Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Full Paper
  • Published:

Promoter haplotypes of the interleukin-10 gene influence proliferation of peripheral blood cells in response to helminth antigen

Genes & Immunity volume 5, pages 256–260 (2004)Cite this article

Abstract

Since interleukin (IL)-10 is a key mediator of immunosuppression, and immunosuppression is considered an important element of helminth infection, we studied variants of the putative IL-10 gene promoter in 337 individuals from 130 families heavily exposed to infection by the tissue nematode Onchocerca volvulus. As shown by transmission disequilibrium tests, variants of the IL-10 promoter at positions –1082(G/A), –819(C/T), and –592(C/A) in the haplotype of ATA were significantly associated with high peripheral blood cell (PBC) proliferative responses to O. volvulus antigen (OvAg). No associations were observed using phytohemagglutinin-induced PBC proliferation or with qualitative or quantitative phenotypes of onchocerciasis or onchocerciasis-related skin disease. The findings are compatible with the hypothesis that the ATA haplotype causes a decrease in IL-10 production by OvAg-reactive type-1 regulatory T-lymphocytes, thereby alleviating the suppression of other T cells. To our knowledge, this is the first time that an influence of IL-10 promoter variants is shown on the adaptive immune response.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A . Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001; 19: 683–765.

    Article  CAS  PubMed  Google Scholar 

  2. Mahanty S, Mollis SN, Ravichandran M et al. High levels spontaneous and parasite antigen-driven interleukin-10 production are associated with antigen-specific hyporesponsiveness in human lymphatic filariasis. J Infect Dis 1996; 173: 769–773.

    Article  CAS  PubMed  Google Scholar 

  3. Plebanski M, Flanagan KL, Lee EA et al. Interleukin 10-mediated immunosuppression by a variant CD4T cell epitope of Plasmodium falciparum. Immunity 1999; 10: 651–660.

    Article  CAS  PubMed  Google Scholar 

  4. King CL, Mahanty S, Kumaraswami V et al. Cytokine control of parasite-specific anergy in human lymphatic filariasis. Preferential induction of a regulatory T helper type 2 lymphocyte subset. J Clin Invest 1993; 92: 1667–1673.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Osborne J, Devaney E . Interleukin-10 and antigen-presenting cells actively suppress Th1 cells in BALB/c mice infected with the filarial parasite Brugia pahangi. Infect Immun 1999; 67: 1599–1605.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Hoffmann WH, Pfaff AW, Schulz-Key H, Soboslay PT, Soboslav PT . Determinants for resistance and susceptibility to microfilaraemia in Litomosoides sigmodontis filariasis. Parasitology 2001; 122: 641–649.

    Article  CAS  PubMed  Google Scholar 

  7. Namangala B, Noel W, De Baetselier P, Brys L, Beschin A . Relative contribution of interferon-gamma and interleukin-10 to resistance to murine African trypanosomosis. J Infect Dis 2001; 183: 1794–1800.

    Article  CAS  PubMed  Google Scholar 

  8. Li C, Corraliza I, Langhorne J . A defect in interleukin-10 leads to enhanced malarial disease in Plasmodium chabaudi chabaudi infection in mice. Infect Immun 1999; 67: 4435–4442.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W . Interleukin-10-deficient mice develop chronic enterocolitis. Cell 1993; 75: 263–274.

    Article  CAS  PubMed  Google Scholar 

  10. Westendorp RG, Langermans JA, Huizinga TW et al. Genetic influence on cytokine production and fatal meningococcal disease. Lancet 1997; 349: 170–173.

    Article  CAS  PubMed  Google Scholar 

  11. Eskdale J, Gallagher G, Verweij CL, Keijsers V, Westendorp RG, Huizinga TW . Interleukin 10 secretion in relation to human IL-10 locus haplotypes. Proc Natl Acad Sci USA 1998; 95: 9465–9470.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. de Jong BA, Westendorp RG, Eskdale J, Uitdehaag BM, Huizinga TW . Frequency of functional interleukin-10 promoter polymorphism is different between relapse-onset and primary progressive multiple sclerosis. Hum Immunol 2002; 63: 281–285.

