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Decreased systemic IL-7 and soluble IL-7Rα in multiple sclerosis patients

Genes & Immunity volume 13, pages 587–592 (2012)Cite this article

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Abstract

Polymorphisms (single-nucleotide polymorphism (SNP)) in the interleukin-7 receptor-α (IL-7Rα)/IL-7 pathway are associated with an increased risk to develop multiple sclerosis (MS). The rs6897932 SNP in the IL-7Rα leads to increased soluble IL-7Rα production. Given the functional interaction between sIL-7Rα, membrane-bound IL-7Rα and IL-7, we assessed IL-7, mIL-7Rα and sIL-7Rα levels in MS patients and healthy controls (HCs). One-hundred and twenty eight MS patients had significantly lower sIL-7Rα levels compared with 73 HCs. The levels of sIL-7Rα increased dose-dependent upon rs6897932 [C] risk allele carriership in both HCs and MS. Next, we hypothesized that lower sIL-7Rα could result in a higher mIL-7Rα to soluble IL-7Rα ratio. Indeed, 52 MS patients had significantly increased mIL-7Rα to sIL-7Rα ratio for both CD4 and CD8 T cells compared with 44 HCs. Given the supposed role of IL-7 in autoimmunity, we determined whether sIL-7Rα influences IL-7 levels. IL-7 levels were significantly decreased in 40 MS patients compared with 40 HCs. In conclusion, MS patients had lower free IL-7 and a higher membrane to soluble IL-7Rα ratio. The soluble IL-7Rα levels correlate with the rs6897932 [C] risk allele carriership. The skew at the IL-7 and IL-7Rα level may influence responsiveness of IL-7Rα+ cells.

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References

  1. 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  CAS  Google Scholar 

  2. Lundmark F, Duvefelt K, Iacobaeus E, Kockum I, Wallstrom 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 

  3. 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 

  4. 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 

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

    Article  CAS  Google Scholar 

  6. O’Doherty C, Alloza I, Rooney M, Vandenbroeck K . IL7RA polymorphisms and chronic inflammatory arthropathies. Tissue Antigen 2009; 74: 429–431.

    Article  Google Scholar 

  7. Concannon P, Rich SS, Nepom GT . Genetics of type 1A diabetes. N Engl J Med 2009; 360: 1646–1654.

    Article  CAS  Google Scholar 

  8. Hartgring SA, van Roon JA, Wenting-van Wijk M, Jacobs KM, 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 

  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. Haas J, Korporal M, Schwarz A, Balint B, Wildemann B . The interleukin-7 receptor alpha chain contributes to altered homeostasis of regulatory T cells in multiple sclerosis. Eur J Immunol 2011; 41: 845–853.

    Article  CAS  Google Scholar 

  11. Hare KJ, Jenkinson EJ, Anderson G . An essential role for the IL-7 receptor during intrathymic expansion of the positively selected neonatal T cell repertoire. J Immunol 2000; 165: 2410–2414.

    Article  CAS  Google Scholar 

  12. Hug A, Korporal M, Schroder I, Haas J, Glatz K, Storch-Hagenlocher B et al. Thymic export function and T cell homeostasis in patients with relapsing remitting multiple sclerosis. J Immunol 2003; 171: 432–437.

    Article  CAS  Google Scholar 

  13. Mazzucchelli R, Hixon JA, Spolski R, Chen X, Li WQ, Hall VL et al. Development of regulatory T cells requires IL-7Ralpha stimulation by IL-7 or TSLP. Blood 2008; 112: 3283–3292.

    Article  CAS  Google Scholar 

  14. Rose T, Lambotte O, Pallier C, Delfraissy JF, Colle JH . 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 

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

    Article  CAS  Google Scholar 

  16. Kreft KL, Verbraak E, Wierenga-Wolf AF, van Meurs M, Oostra BA, Laman JD et al. The IL-7Ralpha pathway is quantitatively and functionally altered in CD8 T cells in multiple sclerosis. J Immunol 2012; 188: 1874–1883.

    Article  CAS  Google Scholar 

  17. Halwani R, Doroudchi M, Yassine-Diab B, Janbazian L, Shi Y, Said EA et al. Generation and maintenance of human memory cells during viral infection. Springer Semin Immunopathol 2006; 28: 197–208.

    Article  Google Scholar 

  18. Kaneko S, Mastaglio S, Bondanza A, Ponzoni M, Sanvito F, Aldrighetti L et al. IL-7 and IL-15 allow the generation of suicide gene-modified alloreactive self-renewing central memory human T lymphocytes. Blood 2009; 113: 1006–1015.

    Article  CAS  Google Scholar 

  19. Kremlev SG, Gaurnier-Hausser AL, Del Valle L, Perez-Liz G, Dimitrov S, Tuszynski G . Angiocidin promotes pro-inflammatory cytokine production and antigen presentation in multiple sclerosis. J Neuroimmunol 2008; 194: 132–142.

    Article  CAS  Google Scholar 

  20. Sawa S, Kamimura D, Jin GH, Morikawa H, Kamon H, Nishihara M et al. Autoimmune arthritis associated with mutated interleukin (IL)-6 receptor gp130 is driven by STAT3/IL-7-dependent homeostatic proliferation of CD4+ T cells. J Exp Med 2006; 203: 1459–1470.

    Article  CAS  Google Scholar 

  21. Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the ‘McDonald Criteria’. Ann Neurol 2005; 58: 840–846.

    Article  Google Scholar 

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Acknowledgements

We would like to thank Marvin van Luijn (MSc) for critically reading the manuscript and Sandra de Bruin-Versteeg for editorial assistance with the figures. This work was supported by the MS Research Foundation, The Netherlands with an academic grant (07–630 MS).

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Authors and Affiliations

  1. Department of Neurology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

    K L Kreft & R Q Hintzen

  2. Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

    K L Kreft, E Verbraak, A F Wierenga-Wolf, M van Meurs & J D Laman

  3. MS Centre ErasMS, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

    K L Kreft, E Verbraak, A F Wierenga-Wolf, M van Meurs, J D Laman & R Q Hintzen

  4. Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

    B A Oostra

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  1. K L Kreft
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Correspondence to R Q Hintzen.

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Kreft, K., Verbraak, E., Wierenga-Wolf, A. et al. Decreased systemic IL-7 and soluble IL-7Rα in multiple sclerosis patients. Genes Immun 13, 587–592 (2012). https://doi.org/10.1038/gene.2012.34

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