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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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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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