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Gene expression and genotyping studies implicate the interleukin 7 receptor in the pathogenesis of primary progressive multiple sclerosis

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Abstract

Multiple sclerosis (MS) is an enigmatic disease of the central nervous system resulting in sclerotic plaques with the pathological hallmarks of demyelination and axonal damage, which can be directly or indirectly orchestrated by cells from the peripheral circulation. The majority of patients with MS follow a relapsing–remitting course in the early stages of the disease (RRMS) but most ultimately enter a secondary progressive phase (SPMS). About 10% of patients follow a primary progressive course from the onset (PPMS). We measured gene expression in whole blood of people with and without chronic progressive MS (CPMS), PPMS and SPMS, to discover genes which may be differentially expressed in peripheral blood in active disease, and so identify pathologically significant genes and pathways; and we investigated genetic differences in the promoters of dysregulated genes encoded in genomic regions associated with MS. If SPMS and PPMS were independently compared to the controls, there was little overlap in the set of most dysregulated genes. Ribosomal protein genes, whose expression is usually associated with cell proliferation and activation, were dramatically over-represented in the set of most down-regulated genes in PPMS compared to SPMS (P<10−4, χ2). The T cell proliferation gene IL7R (CD127) was also underexpressed in PPMS, but was up-regulated in SPMS compared to the controls. One interleukin 7 receptor (IL7R) promoter single nucleotide polymorphism (SNP), −504 C, was undertransmitted in PPMS trios (P=0.05, TDT), and carriers of this allele were under-represented in PPMS cases from two independent patient cohorts (combined P=0.006, FE). The four known IL7R promoter haplotypes were shown to have similar expression levels in healthy controls, but not in CPMS (P<0.01, t test). These data support the hypothesis that PPMS has significant pathogenetic differences from SPMS, and that IL7R may be a useful therapeutic target in PPMS.

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References

  1. Robertson NP, O’Riordan JI, Chataway J, Kingsley DP, Miller DH, Clayton D, Compston DA (1997) Offspring recurrence rates and clinical characteristics of conjugal multiple sclerosis. Lancet 349(9065):1587–1590

    Article  PubMed  Google Scholar 

  2. Dyment DA, Ebers GC, Sadovnick AD (2004) Genetics of multiple sclerosis. Lancet Neurol 3(2):104–110

    Article  PubMed  Google Scholar 

  3. Compston A, Sawcer S (2002) Genetic analysis of multiple sclerosis. Curr Neurol Neurosci Rep 2(3):259–266

    PubMed  Google Scholar 

  4. Lock CB, Heller RA (2003) Gene microarray analysis of multiple sclerosis lesions. Trends Mol Med 9(12):535–541

    Article  PubMed  Google Scholar 

  5. Aune TM, Maas K, Parker J, Moore JH, Olsen NJ (2004) Profiles of gene expression in human autoimmune disease. Cell Biochem Biophys 40(2):81–96

    Article  Google Scholar 

  6. Sturzebecher S, Wandinger KP, Rosenwald A, Sathyamoorthy M, Tzou A, Mattar P, Frank JA, Staudt L, Martin R, McFarland HF (2003) Expression profiling identifies responder and non-responder phenotypes to interferon-beta in multiple sclerosis. Brain 126(Pt 6):1419–1429

    Article  PubMed  Google Scholar 

  7. 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, Oksenberg JR, Raine CS, Heller R, Steinman L (2002) Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med 8(5):500–508

    Article  PubMed  Google Scholar 

  8. Chabas D, Baranzini SE, Mitchell D, Bernard CC, Rittling SR, Denhardt DT, Sobel RA, Lock C, Karpuj M, Pedotti R, Heller R, Oksenberg JR, Steinman L (2001) The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 294(5547):1731–1735

    Article  PubMed  Google Scholar 

  9. Wandinger KP, Lunemann JD, Wengert O, Bellmann-Strobl J, Aktas O, Weber A, Grundstrom E, Ehrlich S, Wernecke KD, Volk HD, Zipp F (2003) TNF-related apoptosis inducing ligand (TRAIL) as a potential response marker for interferon-beta treatment in multiple sclerosis. Lancet 361(9374):2036–2043

    Article  PubMed  Google Scholar 

  10. Whitney AR, Diehn M, Popper SJ, Alizadeh AA, Boldrick JC, Relman DA, Brown PO (2003) Individuality and variation in gene expression patterns in human blood. Proc Natl Acad Sci U S A 100(4):1896–1901

    Article  PubMed  Google Scholar 

  11. Radich JP, Mao M, Stepaniants S, Biery M, Castle J, Ward T, Schimmack G, Kobayashi S, Carleton M, Lampe J, Linsley PS (2004) Individual-specific variation of gene expression in peripheral blood leukocytes. Genomics 83(6):980–988

