Skip to main content
Log in

Celiac disease: role of intestinal compartments in the mucosal immune response

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Different approaches have been used to study the pattern of cytokines in celiac disease (CD). Laser capture microdissection (LCM) is a powerful tool for the isolation of specific tissue compartments. We aimed to investigate the mucosal immune response that takes place in different intestinal compartments of CD patients, dissected by LCM, analyzing cytokine expression profile. Frozen section of jejunum was obtained from 15 untreated CD and 15 control. Surface epithelium and lamina propria compartment were isolated by LCM. RNA from each LCM sample was extracted and, after a retrotranscription step, messenger RNA levels for MxA, IL-15, TNF-α, IFN-γ, IL-17α, IL-21, IL-10, and TGF-β were determined by quantitative reverse transcriptase-PCR. Increased gene expression levels of MxA, IL-15, TNF-α, IL-10, and TGF-β was observed in the surface epithelium of untreated CD with respect to control. Furthermore, all the cytokines investigated were upregulated in the lamina propria of untreated CD as compared to control. Within the untreated CD group the expression of IL-15 was higher, in the surface epithelium than in the lamina propria, whereas the expression levels of IL-17 and IL-21 were higher in the lamina propria than in the surface epithelium. Finally, high levels of IL-10 and TGF-β were detected in both compartments of untreated CD biopsies. In CD, surface epithelium and lamina propria compartments, play a prominent role in determining innate and adaptive immunity, respectively. Conversely, surface epithelium and lamina propria produce high levels of anti-inflammatory cytokines, suggesting that both compartments are involved in the immunoregulatory response.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Maiuri L, Ciacci C, Ricciardelli I, Vacca L, Vacca L, Raia V, Auricchio S, Picard J, Osman M, Quaratino S, Londei M (2003) Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease. Lancet 362:30–37

    Article  CAS  PubMed  Google Scholar 

  2. Brottveit M, Beitnes AC, Tollefsen S, Bratlie JE, Jahnsen FL, Johansen FE, Sollid LM, Lundin KE (2013) Mucosal cytokine response after short-term gluten challenge in celiac disease and non-celiac gluten sensitivity. Am J Gastroenterol 108(5):842–850

    Article  CAS  PubMed  Google Scholar 

  3. Koning F, Schuppan D, Cerf-Bensussan N, Sollid LM (2005) Pathomechanisms in celiac disease. Best Pract Res Clin Gastroenterol 19:373–387

    Article  CAS  PubMed  Google Scholar 

  4. Nilsen EM, Jahnsen FL, Lundin KE, Johansen FE, Fausa O, Sollid LM, Jahnsen J, Scott H, Brandtzaeg P (1998) Gluten induces an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease. Gastroenterology 115:551–563

    Article  CAS  PubMed  Google Scholar 

  5. Troncone R, Gianfrani C, Mazzarella G, Greco L, Guardiola J, Auricchio S, De Berardinis P (1998) Majority of gliadin-specific T-cell clones from celiac small intestinal mucosa produce interferon-gamma and interleukin-4. Dig Dis Sci 43(1):156–161

    Article  CAS  PubMed  Google Scholar 

  6. Lahat N, Shapiro S, Karban A, Gerstein R, Kinarty A, Lerner A (1999) Cytokine profile in coeliac disease. Scand J Immunol 49(4):441–446

    Article  CAS  PubMed  Google Scholar 

  7. Forsberg G, Hernell O, Melgar S, Israelsson A, Hammarström S, Hammarström ML (2002) Paradoxical coexpression of proinflamatory and down-regulatory cytokines in intestinal T cells in childhood celiac disease. Gastroenterology 123(3):667–678

    Article  CAS  PubMed  Google Scholar 

  8. Di Sabatino A, Ciccocioppo R, Cupelli F, Cinque B, Millimaggi D, Clarkson MM, Paulli M, Cifone MG, Corazza GR (2006) Epithelium derived interleukin 15 regulates intraepithelial lymphocyte Th1 cytokine production, cytotoxicity, and survival in coeliac disease. Gut 55(4):469–477

    Article  PubMed Central  PubMed  Google Scholar 

  9. Fosberg G, Hernell O, Hammarström S, Hammarström ML (2007) Concomitant increase of IL-10 and pro-inflammatory cytokines in intraepithelial lymphocyte subsets in celiac disease. Int Immunol 19(8):993–1001

