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IL7RA haplotype-associated alterations in cellular immune function and gene expression patterns in multiple sclerosis

Genes & Immunity volume 14, pages 453–461 (2013)Cite this article

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Abstract

Interleukin-7 receptor alpha (IL7RA) is among the top listed candidate genes influencing the risk to develop multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system. Soluble IL-7RA (sIL-7RA) protein and mRNA levels vary among the four common IL7RA haplotypes. Here we show and confirm that protective haplotype carriers have three times lower sIL-7RA serum levels than the other three haplotypes. High sIL-7RA concentrations significantly decrease IL-7-mediated STAT5 phosphorylation in CD4+ T cells. Transcriptome analysis of unstimulated and stimulated CD4+ T cells of MS patients carrying the different IL7RA haplotypes revealed complex and overlapping patterns in genes participating in cytokine signaling networks, apoptosis, cell cycle progression and cell differentiation. Our findings indicate that genetic variants of IL7RA result in haplotype-associated differential responsiveness to immunological stimuli that influence MS susceptibility not exclusively by varying levels of sIL-7RA.

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References

  1. Sospedra M, Martin R . Immunology of multiple sclerosis. Annu Rev Immunol 2005; 23: 683–747.

    Article  CAS  Google Scholar 

  2. Oksenberg JR, Baranzini SE, Sawcer S, Hauser SL . The genetics of multiple sclerosis: SNPs to pathways to pathogenesis. Nat Rev Genet 2008; 9: 516–526.

    Article  CAS  Google Scholar 

  3. Olerup O, Hillert J . HLA class II-associated genetic susceptibility in multiple sclerosis: a critical evaluation. Tissue Antigens 1991; 38: 1–15.

    Article  CAS  Google Scholar 

  4. Kemppinen A, Sawcer S, Compston A . Genome-wide association studies in multiple sclerosis: lessons and future prospects. Brief Funct Genomics 2011; 10: 61–70.

    Article  CAS  Google Scholar 

  5. Sawcer S, Hellenthal G, Pirinen M, Spencer CCa, Patsopoulos Na, Moutsianas L et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011; 476: 214–219.

    Article  CAS  Google Scholar 

  6. Lundmark F, Duvefelt K, Iacobaeus E, Kockum I, Wallström E, Khademi M et al. Variation in interleukin 7 receptor alpha chain (IL7R) influences risk of multiple sclerosis. Nat Genet 2007; 39: 1108–1113.

    Article  CAS  Google Scholar 

  7. Gregory SG, Schmidt S, Seth P, Oksenberg JR, Hart J, Prokop A et al. Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genet 2007; 39: 1083–1091.

    Article  CAS  Google Scholar 

  8. The International Multiple Sclerosis Genetics Consortium. Hafler DA, Compston A, Sawcer S, Lander ES, Daly MJ, De Jager PL et al. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 2007; 357: 851–862.

    Article  Google Scholar 

  9. Hoe E, McKay FC, Schibeci SD, Gandhi K, Heard RN, Stewart GJ et al. Functionally significant differences in expression of disease-associated IL-7 receptor alpha haplotypes in CD4 T cells and dendritic cells. J Immunol 2010; 184: 2512–2517.

    Article  CAS  Google Scholar 

  10. McKay FC, Swain LI, Schibeci SD, Rubio JP, Kilpatrick TJ, Heard RN et al. Haplotypes of the interleukin 7 receptor alpha gene are correlated with altered expression in whole blood cells in multiple sclerosis. Genes Immun 2008; 9: 1–6.

    Article  CAS  Google Scholar 

  11. Broux B, Hellings N, Venken K, Rummens J-L, Hensen K, Van Wijmeersch B et al. Haplotype 4 of the multiple sclerosis-associated interleukin-7 receptor alpha gene influences the frequency of recent thymic emigrants. Genes Immun 2010; 11: 326–333.

    Article  CAS  Google Scholar 

  12. Hoe E, McKay F, Schibeci S, Heard R, Stewart G, Booth D . Interleukin 7 receptor alpha chain haplotypes vary in their influence on multiple sclerosis susceptibility and response to interferon Beta. J Interferon Cytokine Res 2010; 30: 291–298.

