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Dynamics of Non-conventional Intraepithelial Lymphocytes—NK, NKT, and γδ T—in Celiac Disease: Relationship with Age, Diet, and Histopathology

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Abstract

Background

Intraepithelial lymphocytes (IEL) are a heterogeneous population of lymphocytes raised in celiac disease (CD), whose role in CD pathogenesis remains to be defined.

Aims

To investigate how the age of diagnosis, diet, and the severity of the histological lesions are related to the changes observed in unconventional IEL populations.

Methods

Prospective analysis of 101 confirmed celiac patients from a single center, including 66 at diagnosis (45 children, 21 adults) and 112 non-celiac controls (12 children, 100 adults). IEL from duodenal biopsies were studied by six-color flow cytometry. The results were analyzed in relationship with age, diet (gluten intake), and histopathology (Marsh type).

Results

In comparison with respective age controls, both children and adult patients showed duodenal intraepithelial lymphocytosis with significant differences in every single non-conventional IEL population: CD3+ TCR γδ, NK (CD3−, CD16+, CD56+), NKT (CD3+, CD161+, CD56+), and iNKT (CD3+ Vα24) (P < 0.001 for all). Gluten intake was not only directly associated with severe atrophy, but also with decreased percentages of NK (P = 0.02), NKT (P = 0.003), and iNKT (P = 0.03). Changes in iNKT and γδ IEL were more marked in celiac children compared with celiac adults (P = 0.02 and 0.01, respectively). In contrast, increased CD3+ TCR γδ were diet- and Marsh grade-independent.

Conclusions

The typical phenotypical profile of intraepithelial lymphocytosis in untreated pediatric and adult celiacs consists of increased CD3+ TCR γδ populations with decreased NK, NKT, and iNKT cells. NK, NKT, and iNKT IEL, but not γδ IEL, are dynamic populations associated with diet, age, and histopathology.

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References

  1. Green PH, Cellier C. Celiac disease. N Engl J Med. 2007;357:1731–1743.

    Article  PubMed  CAS  Google Scholar 

  2. Jabri B, Sollid LM. Mechanisms of disease: immunopathogenesis of celiac disease. Nat Clin Pract Gastroenterol Hepatol. 2006;3:516–525.

    Article  PubMed  CAS  Google Scholar 

  3. Hayday A, Theodoridis E, Ramsburg E, et al. Intraepithelial lymphocytes: exploring the Third Way in immunology. Nat Immunol. 2001;2:997–1003.

    Article  PubMed  CAS  Google Scholar 

  4. Ferguson A, Murray D. Quantitation of intraepithelial lymphocytes in human jejunum. Gut. 1971;12:988–994.

    Article  PubMed  CAS  Google Scholar 

  5. Collin P, Wahab PJ, Murray JA. Intraepithelial lymphocytes and coeliac disease. Best Pract Res Clin Gastroenterol. 2005;19:341–350.

    Article  PubMed  CAS  Google Scholar 

  6. Vande Voort JL, Murray JA, Lahr BD, et al. Lymphocytic duodenosis and the spectrum of celiac disease. Am J Gastroenterol. 2009;104:142–148.

    Article  Google Scholar 

  7. Wahnschaffe U, Ullrich R, Riecken EO, et al. Celiac disease-like abnormalities in a subgroup of patients with irritable bowel syndrome. Gastroenterology. 2001;121(6):1329–1338.

    Article  PubMed  CAS  Google Scholar 

  8. Järvinen TT, Kaukinen K, Laurila K, et al. Intraepithelial lymphocytes in celiac disease. Am J Gastroenterol. 2003;98:1332–1337.

    Article  PubMed  Google Scholar 

  9. Mäki M, Holm K, Collin P, et al. Increase in γδ T cell receptor bearing lymphocytes in normal small bowel mucosa in latent coeliac disease. Gut. 1991;32:1412–1414.

    Article  PubMed  Google Scholar 

  10. Sollid LM. Intraepithelial lymphocytes in celiac disease: license to kill revealed. Immunity. 2004;21:303–304.

    PubMed  CAS  Google Scholar 

  11. Meresse B, Chen Z, Ciszewski C, et al. Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity. 2004;21:357–366.

    Article  PubMed  CAS  Google Scholar 

  12. Kutlu T, Brousse N, Rambaud C, et al. Numbers of T cell receptor (TCR) alpha beta+ but not of TcR gamma delta+ intraepithelial lymphocytes correlate with the grade of villous atrophy in coeliac patients on a long term normal diet. Gut. 1993;34:208–214.

    Article  PubMed  CAS  Google Scholar 

  13. Hüe S, Mention JJ, Monteiro RC, et al. A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. Immunity. 2004;21:367–377.

    Article  PubMed  Google Scholar 

  14. Bhagat G, Naiyer AJ, Shah JG, et al. Small intestinal CD8+TCRgammadelta+NKG2A+ intraepithelial lymphocytes have attributes of regulatory cells in patients with celiac disease. J Clin Invest. 2008;118:281–293.

    Article  PubMed  CAS  Google Scholar 

  15. van der Vliet HJ, von Blomberg BM, Nishi N, et al. Circulating V(alpha24+) Vbeta11+ NKT cell numbers are decreased in a wide variety of diseases that are characterized by autoreactive tissue damage. Clin Immunol. 2001;100:144–148.