    Article  Google Scholar 

  10. Simone NL, Bonner RF, Gillespie Emmert-Buck MR, Liotta LA (1998) Laser-capture microdissection: opening the microscopic frontier to molecular analysis. Trends Genet 14(7):272–276

    Article  CAS  PubMed  Google Scholar 

  11. Curran S, McKay JA, McLeod HL, Murray GI (2000) Laser-capture microscopy. Mol Pathol 53(2):64–68

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Lawrie LC, Curran S (2005) Laser-capture microdissection and colorectal cancer proteomics. Methods Mol Biol 293:245–253

    CAS  PubMed  Google Scholar 

  13. Yen TH, Wright NA (2006) The gastrointestinal tract stem cell niche. Stem Cell Rev 2(3):203–212

    Article  CAS  PubMed  Google Scholar 

  14. Hüe S, Mention JJ, Monteiro RC, Zhang S, Cellier C, Schmitz J, Verkarre V, Fodil N, Bahram S, Cerf-Bensussan N, Caillat-Zucman S (2004) A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. Immunity 21:367–377

    Article  PubMed  Google Scholar 

  15. Monteleone G, Pender SL, Alstead E, Hauer AC, Lionetti P, McKenzie C, MacDonald TT (2001) Role of interferon alpha in promoting T helper cell type 1 responses in the small intestine in coeliac disease. Gut 48(3):425–429

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Weissmann C, Nagata S, Boll W, Fountoulakis M, Fujisawa A, Fujisawa JI, Haynes J, Henco K, Mantei N, Ragg H, Schein C, Schmid J, Shaw G, Streuli M, Taira H, Todokoro K, Weidle U (1094) Structure and expression of human IFN-alpha genes. Philos Trans R Soc Lond B Biol Sci 24(299):7–28

    Google Scholar 

  17. Feldman E, Ahmed T, Lutton JD, Farley T, Tani K, Freund M, Asano S, Abraham NG (1997) Adenovirus mediated alpha interferon (IFN-alpha) gene transfer into CD34 + cells and CML mononuclear cells. Stem Cells 15(5):386–395

    Article  CAS  PubMed  Google Scholar 

  18. Airò P, Ghidini C, Zanotti C, Scarsi M, Cattaneo R, Caimi L, Imberti L (2008) Upregulation of myxovirus-resistance protein A: a possible marker of type I interferon induction in systemic sclerosis. Rheumatology 35(11):2192–2200

    Article  Google Scholar 

  19. van der Voort LF, Vennegoor A, Visser A, Knol DL, Uitdehaag BM, Barkhof F, Oudejans CB, Polman CH, Killestein J (2010) Spontaneous MxA mRNA level predicts relapses in patients with recently diagnosed MS. Neurology 75(14):1228–1233

  20. Maiuri L, Ciacci C, Auricchio S, Brown V, Quaratino S, Londei M (2000) Interleukin 15 mediates epithelial changes in celiac disease. Gastroenterology 119:996–1006

    Article  CAS  PubMed  Google Scholar 

  21. Mention JJ, Ben Ahmed M, Begue B, Barbe U, Verkarre V, Asnafi V, Colombel JF, Cugnenc PH, Ruemmele FM, McIntyre E, Brousse N, Cellier C, Cerf-Bensussan N (2003) Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease. Gastroenterology 125:730–745

    Article  CAS  PubMed  Google Scholar 

  22. Bernardo D, Garrote JA, Allegretti Y, León A, Gómez E, Bermejo-Martin JF, Calvo C, Riestra S, Fernández-Salazar L, Blanco-Quirós A, Chirdo F, Arranz E (2008) Higher constitutive IL15Ra expression and lower IL-15 response threshold in coeliac disease patients. Clin Exp Immunol 154(1):64–73

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Monteleone G, Pender SL, Wathen NC, MacDonald TT (2001) Interferon-alphadrives T cell-mediated immunopathology in the intestine. Eur J Immunol 31:2247–2255

    Article  CAS  PubMed  Google Scholar 

  24. Fernandez S, Molina IJ, Romero P, González R, Peña J, Sánchez F, Reynoso FR, Pérez-Navero JL, Estevez O, Ortega C, Santamaría M (2011) Characterization of gliadin-specific Th17 cells from the mucosa of celiac disease patients. Am J Gastroenterol 106:528–538