    Article  CAS  Google Scholar 

  13. Plum J, De Smedt M, Leclercq G, Verhasselt B, Vandekerckhove B . Interleukin-7 is a critical growth factor in early human T-cell development. Blood 1996; 88: 4239–4245.

    CAS  PubMed  Google Scholar 

  14. Zuvich RL, McCauley JL, Oksenberg JR, Sawcer SJ, De Jager PL, Aubin C et al. Genetic variation in the IL7RA/IL7 pathway increases multiple sclerosis susceptibility. Hum Genet 2010; 127: 525–535.

    Article  CAS  Google Scholar 

  15. Mackall CL, Fry TJ, Gress RE . Harnessing the biology of IL-7 for therapeutic application. Nat Rev Immunol 2011; 11: 330–342.

    Article  CAS  Google Scholar 

  16. Palmer MJ, Mahajan VS, Trajman LC, Irvine DJ, Lauffenburger Da, Chen J . Interleukin-7 receptor signaling network: an integrated systems perspective. Cell Mol Immunol 2008; 5: 79–89.

    Article  CAS  Google Scholar 

  17. Sorg RV, McLellan AD, Hock BD, Fearnley DB, Hart DN . Human dendritic cells express functional interleukin-7. Immunobiology 1998; 198: 514–526.

    Article  CAS  Google Scholar 

  18. Mazzucchelli R, Durum SK . Interleukin-7 receptor expression: intelligent design. Nat Rev Immunol 2007; 7: 144–154.

    Article  CAS  Google Scholar 

  19. Rochman Y, Spolski R, Leonard WJ . New insights into the regulation of T cells by gamma(c) family cytokines. Nat Rev Immunol 2009; 9: 480–490.

    Article  CAS  Google Scholar 

  20. Van Roon JAG, Glaudemans KAFM, Bijlsma JWJ, Lafeber FPJG . Interleukin 7 stimulates tumour necrosis factor alpha and Th1 cytokine production in joints of patients with rheumatoid arthritis. Ann Rheum Dis 2003; 62: 113–119.

    Article  CAS  Google Scholar 

  21. Hartgring SaY, Van Roon JaG, Wenting-van Wijk M, Jacobs KMG, Jahangier ZN, Willis CR et al. Elevated expression of interleukin-7 receptor in inflamed joints mediates interleukin-7-induced immune activation in rheumatoid arthritis. Arthritis Rheum 2009; 60: 2595–2605.

    Article  CAS  Google Scholar 

  22. Lee L-F, Axtell R, Tu GH, Logronio K, Dilley J, Yu J et al. IL-7 promotes TH1 development and serum IL-7 predicts clinical response to interferon-β in multiple sclerosis. Sci Transl Med 2011; 3: 93ra68–93ra68.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Ashbaugh JJ, Brambilla R, Karmally Sa, Cabello C, Malek TR, Bethea JR . IL7Rα contributes to experimental autoimmune encephalomyelitis through altered T cell responses and nonhematopoietic cell lineages. J Immunol 2013; 190: 4525–4534.

    Article  CAS  Google Scholar 

  24. Hartgring SAY, Willis CR, Alcorn D, Nelson LJ, Bijlsma JWJ, Lafeber FPJG et al. Blockade of the interleukin-7 receptor inhibits collagen-induced arthritis and is associated with reduction of T cell activity and proinflammatory mediators. Arthritis Rheum 2010; 62: 2716–2725.

    Article  CAS  Google Scholar 

  25. Pellegrini M, Calzascia T, Toe JG, Preston SP, Lin AE, Elford AR et al. IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology. Cell 2011; 144: 601–613.

    Article  CAS  Google Scholar 

  26. Weber F, Fontaine B, Cournu-Rebeix I, Kroner a, Knop M, Lutz S et al. IL2RA and IL7RA genes confer susceptibility for multiple sclerosis in two independent European populations. Genes Immun 2008; 9: 259–263.

    Article  CAS  Google Scholar 

  27. Goodwin RG, Friend D, Ziegler SF, Jerzy R, Falk Ba, Gimpel S et al. Cloning of the human and murine interleukin-7 receptors: demonstration of a soluble form and homology to a new receptor superfamily. Cell 1990; 60: 941–951.