    Article  CAS  PubMed  Google Scholar 

  13. Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV . An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet 1997; 24: 1–8.

    Article  CAS  PubMed  Google Scholar 

  14. Crawley E, Kay R, Sillibourne J, Patel P, Hutchinson I, Woo P . Polymorphic haplotypes of the interleukin-10 5' flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis. Arthritis Rheum 1999; 42: 1101–1108.

    Article  CAS  PubMed  Google Scholar 

  15. Koss K, Satsangi J, Fanning GC, Welsh KI, Jewell DP . Cytokine (TNF alpha, LT alpha and IL-10) polymorphisms in inflammatory bowel diseases and normal controls: differential effects on production and allele frequencies. Genes Immun 2000; 1: 185–190.

    Article  CAS  PubMed  Google Scholar 

  16. Lowe PR, Galley HF, Abdel-Fattah A, Webster NR . Influence of interleukin-10 polymorphisms on interleukin-10 expression and survival in critically ill patients. Crit Care Med 2003; 31: 34–38.

    Article  CAS  PubMed  Google Scholar 

  17. Gibson AW, Edberg JC, Wu J, Westendorp RG, Huizinga TW, Kimberly RP . Novel single nucleotide polymorphisms in the distal IL-10 promoter affect IL-10 production and enhance the risk of systemic lupus erythematosus. J Immunol 2001; 166: 3915–3922.

    Article  CAS  PubMed  Google Scholar 

  18. Kaluza W, Leirisalo-Repo M, Marker-Hermann E et al. IL10.G microsatellites mark promoter haplotypes associated with protection against the development of reactive arthritis in Finnish patients. Arthritis Rheum 2001; 44: 1209–1214.

    Article  CAS  PubMed  Google Scholar 

  19. Craven NM, Jackson CW, Kirby B et al. Cytokine gene polymorphisms in psoriasis. Br J Dermatol 2001; 144: 849–853.

    Article  CAS  PubMed  Google Scholar 

  20. Hulkkonen J, Pertovaara M, Antonen J, Lahdenpohja N, Pasternack A, Hurme M . Genetic association between interleukin-10 promoter region polymorphisms and primary Sjogren's syndrome. Arthritis Rheum 2001; 44: 176–179.

    Article  CAS  PubMed  Google Scholar 

  21. Hoerauf A, Brattig N . Resistance and susceptibility in human onchocerciasis—beyond Th1 vs Th2. Trends Parasitol 2002; 18: 25–31.

    Article  CAS  PubMed  Google Scholar 

  22. Timmann C, Abraha RS, Hamelmann C et al. Cutaneous pathology in onchocerciasis associated with pronounced systemic T-helper 2-type responses to Onchocerca volvulus. Br J Dermatol 2003; 149: 782–787.

    Article  CAS  PubMed  Google Scholar 

  23. Doetze A, Satoguina J, Burchard G et al. Antigen-specific cellular hyporesponsiveness in a chronic human helminth infection is mediated by T(h)3/T(r)1-type cytokines IL-10 and transforming growth factor-beta but not by a T(h)1 to T(h)2 shift. Int Immunol 2000; 12: 623–630.

    Article  CAS  PubMed  Google Scholar 

  24. Bloemena E, Roos MT, Van Heijst JL, Vossen JM, Schellekens PT . Whole-blood lymphocyte cultures. J Immunol Methods 1989; 122: 161–167.

    Article  CAS  PubMed  Google Scholar 

  25. Fleischer B . Activation of human T lymphocytes II. Involvement of the T3 antigen in polyclonal T cell activation by mitogenic lectins and oxidation. Eur J Immunol 1984; 14: 748–752.

