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Regulatory T-Cell Function Is Impaired in Celiac Disease

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Abstract

Celiac disease (CD) is characterized by intolerance to gluten and high risk of developing autoimmune phenomena. Possible defects in immune tolerance could have a role in the pathogenesis of the disease. As regulatory T-cells (Tregs) are the main population involved in maintaining peripheral tolerance, we investigated the number of these cells in celiac patients as compared with healthy donors. Moreover, we analyzed the suppressive function of CD4+CD25+ T-cells from celiac disease patients and controls on autologous responder T-cells (CD4+CD25−). The percentage of CD4+CD25+FOXP3+ cells was not different in celiacs and in healthy controls, and among positive cells the level of expression of the two regulatory markers was comparable. However, the suppressor activity of Tregs was significantly impaired in CD patients. These results suggest that a defect in Tregs function could play a role in the pathogenesis of CD and in CD-associated autoimmunity.

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References

  1. Schuppan D. Current concepts of celiac disease pathogenesis. Gastroenterology. 2000;119:234–242. doi:10.1053/gast.2000.8521.

    Article  PubMed  CAS  Google Scholar 

  2. Auricchio S, Troncone R, Maurano F. Coeliac disease in the year 2000. Ital J Gastroenterol Hepatol. 1999;31:773–780.

    PubMed  CAS  Google Scholar 

  3. Green PH, Cellier C. Celiac disease. N Engl J Med. 2007;357:1731–1743. doi:10.1056/NEJMra071600.

    Article  PubMed  CAS  Google Scholar 

  4. Green FH, Carty JE. Letter: coeliac disease and autoimmunity. Lancet. 1976;1:964. doi:10.1016/S0140-6736(76)92742-2.

    Article  PubMed  CAS  Google Scholar 

  5. Collin P, Maki M. Associated disorders in coeliac disease: clinical aspects. Scand J Gastroenterol. 1994;29:769–775. doi:10.3109/00365529409092508.

    Article  PubMed  CAS  Google Scholar 

  6. Ventura A, Magazzu G, Greco L. Duration of exposure to gluten and risk for autoimmune disorders in patients with celiac disease. Sigep study group for autoimmune disorders in celiac disease. Gastroenterology. 1999;117:297–303. doi:10.1053/gast.1999.0029900297.

    Article  PubMed  CAS  Google Scholar 

  7. Not T, Tommasini A, Tonini G, et al. Undiagnosed coeliac disease and risk of autoimmune disorders in subjects with type i diabetes mellitus. Diabetologia. 2001;44:151–155. doi:10.1007/s001250051593.

    Article  PubMed  CAS  Google Scholar 

  8. Barker JM. Clinical review: type 1 diabetes-associated autoimmunity: natural history, genetic associations, and screening. J Clin Endocrinol Metab. 2006;91:1210–1217. doi:10.1210/jc.2005-1679.

    Article  PubMed  CAS  Google Scholar 

  9. Aaltonen J, Björses P, Perheentupa J, et al. An autoimmune disease, apeced, caused by mutations in a novel gene featuring two phd-type zinc-finger domains. Nat Genet. 1997;17:399–403. doi:10.1038/ng1297-399.

    Article  Google Scholar 

  10. Anderson MS, Venanzi ES, Klein L, et al. Projection of an immunological self shadow within the thymus by the aire protein. Science. 2002;298:1395–1401. doi:10.1126/science.1075958.

    Article  PubMed  CAS  Google Scholar 

  11. Bennett CL, Christie J, Ramsdell F, et al. The immune dysregulation, polyendocrinopathy, enteropathy, x-linked syndrome (ipex) is caused by mutations of foxp3. Nat Genet. 2001;27:20–21. doi:10.1038/83713.

    Article  PubMed  CAS  Google Scholar 

  12. Wildin RS, Ramsdell F, Peake J, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet. 2001;27:18–20. doi:10.1038/83707.

    Article  PubMed  CAS  Google Scholar 

  13. Kriegel MA, Lohmann T, Gabler C, Blank N, Kalden JR, Lorenz HM. Defective suppressor function of human cd4+cd25+ regulatory t cells in autoimmune polyglandular syndrome type ii. J Exp Med. 2004;199:1285–1291. doi:10.1084/jem.20032158.

    Article  PubMed  CAS  Google Scholar 

  14. Baecher-Allan C, Viglietta V, Hafler DA. Inhibition of human cd4(+)cd25(+high) regulatory t cell function. J Immunol. 2002;169:6210–6217.

    PubMed  CAS  Google Scholar 

  15. Lindley S, Dayan CM, Bishop A, Roep BO, Peakman M, Tree TI. Defective suppressor function in cd4(+)cd25(+) t-cells from patients with type 1 diabetes. Diabetes. 2005;54:92–99. doi:10.2337/diabetes.54.1.92.

