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Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis

Nature Medicine volume 8, pages 500–508 (2002)Cite this article

Abstract

Microarray analysis of multiple sclerosis (MS) lesions obtained at autopsy revealed increased transcripts of genes encoding inflammatory cytokines, particularly interleukin-6 and -17, interferon-γ and associated downstream pathways. Comparison of two poles of MS pathology—acute lesions with inflammation versus 'silent' lesions without inflammation—revealed differentially transcribed genes. Some products of these genes were chosen as targets for therapy of experimental autoimmune encephalomyelitis (EAE) in mice. Granulocyte colony-stimulating factor is upregulated in acute, but not in chronic, MS lesions, and the effect on ameliorating EAE is more pronounced in the acute phase, in contrast to knocking out the immunoglobulin Fc receptor common γ chain where the effect is greatest on chronic disease. These results in EAE corroborate the microarray studies on MS lesions. Large-scale analysis of transcripts in MS lesions elucidates new aspects of pathology and opens possibilities for therapy.

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Figure 1: Histopathology of analyzed MS plaques.
Figure 2: Genes increased in 4 of 4 MS samples.
Figure 3: Genes decreased in 4 of 4 MS samples.
Figure 4: EAE in immunoglobulin FcRγ-chain-knockouts.
Figure 5: Effect of G-CSF on EAE, two consecutive experiments.

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References

  1. Raine, C.S. The neuropathology of multiple sclerosis. in Multiple Sclerosis: Clinical and Pathogenetic Basis (eds. Raine, C.S., McFarland, H.F. & Tourtelotte, W.W) 151–171 (Chapman and Hall, London, 1997).

    Google Scholar 

  2. Eisen, M.B., Spellman, P.T., Brown, P.O. & Botstein, D. Cluster analysis and display of genome-wide expression patterns. Proc. Natl. Acad. Sci. USA 95, 14863–14868 (1998).

    CAS  PubMed  Google Scholar 

  3. Waring, J.F. et al. Clustering of hepatotoxins based on mechanism of toxicity using gene expression profiles. Toxicol. Appl. Pharmacol. 175, 28–42 (2001).

    CAS  PubMed  Google Scholar 

  4. 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).

    CAS  PubMed  Google Scholar 

  5. Schadt, E.E., Li, C., Ellis, B. & Wong, W.H. Feature extraction and normalization algorithms for high-density oligonucleotide gene expression array data. J. Cell Biochem. Suppl., 120–125 (2001).

  6. Hong, J.X., Wilson, G.L., Fox, C.H. & Kehrl, J.H. Isolation and characterization of a novel B cell activation gene. J. Immunol. 150, 3895–3904 (1993).

    CAS  PubMed  Google Scholar 

  7. Dabiri, G.A., Young, C.L., Rosenbloom, J. & Southwick, F.S. Molecular cloning of human macrophage capping protein cDNA. A unique member of the gelsolin/villin family expressed primarily in macrophages. J. Biol. Chem 267, 16545–16552 (1992).

    CAS  PubMed  Google Scholar 

  8. Kozopas, K.M., Yang, T., Buchan, H.L., Zhou, P. & Craig, R.W. MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2. Proc. Natl. Acad. Sci. USA 90, 3516–3520 (1993).

    CAS  PubMed  Google Scholar 

  9. Rehli, M., Krause, S.W. & Andreesen, R. Molecular characterization of the gene for human cartilage gp-39 (CHI3L1), a member of the chitinase protein family and marker for late stages of macrophage differentiation. Genomics 43, 221–225 (1997).

    CAS  PubMed  Google Scholar 

  10. Davoust, N. et al. Central nervous system-targeted expression of the complement inhibitor sCrry prevents experimental allergic encephalomyelitis. J. Immunol. 163, 6551–6556 (1999).

    CAS  PubMed  Google Scholar 

  11. Walsh, L.A., Tone, M., Thiru, S. & Waldmann, H. The CD59 antigen—a multifunctional molecule. Tissue Antigens 40, 213–220 (1992).

    CAS  PubMed  Google Scholar 

  12. Hauser, S.L., Doolittle, T.H., Lincoln, R., Brown, R.H. & Dinarello, C.A. Cytokine accumulations in CSF of multiple sclerosis patients: Frequent detection of interleukin-1 and tumor necrosis factor but not interleukin-6. Neurology 40, 1735–1739 (1990).