    Article  PubMed  Google Scholar 

  12. McDonnell GV, Hawkins SA (2002) Primary progressive multiple sclerosis: increasing clarity but many unanswered questions. J Neurol Sci 199(1–2):1–15

    Article  PubMed  Google Scholar 

  13. Duran I, Martinez-Caceres EM, Rio J, Barbera N, Marzo ME, Montalban X (1999) Immunological profile of patients with primary progressive multiple sclerosis. Expression of adhesion molecules. Brain 122(Pt 12):2297–2307

    Article  PubMed  Google Scholar 

  14. Raghavan A, Ogilvie RL, Reilly C, Abelson ML, Raghavan S, Vasdewani J, Krathwohl M, Bohjanen PR (2002) Genome-wide analysis of mRNA decay in resting and activated primary human T lymphocytes. Nucleic Acids Res 30(24):5529–5538

    Article  PubMed  Google Scholar 

  15. Debey S, Schoenbeck U, Hellmich M, Gathof BS, Pillai R, Zander T, Schultze JL (2004) Comparison of different isolation techniques prior gene expression profiling of blood derived cells: impact on physiological responses, on overall expression and the role of different cell types. Pharmacogenomics J [Epub ahead of print]

    Google Scholar 

  16. Ban M, Sawcer SJ, Heard RN, Bennetts BH, Adams S, Booth D, Perich V, Setakis E, Compston A, Stewart GJ (2003) A genome-wide screen for linkage disequilibrium in Australian HLA-DRB1*1501 positive multiple sclerosis patients. J Neuroimmunol 143(1–2):60–64

    Article  PubMed  Google Scholar 

  17. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, Johnson KP, Sibley WA, Silberberg DH, Tourtellotte WW (1983) New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 13(3):227–231

    Article  PubMed  Google Scholar 

  18. Thompson AJ, Montalban X, Barkhof F, Brochet B, Filippi M, Miller DH, Polman CH, Stevenson VL, McDonald WI (2000) Diagnostic criteria for primary progressive multiple sclerosis: a position paper. Ann Neurol 47(6):831–835

    Article  PubMed  Google Scholar 

  19. Yang YH, Speed T (2002) Design issues for cDNA microarray experiments. Nat Rev Genet 3(8):579–588

    PubMed  Google Scholar 

  20. Tusher VG, Tibshirani R, Chu G (2001) Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci U S A 98(9):5116–5121

    Article  PubMed  Google Scholar 

  21. Beissbarth T, Speed T (2004) GOstat: find statistically overrepresented Gene Ontologies within a group of genes. Bioinformatics [Epub ahead of print]

  22. Teutsch SM, Booth DR, Bennetts BH, Heard RN, Stewart GJ (2003) Identification of 11 novel and common single nucleotide polymorphisms in the interleukin-7 receptor-alpha gene and their associations with multiple sclerosis. Eur J Hum Genet 11(7):509–515

    Article  PubMed  Google Scholar 

  23. Rubio JP, Bahlo M, Tubridy N, Stankovich J, Burfoot R, Butzkueven H, Chapman C, Johnson L, Marriott M, Mraz G, Tait B, Wilkinson C, Taylor B, Speed TP, Foote SJ, Kilpatrick TJ (2004) Extended haplotype analysis in the HLA complex reveals an increased frequency of the HFE-C282Y mutation in individuals with multiple sclerosis. Hum Genet 114(6):573–580

    Article  PubMed  Google Scholar 

  24. Whelan JA, Russell NB, Whelan MA (2003) A method for the absolute quantification of cDNA using real-time PCR. J Immunol Methods 278(1–2):261–269

    Article  PubMed  Google Scholar 

  25. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25(4):402–408

    Article  PubMed  Google Scholar 

  26. Korte A, Kochling J, Badiali L, Eckert C, Andreae J, Geilen W, Kebelmann-Betzing C, Taube T, Wu S, Henze G, Seeger K (2000) Expression analysis and characterization of alternatively spliced transcripts of human IL-7Ralpha chain encoding two truncated receptor proteins in relapsed childhood all. Cytokine 12(11):1597–1608

    Article  PubMed  Google Scholar 

  27. Yan H, Yuan W, Velculescu VE, Vogelstein B, Kinzler KW (2002) Allelic variation in human gene expression. Science 297(5584):1143

    Article  PubMed  Google Scholar 

  28. Whitney LW, Ludwin SK, McFarland HF, Biddison WE (2001) Microarray analysis of gene expression in multiple sclerosis and EAE identifies 5-lipoxygenase as a component of inflammatory lesions. J Neuroimmunol 121(1–2):40–48