    Article  PubMed  CAS  Google Scholar 

  16. Brusko T, Atkinson M. Treg in type 1 diabetes. Cell Biochem Biophys. 2007;48:165–175. doi:10.1007/s12013-007-0018-5.

    Article  PubMed  CAS  Google Scholar 

  17. Venken K, Hellings N, Thewissen M, Somers V, Hensen K, Rummens JL, et al. Compromised cd4(+) cd25(high) regulatory t-cell function in patients with relapsing-remitting multiple sclerosis is correlated with a reduced frequency of foxp3-positive cells and reduced foxp3 expression at the single-cell level. Immunology. 2008;123(1):79–89.

    Article  PubMed  CAS  Google Scholar 

  18. Gianfrani C, Levings MK, Sartirana C, et al. Gliadin-specific type 1 regulatory t cells from the intestinal mucosa of treated celiac patients inhibit pathogenic t cells. J Immunol. 2006;177:4178–4186.

    PubMed  CAS  Google Scholar 

  19. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated t cells expressing il-2 receptor alpha-chains (cd25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995;155:1151–1164.

    PubMed  CAS  Google Scholar 

  20. Marie JC, Letterio JJ, Gavin M, Rudensky AY. Tgf-beta1 maintains suppressor function and foxp3 expression in cd4+cd25+ regulatory t cells. J Exp Med. 2005;201:1061–1067. doi:10.1084/jem.20042276.

    Article  PubMed  CAS  Google Scholar 

  21. Ramsdell F. Foxp3 and natural regulatory t cells: key to a cell lineage? Immunity. 2003;19:165–168. doi:10.1016/S1074-7613(03)00207-3.

    Article  PubMed  CAS  Google Scholar 

  22. Tiittanen M, Westerholm-Ormio M, Verkasalo M, Savilahti E, Vaarala O. Infiltration of forkhead box p3-expressing cells in small intestinal mucosa in coeliac disease but not in type 1 diabetes. Clin Exp Immunol. 2008;152:498–507.

    Article  PubMed  CAS  Google Scholar 

  23. Wan YY, Flavell RA. Identifying foxp3-expressing suppressor t cells with a bicistronic reporter. Proc Natl Acad Sci USA. 2005;102:5126–5131. doi:10.1073/pnas.0501701102.

    Article  PubMed  CAS  Google Scholar 

  24. Allan SE, Crome SQ, Crellin NK, et al. Activation-induced foxp3 in human t effector cells does not suppress proliferation or cytokine production. Int Immunol. 2007;19:345–354. doi:10.1093/intimm/dxm014.

    Article  PubMed  CAS  Google Scholar 

  25. van Heel DA, Hunt K, Greco L, Wijmenga C. Genetics in coeliac disease. Best Pract Res Clin Gastroenterol. 2005;19:323–339. doi:10.1016/j.bpg.2005.01.001.

    Article  PubMed  CAS  Google Scholar 

  26. Abdulahad WH, Stegeman CA, van der Geld YM, Doornbos-van der Meer B, Limburg PC, Kallenberg CG. Functional defect of circulating regulatory cd4+ t cells in patients with wegener’s granulomatosis in remission. Arthritis Rheum. 2007;56:2080–2091. doi:10.1002/art.22692.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Laboratory of Immunology, IRCCS Burlo Garofolo, Via dell’Istria 65/1, 34137, Trieste, Italy

    Marilena Granzotto, Alberto Tommasini & Elisa Piscianz

  2. Department of Reproductive and Developmental Sciences, University of Trieste, Trieste, Italy

    Sara dal Bo, Sara Quaglia, Alberto Tommasini, Erica Valencic, Fortunato Ferrara, Stefano Martelossi, Alessandro Ventura & Tarcisio Not

  3. Department of Pediatrics, IRCCS Burlo Garofolo, Via dell’Istria 65/1, 34137, Trieste, Italy

    Alessandro Ventura & Tarcisio Not

Authors
  1. Marilena Granzotto
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  2. Sara dal Bo
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  3. Sara Quaglia
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  4. Alberto Tommasini
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  5. Elisa Piscianz
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  6. Erica Valencic
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  7. Fortunato Ferrara
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  8. Stefano Martelossi
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  9. Alessandro Ventura
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  10. Tarcisio Not
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Correspondence to Marilena Granzotto.

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Granzotto, M., dal Bo, S., Quaglia, S. et al. Regulatory T-Cell Function Is Impaired in Celiac Disease. Dig Dis Sci 54, 1513–1519 (2009). https://doi.org/10.1007/s10620-008-0501-x

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  • DOI: https://doi.org/10.1007/s10620-008-0501-x

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