    CAS  PubMed  Google Scholar 

  13. Jacobs, C.A. et al. Experimental autoimmune encephalomyelitis is exacerbated by IL-1 α and suppressed by soluble IL-1 receptor. J. Immunol. 146, 2983–2989 (1991).

    CAS  PubMed  Google Scholar 

  14. Matusevicius, D. et al. Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult. Scler. 5, 101–104 (1999).

    CAS  PubMed  Google Scholar 

  15. Raine, C.S., Bonetti, B. & Cannella, B. Multiple sclerosis: Expression of molecules of the tumor necrosis factor ligand and receptor families in relationship to the demyelinated plaque. Rev. Neurol. (Paris) 154, 577–585 (1998).

    CAS  Google Scholar 

  16. Akira, S. & Kishimoto, T. IL-6 and NF-IL6 in acute-phase response and viral infection. Immunol. Rev. 127, 25–50 (1992).

    CAS  PubMed  Google Scholar 

  17. Gijbels, K., Brocke, S., Abrams, J.S. & Steinman, L. Administration of neutralizing antibodies to interleukin-6 (IL-6) reduces experimental autoimmune encephalomyelitis and is associated with elevated levels of IL-6 bioactivity in central nervous system and circulation. Mol. Med. 1, 795–805 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Akassoglou, K., Probert, L., Kontogeorgos, G. & Kollias, G. Astrocyte-specific but not neuron-specific transmembrane TNF triggers inflammation and degeneration in the central nervous system of transgenic mice. J. Immunol. 158, 438–445 (1997).

    CAS  PubMed  Google Scholar 

  19. Mao, Z., Bonni, A., Xia, F., Nadal-Vicens, M. & Greenberg, M.E. Neuronal activity-dependent cell survival mediated by transcription factor MEF2. Science 286, 785–790 (1999).

    CAS  PubMed  Google Scholar 

  20. Penkowa, M. et al. Altered inflammatory response and increased neurodegeneration in metallothionein I+II deficient mice during experimental autoimmune encephalomyelitis. J. Neuroimmunol. 119, 248–260 (2001).

    CAS  PubMed  Google Scholar 

  21. Pitt, D., Werner, P. & Raine, C.S. Glutamate excitotoxicity in a model of multiple sclerosis. Nature Med. 6, 67–70 (2000).

    CAS  PubMed  Google Scholar 

  22. Trapp, B.D. et al. Axonal transection in the lesions of multiple sclerosis. N. Engl. J. Med. 338, 278–285 (1998).

    CAS  PubMed  Google Scholar 

  23. Yan, Y., Lagenaur, C. & Narayanan, V. Molecular cloning of M6: Identification of a PLP/DM20 gene family. Neuron 11, 423–431 (1993).

    CAS  PubMed  Google Scholar 

  24. Yednock, T.A. et al. Prevention of experimental autoimmune encephalomyelitis by antibodies against α4β1 integrin. Nature 356, 63–66 (1992).

    CAS  PubMed  Google Scholar 

  25. Steinman, L. Assessment of the utility of animal models for MS and demyelinating disease in the design of rational therapy. Neuron 24, 511–514 (1999).

    CAS  PubMed  Google Scholar 

  26. Takai, T., Li, M., Sylvestre, D., Clynes, R. & Ravetch, J.V. FcRγ chain deletion results in pleiotrophic effector cell defects. Cell 76, 519–529 (1994).

    CAS  PubMed  Google Scholar 

  27. Miyajima, I. et al. Systemic anaphylaxis in the mouse can be mediated largely through IgG1 and FcγRIII. Assessment of the cardiopulmonary changes, mast cell degranulation, and death associated with active or IgE- or IgG1- dependent passive anaphylaxis. J. Clin. Invest. 99, 901–914 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Samuelsson, A., Towers, T.L. & Ravetch, J.V. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 291, 484–486 (2001).

    CAS  PubMed  Google Scholar 

  29. Achiron, A. et al. Intravenous immunoglobulin treatment of experimental T cell-mediated autoimmune disease. Upregulation of T-cell proliferation and downregulation of tumor necrosis factor α secretion. J. Clin. Invest. 93, 600–605 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Wucherpfennig, K.W. et al. Recognition of the immunodominant myelin basic protein peptide by autoantibodies and HLA-DR2-restricted T-cell clones from multiple sclerosis patients. Identity of key contact residues in the B-cell and T-cell epitopes. J. Clin. Invest. 100, 1114–1122 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Warren, K.G., 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).