    Article  PubMed  Google Scholar 

  16. Grose RH, Cummins AG, Thompson FM. Deficiency of invariant natural killer T cells in coeliac disease. Gut. 2007;56:790–795.

    Article  PubMed  CAS  Google Scholar 

  17. Salmi TT, Collin P, Reunala T, et al. Diagnostic methods beyond conventional histology in coeliac disease diagnosis. Dig Liver Dis. 2010;42:28–32.

    Article  PubMed  CAS  Google Scholar 

  18. Oberhuber G, Granditsch G, Vogelsang H. The histopathology of coeliac disease: time for a standardized report scheme for pathologists. Eur J Gastroenterol Hepatol. 1999;11:1185–1194.

    Article  PubMed  CAS  Google Scholar 

  19. Maiuri L, Ciacci C, Ricciardelli I, et al. Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease. Lancet. 2003;362:30–37.

    Article  PubMed  CAS  Google Scholar 

  20. Cseh A, Vásárhelyi B, Szalay B, et al. Immune phenotype of children with newly diagnosed and gluten-free diet-treated celiac disease. Dig Dis Sci. 2010;(in press). doi:10.1007/s10620-010-1363-6. Accessed 20 August 2010.

  21. Camarero C, León F, Sánchez L, et al. Age-related variation of intraepithelial lymphocytes subsets in normal human duodenal mucosa. Dig Dis Sci. 2007;52:685–691.

    Article  PubMed  CAS  Google Scholar 

  22. Vivas S, Ruiz de Morales JM, Fernandez M, et al. Age-related clinical, serological, and histopathological features of celiac disease. Am J Gastroenterol. 2008;103:2360–2365.

    Article  PubMed  Google Scholar 

  23. Verkasalo MA, Arató A, Savilahti E, et al. Effect of diet and age on jejunal and circulating lymphocyte subsets in children with coeliac disease: persistence of CD4-8- intraepithelial T cells through treatment. Gut. 1990;31:422–425.

    Article  PubMed  CAS  Google Scholar 

  24. Holm K, Mäki M, Savilahti E, et al. Intraepithelial gamma delta T-cell-receptor lymphocytes and genetic susceptibility to coeliac disease. Lancet. 1992;339:1500–1503.

    Article  PubMed  CAS  Google Scholar 

  25. Montoya CJ, Pollard D, Martinson J, et al. Characterization of human invariant natural killer T subsets in health and disease using a novel invariant natural killer T cell-clonotypic monoclonal antibody, 6B11. Immunology. 2007;122:1–14.

    Article  PubMed  CAS  Google Scholar 

  26. Exley MA, Hou R, Shaulov A, et al. Selective activation, expansion, and monitoring of human iNKT cells with a monoclonal antibody specific for the TCR alpha-chain CDR3 loop. Eur J Immunol. 2008;38:1756–1766.

    Article  PubMed  CAS  Google Scholar 

  27. Grose RH, Thompson FM, Cummins AG. Deficiency of 6B11+ invariant NK T-cells in celiac disease. Dig Dis Sci. 2008;53:1846–1851.

    Article  PubMed  CAS  Google Scholar 

  28. Bernardo D, van Hoogstraten IM, Verbeek WH, et al. Decreased circulating iNKT cell numbers in refractory coeliac disease. Clin Immunol. 2008;126:172–179.

    Article  PubMed  Google Scholar 

  29. Lee PT, Putnam A, Benlagha K, et al. Testing the NKT cell hypothesis of human IDDM pathogenesis. J Clin Invest. 2002;110:793–800.

    PubMed  CAS  Google Scholar 

  30. Spencer J, MacDonald TT, Diss TC, et al. Changes in intraepithelial lymphocyte subpopulations in coeliac disease and enteropathy associated T cell lymphoma (malignant histiocytosis of the intestine). Gut. 1989;30:339–346.

    Article  PubMed  CAS  Google Scholar 

  31. Hadziselimovic F, Emmons LR, Schaub U, et al. Occurrence of large granular lymphocytes and natural killer cells in the epithelium of the gut distinguishes two different coeliac diseases. Gut. 1992;33:767–772.

    Article  PubMed  CAS  Google Scholar 

  32. León F, Camarero C, Eiras P, et al. Specificity of IEL profiling in the diagnosis of celiac disease. Am J Gastroenterol. 2004;99:958.

    Article  PubMed  Google Scholar 

  33. León F, Roldán E, Sánchez L, et al. Human small-intestinal epithelium contains functional natural killer lymphocytes. Gastroenterology. 2003;125:345–356.

    Article  PubMed  Google Scholar 

  34. León F, Sánchez L, Camarero C, et al. Cytokine production by intestinal intraepithelial lymphocyte subsets in celiac disease. Dig Dis Sci. 2005;50:593–600.

    Article  PubMed  Google Scholar 

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Acknowledgments

This study was supported by a grant from the Instituto de Salud Carlos III (FIS PI070611) and by a grant from the Junta de Castilla y León, Consejería de Sanidad (318/A/08).

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Correspondence to Jose G. Ruiz de Morales.

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Calleja, S., Vivas, S., Santiuste, M. et al. Dynamics of Non-conventional Intraepithelial Lymphocytes—NK, NKT, and γδ T—in Celiac Disease: Relationship with Age, Diet, and Histopathology. Dig Dis Sci 56, 2042–2049 (2011). https://doi.org/10.1007/s10620-010-1534-5

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  • DOI: https://doi.org/10.1007/s10620-010-1534-5

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