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.

Identification of tissue transglutaminase as the autoantigen of celiac disease

Abstract

Celiac disease is characterized by small intestinal damage with loss of absorptive villi and hyperplasia of the crypts, typically leading to malabsorption1. In addition to nutrient deficiencies, prolonged celiac disease is associated with an increased risk for malignancy, especially intestinal T-cell lymphoma1–3. Celiac disease is precipitated by ingestion of the protein gliadin, a component of wheat gluten, and usually resolves on its withdrawal. Gliadin initiates mucosal damage which involves an immunological process in individuals with a genetic predisposition. However, the mechanism responsible for the small intestinal damage characteristic of celiac disease is still under debate4–6. Small intestinal biopsy with the demonstration of a flat mucosa which is reversed on a gluten-free diet is considered the main approach for diagnosis of classical celiac disease7. In addition, IgA antibodies against gliadin and endomysium, a structure of the smooth muscle connective tissue, are valuable tools for the detection of patients with celiac disease and for therapy control7–9. Incidence rates of childhood celiac disease range from 1:300 in Western Ireland to 1:4700 in other European countries10–12, and subclinical cases detected by serological screening revealed prevalences of 3.3 and 4 per 1000 in Italy and the USA, respectively13,14. IgA antibodies to endomysium are particularly specific indicators of celiac disease9,15, suggesting that this structure contains one or more target autoantigens that play a role in the pathogenesis of the disease16,17. However, the identification of the endomysial autoantigen(s) has remained elusive. We identified tissue transglutaminase as the unknown endomysial autoantigen. Interestingly, gliadin is a preferred substrate for this enzyme, giving rise to novel antigenic epitopes.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Similar content being viewed by others

References

  1. Trier, J.S. Celiac sprue. N. Engl. J. Med. 325, 1709–1719 (1991).

    Article  CAS  Google Scholar 

  2. Holmes, G.K.T., Prior, P., Lane, M.R., Pope, D. & Allan, R.N. Malignancy in coeliac disease—effect of a gluten-free diet. Gut 30, 333–338 (1989).

    Article  CAS  Google Scholar 

  3. Logan, R.F.A., Rifkin, E.A., Turner, I.D. & Ferguson, A. Mortality in celiac disease. Gastroenterology 97, 265–271 (1989).

    Article  CAS  Google Scholar 

  4. Marsh, M.N., Gluten, major histocompatibility complex, and the small intestine: A molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac spruce’). Gastroenterology 102, 330–354 (1992).

    Article  CAS  Google Scholar 

  5. Sturgess, R. et al. Wheat peptide challenge in coeliac disease. Lancet 343, 758–761 (1994).

    Article  CAS  Google Scholar 

  6. Ferguson, A., Arranz, E. & Kingstone, K. Clinical and pathological spectrum of coeliac disease. in: Malignancy and Chronic Inflammation in the Gastrointestinal Tract — New Concepts. (eds. Riecken, E.O., Zeitz, M., Stallmach, A. & Heise, W.) 51–63 (Kluwer Acad. Press, Dordrecht, the Netherlands, 1995).

    Google Scholar 

  7. Walker-Smith, J.A., Guandalini, S., Schmitz, J., Shmerling, D.H. & Visakorpi, J.K. Revised criteria for diagnosis of coeliac disease. Arch. Dis. Child. 65, 909–911 (1990).

    Article  Google Scholar 

  8. Bürgin-Wolff, A. et al. Antigliadin and antiendomysium antibody determination for coeliac disease. Arch. Dis. Child. 66, 941–947 (1991).

    Article  Google Scholar 

  9. Volta, U., Molinaro, N., Fusconi, M., Cassani, F. & Bianchi, F.B. IgA antiendomysial anti body test: A step forward in celiac disease screening. Dig. Dis. Sci. 36, 752–756 (1991).

    Article  CAS  Google Scholar 

  10. Mylotte, A., Egan-Mitchell, B., McCarthy, C.F. & McNicholl, B. Incidence of coeliac disease in the west of Ireland. Br. Med. J. 1, 703–705 (1973).

    Article  CAS  Google Scholar 

  11. Greco, L., Mäki, M., Di Donato, F. & Visakorpi, J.K. Epidemiology of coeliac disease in Europe and the Mediterranean Area. in: Common Food Intolerances, Vol. I, Epidemiology of Coeliac Disease. (eds. Auricchio, S. & Visakorpi, J.K.) 25–44 (Karger, Basel, Switzerland, 1992).

    Google Scholar 

  12. Sandforth, F. et al. Inzidenz der einheimischen Sprue/Zöliakie in Berlin (West): Eine prospektive Untersuchung mit kurzer Falldiskussion. Z. Gastroenterol. 29, 327–332 (1991).

    CAS  PubMed  Google Scholar 

  13. Catassi, C. et al. Coeliac disease in the year 2000: Exploring the iceberg. Lancet 343, 200–203 (1994).

    Article  CAS  Google Scholar 

  14. Not, T. et al. Endomysium antibodies in blood donors predicts a high prevalence of celiac disease in the USA. Gastroenterology 110, A351 (1996).

    Article  Google Scholar 

  15. Lerner, A., Kumar, V. & lancu, T.C. Immunological diagnosis of childhood coeliac disease: comparison between antigliadin, antireticulin and antiendomysial antibodies. Clin. Exp. Immunol. 95, 78–82 (1994).

    Article  CAS  Google Scholar 

  16. Picarelli, A. et al. Production of antiendomysial antibodies after in-vitro gliadin chal lenge of small intestine biopsy samples from patients with coeliac disease. Lancet 348, 1065–1067 (1996).