    Article  CAS  Google Scholar 

  28. Crawley AM, Faucher S, Angel JB . Soluble IL-7 R alpha (sCD127) inhibits IL-7 activity and is increased in HIV infection. J Immunol 2010; 184: 4679–4687.

    Article  CAS  Google Scholar 

  29. Blom-Potar M-C, Bugault F, Lambotte O, Delfraissy J-F, Thèze J . Soluble IL-7Ralpha (sCD127) and measurement of IL-7 in the plasma of HIV patients. J Acquir Immune Defic Syndr 2009; 51: 104–105.

    Article  Google Scholar 

  30. Rose T, Lambotte O, Pallier C, Delfraissy J-F, Colle J-H . Identification and biochemical characterization of human plasma soluble IL-7R: lower concentrations in HIV-1-infected patients. J Immunol 2009; 182: 7389–7397.

    Article  CAS  Google Scholar 

  31. Zhu B, Kang K, Yu J, Chen W . Genome-wide analyses reveal the extent of opportunistic STAT5 binding that does not yield transcriptional activation of neighboring genes. Nucleic Acids Res 2012; 40: 4461–4472.

    Article  CAS  Google Scholar 

  32. Carrette F, Surh CD . IL-7 signaling and CD127 receptor regulation in the control of T cell homeostasis. Semin Immunol 2012; 24: 209–217.

    Article  CAS  Google Scholar 

  33. Lee L, Logronio K, Tu GH, Zhai W, Ni I, Mei L et al. Anti-IL-7 receptor-α reverses established type 1 diabetes in nonobese diabetic mice by modulating effector T-cell function. Proc Natl Acad Sci USA 2012; 109: 12674–12679.

    Article  CAS  Google Scholar 

  34. Willis CR, Seamons A, Maxwell J, Treuting PM, Nelson L, Chen G et al. Interleukin-7 receptor blockade suppresses adaptive and innate inflammatory responses in experimental colitis. J Inflamm 2012; 9: 39.

    Article  CAS  Google Scholar 

  35. Kittipatarin C, Khaled AR . Interlinking interleukin-7. Cytokine 2007; 39: 75–83.

    Article  CAS  Google Scholar 

  36. Perales M-A, Goldberg JD, Yuan J, Koehne G, Lechner L, Papadopoulos EB et al. Recombinant human interleukin-7 (CYT107) promotes T-cell recovery after allogeneic stem cell transplantation. Blood 2012; 120: 4882–4891.

    Article  CAS  Google Scholar 

  37. Wandinger K, Jabs W, Siekhaus A, Bubel S, Trillenberg P, Wagner H et al. Association between clinical disease activity and Epstein-Barr virus reactivation in MS. Neurology 2000; 55: 178–184.

    Article  CAS  Google Scholar 

  38. Limou S, Melica G, Coulonges C, Lelièvre J-D, Do H, McGinn S et al. Identification of IL7RA risk alleles for rapid progression during HIV-1 infection: a comprehensive study in the GRIV cohort. Curr HIV Res 2012; 10: 143–150.

    Article  CAS  Google Scholar 

  39. Colonna M, Jonjic S, Watzl C . Natural killer cells: fighting viruses and much more. Nat Immunol 2011; 12: 107–110.

    Article  CAS  Google Scholar 

  40. Bielekova B, Richert N, Howard T, Blevins G, Markovic-Plese S, McCartin J et al. Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon beta. Proc Natl Acad Sci USA 2004; 101: 8705–8708.

    Article  CAS  Google Scholar 

  41. Munschauer FE, Hartrich LA, Stewart CC, Jacobs L . Circulating natural killer cells but not cytotoxic T lymphocytes are reduced in patients with active relapsing multiple sclerosis and little clinical disability as compared to controls. J Neuroimmunol 1995; 62: 177–181.

    Article  CAS  Google Scholar 

  42. Bielekova B, Catalfamo M . Regulatory CD56 (bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis. Proc Natl Acad Sci USA 2006; 103: 5941–5946.

    Article  CAS  Google Scholar 

  43. Gregory AP, Dendrou Ca, Attfield KE, Haghikia A, Xifara DK, Butter F et al. TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis. Nature 2012; 488: 508–511.