    Article  PubMed  Google Scholar 

  29. English WR, Puente XS, Freije JM, Knauper V, Amour A, Merryweather A, Lopez-Otin C, Murphy G (2000) Membrane type 4 matrix metalloproteinase (MMP17) has tumor necrosis factor-alpha convertase activity but does not activate pro-MMP2. J Biol Chem 275(19):14046–14055

    Article  PubMed  Google Scholar 

  30. Grossman WJ, Verbsky JW, Barchet W, Colonna M, Atkinson JP, Ley TJ (2004) Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 21(4):589–601

    Article  PubMed  Google Scholar 

  31. Grewal R, Stepczynski J, Kelln R, Erickson T, Darrow R, Barsalou L, Patterson M, Organisciak DT, Wong P (2004) Coordinated changes in classes of ribosomal protein gene expression is associated with light-induced retinal degeneration. Investig Ophthalmol Vis Sci 45(11):3885–3895

    Article  Google Scholar 

  32. Xue HH, Bollenbacher J, Rovella V, Tripuraneni R, Du YB, Liu CY, Williams A, McCoy JP, Leonard WJ (2004) GA binding protein regulates interleukin 7 receptor alpha-chain gene expression in T cells. Nat Immunol 5(10):1036–1044

    Article  PubMed  Google Scholar 

  33. Ramanathan M, Weinstock-Guttman B, Nguyen LT, Badgett D, Miller C, Patrick K, Brownscheidle C, Jacobs L (2001) In vivo gene expression revealed by cDNA arrays: the pattern in relapsing–remitting multiple sclerosis patients compared with normal subjects. J Neuroimmunol 116(2):213–219

    Article  PubMed  Google Scholar 

  34. Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, Gilliet M, Ho S, Antonenko S, Lauerma A, Smith K, Gorman D, Zurawski S, Abrams J, Menon S, McClanahan T, de Waal-Malefyt R, Bazan F, Kastelein RA, Liu YJ (2002) Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 3(7):673–680

    PubMed  Google Scholar 

  35. Leung YF, Cavalieri D (2003) Fundamentals of cDNA microarray data analysis. Trends Genet 19(11):649–659

    Article  PubMed  Google Scholar 

  36. Leary SM, Miller DH, Stevenson VL, Brex PA, Chard DT, Thompson AJ (2003) Interferon beta-1a in primary progressive MS: an exploratory, randomized, controlled trial. Neurology 60(1):44–51

    PubMed  Google Scholar 

  37. Dalton CM, Miszkiel KA, Barker GJ, MacManus DG, Pepple TI, Panzara M, Yang M, Hulme A, O’Connor P, Miller DH (2004) Effect of natalizumab on conversion of gadolinium enhancing lesions to T1 hypointense lesions in relapsing multiple sclerosis. J Neurol 251(4):407–413

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank all those who contributed to the establishment of the Westmead MS DNA bank, Bruce Bennetts for useful discussions, Najwa Marmash for genotyping assistance and the patients and healthy controls who donated blood. This work was funded by a grant-in-aid from the Trish MS Research Foundation (2003), the Australian MS Society (2004) and Australian NHMRC project grant 153990. Ariel Arthur was supported by an Australian Postgraduate Award and The Nerve Foundation of the University of Sydney. Suzy Teutsch was supported by a Dora Lush NHMRC scholarship.

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Authors and Affiliations

  1. Institute for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Westmead, Australia

    D. R. Booth, S. M. Teutsch, C. Bye, R. N. S. Heard & G. J. Stewart

  2. Department of Medicine, University of Sydney, Sydney, Australia

    A. T. Arthur, P. J. Armati & J. D. Pollard

  3. University of Melbourne, Melbourne, Australia

    J. Rubio

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  1. D. R. Booth
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The Southern MS Genetics Consortium

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Correspondence to D. R. Booth.

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Members of the Southern MS Genetics Consortium: Justin Rubio, Trevor Kilpatrick, Helmut Butzkueven, Niall Tubridy, Mark Mariott, Caron Chapman, John Carey, Jo Baker, Laura Johnson, Rachel Tan, Simon Foote, Stewart Huxtable, Melanie Bahlo, Jim Stankovich, Terry Speed

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Booth, D.R., Arthur, A.T., Teutsch, S.M. et al. Gene expression and genotyping studies implicate the interleukin 7 receptor in the pathogenesis of primary progressive multiple sclerosis. J Mol Med 83, 822–830 (2005). https://doi.org/10.1007/s00109-005-0684-y

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  • DOI: https://doi.org/10.1007/s00109-005-0684-y

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