    Article  CAS  Google Scholar 

  17. Mäki, M. Coeliac disease and autoimmunity due to unmasking of cryptic epitopes? Lancet 348, 1046–1047 (1996)

    Article  Google Scholar 

  18. Cordell, J.L. et al. Immunoenzymatic labeling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP) complexes. J. Histochem. Cytochem. 32, 219–229 (1984).

    Article  CAS  Google Scholar 

  19. Gentile, V.J. et al. Isolation and characterization of cDNA clones to mouse macrophage and human endothelial cell tissue transglutaminases. J. Biol. Chem. 266, 478–483 (1991).

    CAS  PubMed  Google Scholar 

  20. Barsigian, C. Stern, A.M. & Martinez, J. Tissue (type II) transglutaminase covalently incorporates itself, fibrinogen, or fibronectin into high molecular weight complexes on the extracellular surface of isolated hepatocytes. J. Biol. Chem. 266, 22501–22509 (1991).

    CAS  PubMed  Google Scholar 

  21. Greenberg, C.S., Birckbichler, P.J. & Rice, R.H., Transglutaminases:Multifunctional cross-linking enzymes that stabilize tissues. FASEB J. 5, 3071–3077 (1991).

    Article  CAS  Google Scholar 

  22. Upchurch, H.F., Conway, E., Patterson, M.K. & Maxwell, M.D. Localization of cellular transglutaminase on the extracellular matrix after wounding: Characteristics of the matrix bound enzyme. J. Cell Physiol. 149, 375–382 (1991).

    Article  CAS  Google Scholar 

  23. Martinez, J., Chalupowicz, D.G., Roush, R.K., Sheth, A. & Barsigian, C. Transglutaminase-mediated processing of fibronectin by endothelial cell monolayers. Biochemistry 33, 2538–2545 (1994).

    Article  CAS  Google Scholar 

  24. Aeschlimann, D., Kaupp, O. & Paulsson, M. Transglutaminase-catalyzed matrix cross-linking in differentiating cartilage: Identification of osteonectin as a major glutaminyl substrate. J. Cell Biol. 129, 881–892 (1995).

    Article  CAS  Google Scholar 

  25. Kleman, J., Aeschlimann, D., Paulsson, M. & van der Rest, M. Transglutaminase-catalyzed cross-linking of fibrils of collagen V/XI in A204 rhabdomyosarcoma cells. Biochemistry 34, 13768–1 3775 (1995).

    Article  CAS  Google Scholar 

  26. Bowness, J.M., Folk, J.E. & Timpl, R.J. Identification of a substrate site for liver transglutaminase on the aminopropeptrde of type III collagen. J. Biol. Chem. 262, 1022–1024 (1987).

    CAS  PubMed  Google Scholar 

  27. Aeschlimann, D. & Paulsson, M. Cross-linking of laminin-nidogen complexes by tissue transglutaminase. J. Biol. Chem. 266, 15308–15317 (1991).

    CAS  PubMed  Google Scholar 

  28. Piacentini, M. Tissue transglutaminase: A candidate effector element of physiological cell death. Curr. Top. Microbiol. Immunol. 200, 163–175 (1995).

    CAS  PubMed  Google Scholar 

  29. Knight, C.R.L., Rees, R.C. & Griffin, M. Apoptosis: A potential role for cytosolic transglutaminase and its importance in tumour progression. Biochim. Biophys. Acta 1096, 312–318 (1991).

    Article  CAS  Google Scholar 

  30. Bruce, S.E., Bjarnason, I. & Peters, T.J. Human jejunal transglutaminase: Demonstration of activity, enzyme kinetics and substrate specificity with special relation to gliadin and coeliac disease. Clin. Sci. 68, 573–579 (1985).

    Article  CAS  Google Scholar 

  31. Szabolcs, M., Sipka, S. & Csorba, S. In vitro cross-linking of gluten into high-molecular-weight polymers with transglutaminase. Acda Paediatr. Hung. 28, 215–227 (1987).

    CAS  Google Scholar 

  32. Ladinser, B., Rossipal, E. & Pittschieler, K. Endomysium antibodies in coeliac disease: An improved method. Gut 35, 776–778 (1994).

    Article  CAS  Google Scholar 

  33. Lundin, K.E.A. et al. Gliadin-specific, HLA-DQ(α1*0501,β1*0201) restricted T cells isolated from the small intestinal mucosa of celiac disease patients. J. Exp. Med. 178, 187–196 (1993).

    Article  CAS  Google Scholar 

  34. Lankisch, P.G. et al. Diagnostic intervals for recognizing celiac disease. Z. Gastroenterol. 34, 473–477 (1996).

    CAS  PubMed  Google Scholar 

  35. Sosroseno, W. A review of the mechanisms of oral tolerance and immunotherapy. J. R. Soc. Med. 88, 14–17 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Lämmli, U.K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227, 680–685 (1970).

    Article  Google Scholar 

  37. Schägger, H. & von Jagow, G. Tricine-sodium dodecyl sulfate-polyacrylamide gel electrophoresis for the separation of proteins in the range from 1 to 10 kDa. Anal. Biochem. 166, 368–379 (1987).

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Additional information

Research Laboratories of ScheringAG, 13342, Berlin, Germany

Istituto di Clinical Medical generale e Terapia Medica, Policlinico S.Orsola, via Massarenti 9, 40138, Bologna, Italy

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dieterich, W., Ehnis, T., Bauer, M. et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med 3, 797–801 (1997). https://doi.org/10.1038/nm0797-797

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0797-797

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing