acad. Sci. USA 80, 2713–2717 (1983).

    Article  CAS  Google Scholar 

  34. Sriram, S. & Steinman, L. Anti I-A antibody suppresses active encephalomyelitis: treatment model for IR gene linked diseases. J. Exp. Med. 158, 1362–1367 (1983).

    Article  CAS  Google Scholar 

  35. Vladutiu, A. & Steinman, L. Inhibition of experimental autoimmune thyroiditis in mice by anti-I-A antibodies. Cell. Immunol. 109, 169–180 (1987).

    Article  CAS  Google Scholar 

  36. Youssef, S. et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a TH2 bias and reverses paralysis in CNS autoimmune disease. Nature 420, 78–84 (2002). This paper describes the surprising role of statins as immunomodulators. Statins induce a T helper 2 (T H 2) cytokine shift.

    Article  CAS  Google Scholar 

  37. Neuhaus, O. et al. Statins as immunomodulators: comparison with interferon-β1b in MS. Neurology 59, 990–997 (2002).

    Article  CAS  Google Scholar 

  38. Stanislaus, R., Pahan, K., Singh, A. K. & Singh, I. Amelioration of experimental allergic encephalomyelitis in Lewis rats by lovastatin. Neurosci. Lett. 269, 71–74 (1999).

    Article  CAS  Google Scholar 

  39. Steinman, L., Conlon, P., Maki, R. & Foster, A. The intricate interplay among body weight, stress and the immune response to friend or foe. J. Clin. Invest. 111, 183–185 (2003).

    Article  CAS  Google Scholar 

  40. Matarese, G. et al. Requirement for leptin in induction and progression of experimental autoimmune encephalomyelitis. J. Immunol. 166, 5909–5916 (2001).

    Article  CAS  Google Scholar 

  41. Sanna, V. et al. Leptin surge precedes autoimmune encephalomyelitis and correlates with disease susceptibility, inflammatory anorexia and the development of pathogenic T cell responses. J. Clin. Invest. 111, 241–250 (2003). A description of how leptins modulate T H 1-cell-mediated autoimmunity. Short periods of fasting can modulate T H 1 immune responses.

    Article  CAS  Google Scholar 

  42. Poliak, S. et al. Stress and autoimmunity: the neuropeptides corticotropin releasing factor and urocortin suppress encephalomyelitis via effects on both the hypothalamic–pituitary–adrenal axis and the immune system. J. Immunol. 158, 5751–5756 (1997).

    CAS  PubMed  Google Scholar 

  43. Cohen, P. et al. Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss. Science 297, 240–243 (2002).

    Article  CAS  Google Scholar 

  44. Ehrlich, P. Die Schutzstoffe des Blutes. Dtsch. med. Wschr. 27, 913–916 (1901) (in German).

    Article  Google Scholar 

  45. Pedotti, R. et al. An unexpected version of horror autotoxicus: anaphylactic shock to a self-peptide. Nature Immunol. 2, 216–222 (2001).

    Article  CAS  Google Scholar 

  46. Rivers, T. M., Sprunt, D. H. & Berry, G. P. Observations on attempts to produce acute disseminated encephalomyelitis in monkeys. J. Exp. Med. 58, 39–53 (1933).

    Article  CAS  Google Scholar 

  47. Pedotti, R. et al. Multiple elements of the allergic arm of the immune response modulate autoimmune demyelination. Proc. Natl Acad. Sci. USA 100, 1867–1872 (2003).

    Article  CAS  Google Scholar 

  48. Steinman, L. Optic neuritis, a new variant of experimental encephalomyelitis, a durable model for all seasons, now in its seventieth year. J. Exp. Med. 197, 1065–1071 (2003).

    Article  CAS  Google Scholar 

  49. Ma, R. Z. et al. Identification of Bphs, an autoimmune disease locus, as histamine receptor H1. Science 297, 620–623 (2002). This paper shows that histamine receptors are crucial for susceptibility to EAE.