    Article  CAS  Google Scholar 

  44. Lundström W, Highfill S, Walsh STR, Beq S, Morse E, Kockum I et al. Soluble IL7Rα potentiates IL-7 bioactivity and promotes autoimmunity. Proc Natl Acad Sci USA 2013; 110: E1761–E1770.

    Article  Google Scholar 

  45. Kappos L, Antel J, Comi G, Montalban X, O′Connor P, Polman CH et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 2006; 355: 1124–1140.

    Article  CAS  Google Scholar 

  46. Hendrickson SL, Lautenberger JA, Chinn LW, Malasky M, Sezgin E, Kingsley LA et al. Genetic variants in nuclear-encoded mitochondrial genes influence AIDS progression. PLoS ONE 2010; 5: 8.

    Article  Google Scholar 

  47. Campbell GR, Ohno N, Turnbull DM, Mahad DJ . Mitochondrial changes within axons in multiple sclerosis: an update. Curr Opin Neurol 2012; 25: 221–230.

    Article  CAS  Google Scholar 

  48. Michaelson MD, Mehler MF, Xu H, Gross RE, Kessler Ja . Interleukin-7 is trophic for embryonic neurons and is expressed in developing brain. Dev Biol 1996; 179: 251–263.

    Article  CAS  Google Scholar 

  49. Barrette B, Calvo E, Vallières N, Lacroix S . Transcriptional profiling of the injured sciatic nerve of mice carrying the Wld(S) mutant gene: identification of genes involved in neuroprotection, neuroinflammation, and nerve regeneration. Brain Behav Immun 2010; 24: 1254–1267.

    Article  CAS  Google Scholar 

  50. McDonald WI, Compston a, Edan G, Goodkin D, Hartung HP, Lublin FD et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50: 121–127.

    Article  CAS  Google Scholar 

  51. Barrett J, Fry B, Maller J, Daly M . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.

    Article  CAS  Google Scholar 

  52. Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 2004; 5: R80.

    Article  Google Scholar 

  53. Brunet J-P, Tamayo P, Golub TR, Mesirov JP . Metagenes and molecular pattern discovery using matrix factorization. Proc Natl Acad Sci USA 2004; 101: 4164–4169.

    Article  CAS  Google Scholar 

  54. Gaujoux R, Seoighe C . A flexible R package for nonnegative matrix factorization. BMC Bioinformatics 2010; 11: 367.

    Article  Google Scholar 

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Acknowledgements

We thank Dr T Eiermann and Dr T Binder, Department of Transfusion Medicine, University Medical Centre Hamburg-Eppendorf, for generous supply of HD DNA samples and Brenda Reinhart, PhD, Neuroimmunology and MS Research, and Michal Okoniewski, PhD, Neuroimmunology and MS Research and Functional Genomics Center Zurich for helpful comments and carefully reading the manuscript. Funding The Institute for Neuroimmunology and Clinical Multiple Sclerosis Research (inims) was supported by a 5-year grant of the Gemeinnützige Hertie Stiftung; this project was supported by the Deutsche Forschungsgemeinschaft (MA 965/9-1). The Section of Neuroimmunology and MS Research was supported by the Clinical Research Priority Program MS (CRPPMS) of the University Zurich.

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  1. J Jäger and C Schulze: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute for Neuroimmunology and Clinical Multiple Sclerosis Research (inims), Centre for Molecular Neurobiology Hamburg (ZMNH), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

    J Jäger, S Rösner & R Martin

  2. Systems Biology, Centre for Molecular Neurobiology Hamburg (ZMNH), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

    C Schulze

  3. Department of Neurology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

    S Rösner

  4. Department of Neurology, Neuroimmunology and Multiple Sclerosis Research, University Hospital Zurich, University of Zurich, Zurich, Switzerland

    R Martin

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Correspondence to R Martin.

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Competing interests

R. Martin is coinventor on a patent for the combined use of recombinant IL-7 and vaccination with JC polyoma virus capsid protein VP1 to treat progressive multifocal leukoencephalopathy. The remaining authors declare no conflict of interest.

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Jäger, J., Schulze, C., Rösner, S. et al. IL7RA haplotype-associated alterations in cellular immune function and gene expression patterns in multiple sclerosis. Genes Immun 14, 453–461 (2013). https://doi.org/10.1038/gene.2013.40

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