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

Christopher Lock; Guy Hermans; Rosetta Pedotti; Andrea Brendolan; Eric Schadt; Hideki Garren; Annette Langer-Gould; Samuel Strober; Barbara Cannella; John Allard; Paul Klonowski; Angela Austin; Nagin Lad; Naftali Kaminski; Stephen J. Galli; Cedric S. Raine; Renu Heller; Lawrence Steinman

doi:10.1038/nm0502-500

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

Christopher Lock, Guy Hermans, Rosetta Pedotti, Andrea Brendolan, Eric Schadt, Hideki Garren, Annette Langer-Gould, Samuel Strober, Barbara Cannella, John Allard, Paul Klonowski, Angela Austin, Nagin Lad, Naftali Kaminski, Stephen J. Galli, Cedric S. Raine, Renu Heller, Lawrence Steinman

Pathology

Research output: Contribution to journal › Article › peer-review

1462 Scopus citations

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 pathologyacute 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.

Original language	English (US)
Pages (from-to)	500-508
Number of pages	9
Journal	Nature Medicine
Volume	8
Issue number	5
DOIs	https://doi.org/10.1038/nm0502-500
State	Published - 2002

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1038/nm0502-500

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Lock, C., Hermans, G., Pedotti, R., Brendolan, A., Schadt, E., Garren, H., Langer-Gould, A., Strober, S., Cannella, B., Allard, J., Klonowski, P., Austin, A., Lad, N., Kaminski, N., Galli, S. J., Raine, C. S., Heller, R., & Steinman, L. (2002). Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nature Medicine, 8(5), 500-508. https://doi.org/10.1038/nm0502-500

Lock, C, Hermans, G, Pedotti, R, Brendolan, A, Schadt, E, Garren, H, Langer-Gould, A, Strober, S, Cannella, B, Allard, J, Klonowski, P, Austin, A, Lad, N, Kaminski, N, Galli, SJ, Raine, CS, Heller, R & Steinman, L 2002, 'Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis', Nature Medicine, vol. 8, no. 5, pp. 500-508. https://doi.org/10.1038/nm0502-500

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title = "Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis",

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 pathologyacute 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.",

author = "Christopher Lock and Guy Hermans and Rosetta Pedotti and Andrea Brendolan and Eric Schadt and Hideki Garren and Annette Langer-Gould and Samuel Strober and Barbara Cannella and John Allard and Paul Klonowski and Angela Austin and Nagin Lad and Naftali Kaminski and Galli, {Stephen J.} and Raine, {Cedric S.} and Renu Heller and Lawrence Steinman",

note = "Funding Information: Acknowledgments 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 postdoctoral 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.",

year = "2002",

doi = "10.1038/nm0502-500",

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AU - Lock, Christopher

AU - Hermans, Guy

AU - Pedotti, Rosetta

AU - Brendolan, Andrea

AU - Schadt, Eric

AU - Garren, Hideki

AU - Langer-Gould, Annette

AU - Strober, Samuel

AU - Cannella, Barbara

AU - Allard, John

AU - Klonowski, Paul

AU - Austin, Angela

AU - Lad, Nagin

AU - Kaminski, Naftali

AU - Galli, Stephen J.

AU - Raine, Cedric S.

AU - Heller, Renu

AU - Steinman, Lawrence

N1 - Funding Information: Acknowledgments 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 postdoctoral 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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N2 - 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 pathologyacute 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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Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis

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