    Article  CAS  PubMed  Google Scholar 

  26. Brattig NW, Lepping B, Timmann C et al. Onchocerca volvulus-exposed persons fail to produce interferon-gamma in response to O. volvulus antigen but mount proliferative responses with interleukin-5 and IL-13 production that decrease with increasing microfilarial density. J Infect Dis 2002; 185: 1148–1154.

    Article  CAS  PubMed  Google Scholar 

  27. Huang L, Krieg AM, Eller N, Scott DE . Induction and regulation of Th1-inducing cytokines by bacterial DNA, lipopolysaccharide, and heat-inactivated bacteria. Infect Immun 1999; 67: 6257–6263.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Reuss E, Fimmers R, Kruger A, Becker C, Rittner C, Hohler T . Differential regulation of interleukin-10 production by genetic and environmental factors—a twin study. Genes Immun 2002; 3: 407–413.

    Article  CAS  PubMed  Google Scholar 

  29. Satoguina J, Mempel M, Larbi J et al. Antigen-specific T regulatory-1 cells are associated with immunosuppression in a chronic helminth infection (onchocerciasis). Microbes Infect 2002; 4: 1291–1300.

    Article  CAS  PubMed  Google Scholar 

  30. Conti P, Kempuraj D, Frydas S et al. IL-10 subfamily members: IL-19, IL-20, IL-22, IL-24 and IL-26. Immunol Lett 2003; 88: 171–174.

    Article  CAS  PubMed  Google Scholar 

  31. WHO Expert Committee on Onchocerciasis. Third report. World Health Organ Tech Rep Ser 1987; 752: 1–167.

  32. Murdoch ME, Hay RJ, Mackenzie CD et al. A clinical classification and grading system of the cutaneous changes in onchocerciasis. Br J Dermatol 1993; 129: 260–269.

    Article  CAS  PubMed  Google Scholar 

  33. Abecasis GR, Cookson WO . GOLD—graphical overview of linkage disequilibrium. Bioinformatics 2000; 16: 182–183.

    Article  CAS  PubMed  Google Scholar 

  34. Kruglyak L, Lander ES . Complete multipoint sib-pair analysis of qualitative and quantitative traits. Am J Hum Genet 1995; 57: 439–454.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Abecasis GR, Cardon LR, Cookson WO . A general test of association for quantitative traits in nuclear families. Am J Hum Genet 2000; 66: 279–292.

    Article  CAS  PubMed  Google Scholar 

  36. McIntyre LM, Martin ER, Simonsen KL, Kaplan NL . Circumventing multiple testing: a multilocus Monte Carlo approach to testing for association. Genet Epidemiol 2000; 19: 18–29.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The study was supported by the Deutsche Forschungsgemeinschaft (HO 866/4-1) and the Volkswagen Foundation, Germany. This work is part of the doctoral thesis of CT at the Faculty of Medicine, University of Hamburg, Germany.

Author information

Author notes

  1. S Fuchs

    Present address: Institute for Human Genetics, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

  2. C Thoma

    Present address: Bundeswehrzentralkrankenhaus, Koblenz, Germany

  3. B Müller-Myhsok

    Present address: Computational Genetics Group, Max-Planck-Institute of Psychiatry, Munich, Germany

Authors and Affiliations

  1. Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany

    C Timmann, S Fuchs, C Thoma, B Lepping, N W Brattig, J Sievertsen, T Thye, B Müller-Myhsok & R D Horstmann

Authors
  1. C Timmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Fuchs
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C Thoma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B Lepping
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. N W Brattig
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Sievertsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T Thye
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. B Müller-Myhsok
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. R D Horstmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C Timmann.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Timmann, C., Fuchs, S., Thoma, C. et al. Promoter haplotypes of the interleukin-10 gene influence proliferation of peripheral blood cells in response to helminth antigen. Genes Immun 5, 256–260 (2004). https://doi.org/10.1038/sj.gene.6364094

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6364094

Keywords

This article is cited by

Search

Advanced search

Quick links