    Article  CAS  PubMed  Google Scholar 

  25. Fina D, Sarra M, Caruso R, Del Vecchio Blanco G, Pallone F, MacDonald TT, Monteleone G (2008) Interleukin 21 contributes to the mucosal T helper cell type 1 response in coeliac disease. Gut 57(7):887–892

    Article  CAS  PubMed  Google Scholar 

  26. Bodd M, Ráki M, Tollefsen S, Fallang LE, Bergseng E, Lundin KE, Sollid LM (2010) HLA-DQ2-restricted gluten-reactive T cells produce IL-21 but not IL-17 or IL-22. Mucosal Immunol 3(6):594–601

    Article  CAS  PubMed  Google Scholar 

  27. Sapone A, Lammers KM, Mazzarella G, Mikhailenko I, Cartenì M, Casolaro V, Fasano A (2010) Differential mucosal IL-17 expression in two gliadin-induced disorders: gluten sensitivity and the autoimmune enteropathy celiac disease. Int Arch Allergy Immunol 152(1):75–80

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Monteleone I, Sarra M, Del Vecchio Blanco G, Paoluzi OA, Franzè E, Fina D, Fabrizi A, MacDonald TT, Pallone F, Monteleone G (2010) Characterization of IL-17A-producing cells in celiac disease mucosa. J Immunol 184(4):2211–2218

    Article  CAS  PubMed  Google Scholar 

  29. Lahdenperä AI, Hölttä V, Ruohtula T, Salo HM, Orivuori L, Westerholm-Ormio M, Savilahti E, Fälth-Magnusson K, Högberg L, Ludvigsson J, Vaarala O (2012) Up-regulation of small intestinal interleukin-17 immunity in untreated coeliac disease but not in potential coeliac disease or in type 1 diabetes. Clin Exp Immunol 167(2):226–234

    Article  PubMed Central  PubMed  Google Scholar 

  30. Lahat N, Shapiro S, Karban R, Gerstein R, Kinarty A, Lerner A (1999) Cytokine profile in coeliac disease. Scand J Immunol 49:441–446

    Article  CAS  PubMed  Google Scholar 

  31. Hansson T, Ulfgren AK, Lindroos E, DannAEus A, Dahlbom I, Klareskog L (2002) Transforming growth factor-beta (TGF-beta) and tissue transglutaminase expression in the small intestine in children with coeliac disease. Scand J Immunol 56(5):530–537

    Article  CAS  PubMed  Google Scholar 

  32. Salvati V, Mazzarella G, Gianfrani C, Levings MK, Stefanile R, De Giulio B, Iaquinto G, Giardullo N, Auricchio S, Roncarolo MG, Troncone R (2005) Recombinant human IL-10 suppresses gliadindependent T-cell activation in ex vivo cultured celiac intestinal mucosa. Gut 54:46–53

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Forsberg G, Hernell O, Melgar S, Israelsson A, Hammarström S, Hammarström ML (2002) Paradoxical coexpression of proinflammatory and down-regulatory cytokines in intestinal T-cells in childhood celiac disease. Gastroenterology 123:667–678

    Article  CAS  PubMed  Google Scholar 

  34. Gianfrani C, Leving M, Sartirana C, Mazzarella G, Barba G, Zanzi D, Camarca A, Iaquinto G, Giardullo N, Auricchio S, Troncone R, Roncarolo MG (2006) Gliadin-specific type-1 regulatory T-cells from intestinal mucosa of treated celiac patients inhibit pathogenic T-cells. J Immunol 177:4178–4186

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Rosa Maria Bevilacqua, Maria Cristina Bruno, and Maria Rosaria Volpe (Gastroenterology and Digestive Endoscopy Service, San G. Moscati Hospital, Avellino, Italy) for their help in the collection of mucosal samples. The authors are grateful to Raffaella Mastantuoni and Clemente Meccariello for their technical help. This study was funded by Department of Translational Medicine-Pediatric Section and European Laboratory for the Investigation of Food-Induced Disease (ELFID), University of Naples “Federico II”, via Pansini, 80131 Naples, Italy.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Giuseppe Mazzarella.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Iacomino, G., Marano, A., Stillitano, I. et al. Celiac disease: role of intestinal compartments in the mucosal immune response. Mol Cell Biochem 411, 341–349 (2016). https://doi.org/10.1007/s11010-015-2596-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-015-2596-7

Keywords

Navigation