    CAS  PubMed  Google Scholar 

  32. Genain, C.P., Cannella, B., Hauser, S.L. & Raine, C.S. Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nature Med. 5, 170–175 (1999).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  34. Wraith, D.C., Smilek, D.E., Mitchell, D.J., Steinman, L. & McDevitt, H.O. Antigen recognition in autoimmune encephalomyelitis and the potential for peptide-mediated immunotherapy. Cell 59, 247–255 (1989).

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  36. Lucchinetti, C. et al. Heterogeneity of multiple sclerosis lesions: Implications for the pathogenesis of demyelination. Ann. Neurol. 47, 707–717 (2000).

    CAS  PubMed  Google Scholar 

  37. Haines, J.L. et al. A complete genomic screen for multiple sclerosis underscores a role for the major histocompatability complex. The Multiple Sclerosis Genetics Group. Nature Genet 13, 469–471 (1996).

    CAS  PubMed  Google Scholar 

  38. Ebers, G.C. et al. A full genome search in multiple sclerosis. Nature Genet. 13, 472–476 (1996).

    CAS  PubMed  Google Scholar 

  39. Sawcer, S. et al. A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22. Nature Genet. 13, 464–468 (1996).

    CAS  PubMed  Google Scholar 

  40. Zavala, F. et al. G-CSF therapy of ongoing experimental allergic encephalomyelitis via chemokine- and cytokine-based immune deviation. J. Immunol. 168, 2011–2019 (2002).

    CAS  PubMed  Google Scholar 

  41. Matarese, G. et al. Requirement for leptin in the induction and progression of autoimmune encephalomyelitis. J. Immunol. 166, 5909–16 (2001).

    CAS  PubMed  Google Scholar 

  42. Mountjoy, K.G., Robbins, L.S., Mortrud, M.T. & Cone, R.D. The cloning of a family of genes that encode the melanocortin receptors. Science 257, 1248–1251 (1992).

    CAS  PubMed  Google Scholar 

  43. 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 

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Acknowledgements

We thank J. Woody, R. Booth and H. Van Wart for support during the course of this work; H. Gmuender for help optimizing use of the technology; S. Wilson for developing methods to handle and isolate RNA from human samples; F. Zuo for helpful comments on the manuscript; J. Kumm for advice on bioinformatics; M.C. Jeong for technical help; and Roche Bioscience for support and access to gene-chip technology. This study was supported in part by post-doctoral fellowships from the National Multiple Sclerosis Society to C.L., G.H. and R.P. J.O. is supported by grants from the NIH (NIHAI35761) and the National Multiple Sclerosis Society (RG2901). C.S.R. is supported by NIH grants NS08952 and NS11920. L.S. is supported by NIH grants NIH18235, 30201, 41402 and 28579.

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Author notes

  1. Christopher Lock, Guy Hermans, Rosetta Pedotti and Andrea Brendolan: C.L., G.H., R.P. and A.B. contributed equally to this study.

Authors and Affiliations

  1. Departments of Neurology and Neurological Sciences, Beckman Center, Stanford University, Stanford, California, USA

    Christopher Lock, Guy Hermans, Rosetta Pedotti, Hideki Garren, Annette Langer-Gould & Lawrence Steinman

  2. Medicine, Stanford University, Stanford, California, USA

    Andrea Brendolan & Samuel Strober

  3. Pathology, Stanford University, Stanford, California, USA

    Stephen J. Galli

  4. Informatics, Rosetta Inpharmatics, Kirkland, Washington, USA

    Eric Schadt

  5. Departments of Neurology, San Francisco, California, USA

    Jorge R. Oksenberg

  6. Lung Biology Center and Cardiovascular Research Institute, University of California at San Francisco School of Medicine, San Francisco, California, USA

    Naftali Kaminski

  7. Department of Pathology (Neuropathology) and Neurology, Albert Einstein College of Medicine, Bronx, New York, USA

    Barbara Cannella & Cedric S. Raine

  8. Roche Bioscience, Palo Alto, California, USA

    John Allard, Paul Klonowski, Angela Austin, Nagin Lad & Renu Heller

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Correspondence to Renu Heller or Lawrence Steinman.

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Competing interests

L.S. is on the Scientific Advisory Board of Roche Biosciences. R.H., J.A., P.K., N.L. and A.A. were employees at Roche Biosciences during these studies.

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Lock, C., Hermans, G., Pedotti, R. et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med 8, 500–508 (2002). https://doi.org/10.1038/nm0502-500

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