    Article  CAS  Google Scholar 

  50. Robinson, W., Garren, H., Utz, P. J. & Steinman, L. Millennium Award. Proteomics for the development of DNA tolerizing vaccines to treat autoimmune disease. Clin. Immunol. 103, 7–12 (2002).

    Article  CAS  Google Scholar 

  51. Robinson, W., Steinman, L. & Utz, P. J. Proteomics technologies for the study of autoimmune disease. Arthritis Rheum. 46, 885–893 (2002).

    Article  CAS  Google Scholar 

  52. Garren, H. & Steinman, L. DNA vaccination in the treatment of autoimmune disease. Curr. Direct. Autoimmun. 2, 203–216 (2000).

    Article  CAS  Google Scholar 

  53. Garren, H. et al. Combination of gene delivery and DNA vaccination to protect from and reverse TH1 autoimmune disease via deviation to the TH2 pathway. Immunity 15, 15–22 (2001).

    Article  CAS  Google Scholar 

  54. Urbanek-Ruiz, I. et al. Immunization with DNA encoding an immunodominant peptide of insulin prevents diabetes in NOD mice. Clin. Immunol. 100, 164–171 (2001).

    Article  CAS  Google Scholar 

  55. Youssef, S. et al. Long lasting protective immunity to experimental autoimmune encephalomyelitis following vaccination with naked DNA encoding C-C chemokines. J. Immunol. 161, 3870–3879 (1998).

    CAS  PubMed  Google Scholar 

  56. Youssef, S., Wildbaum, G. & Karin, N. Prevention of experimental autoimmune encephalomyelitis by MIP-1α and MCP-1 naked DNA vaccines. J. Autoimmun. 13, 21–29 (1999).

    Article  CAS  Google Scholar 

  57. Wildbaum, G., Youssef, S., Grabie, N. & Karin, N. Neutralizing antibodies to IFN-γ-inducing factor prevent experimental autoimmune encephalomyelitis. J. Immunol. 161, 6368–6374 (1998).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was funded, in part, by the Phil N. Allen Trust, the National Institutes of Health, the National Multiple Sclerosis Society, the Nancy Davis Foundation, the Maislin Foundation and the Wadsworth Foundation. L.S. has founded two biotechnology companies, Neurocrine Biosciences and Bayhill Therapeutics.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lawrence Steinman.

Related links

Related links

DATABASES

LocusLink

αB-crystallin

acetoacetyl-CoA thiolase

ACTHR

AGRP

CD44

CRF

enoyl-CoA hydratase

H1R

HMG-CoA reductase

ICAM

IFN-γ

IL-10

IL-12

IL-23

iNOS

leptin

LFA1

melanocortin-4 receptor

MOG

NPY

OPN

POMC

propionyl-CoA carboxylase

PGDS

prostatic binding protein

proteolipid protein

PTAFR

ribosomal protein L17

Scd1

stearoyl-CoA desaturase

TNF

transglutaminase

urocortin

OMIM

multiple sclerosis

Glossary

MICROGLIAL CELLS

Bone-marrow-derived macrophages that are resident in the central nervous sytem.

OLIGONUCLEOTIDE MICROARRAYS

Short chains of nucleotides are chemically coupled to a solid surface. There, they hybridize with complementary DNA sequences.

SINGLE-NUCLEOTIDE POLYMORPHISMS

(SNPs). Single base-pair changes that are inherited as Mendelian traits and might associate with a trait such as susceptibility to disease.

EXPRESSED SEQUENCE TAG

(EST). A single-pass, short read of complementary DNA that is generated from a transcribed region of the genome.

EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS

(EAE). Refers to a set of related animal models of multiple sclerosis. Typically, disease is induced by the injection of components of myelin, which leads to demyelination in the central nervous system.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Steinman, L., Zamvil, S. Transcriptional analysis of targets in multiple sclerosis. Nat Rev Immunol 3, 483–492 (2003). https://doi.org/10.1038/nri1108

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri1108

This article is cited by

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