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.
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Trier, J.S. Celiac sprue. N. Engl. J. Med. 325, 1709–1719 (1991).
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).
Logan, R.F.A., Rifkin, E.A., Turner, I.D. & Ferguson, A. Mortality in celiac disease. Gastroenterology 97, 265–271 (1989).
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).
Sturgess, R. et al. Wheat peptide challenge in coeliac disease. Lancet 343, 758–761 (1994).
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).
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).
Bürgin-Wolff, A. et al. Antigliadin and antiendomysium antibody determination for coeliac disease. Arch. Dis. Child. 66, 941–947 (1991).
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).
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).
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).
Sandforth, F. et al. Inzidenz der einheimischen Sprue/Zöliakie in Berlin (West): Eine prospektive Untersuchung mit kurzer Falldiskussion. Z. Gastroenterol. 29, 327–332 (1991).
Catassi, C. et al. Coeliac disease in the year 2000: Exploring the iceberg. Lancet 343, 200–203 (1994).
Not, T. et al. Endomysium antibodies in blood donors predicts a high prevalence of celiac disease in the USA. Gastroenterology 110, A351 (1996).
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).
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).
Mäki, M. Coeliac disease and autoimmunity due to unmasking of cryptic epitopes? Lancet 348, 1046–1047 (1996)
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).
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).
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).
Greenberg, C.S., Birckbichler, P.J. & Rice, R.H., Transglutaminases:Multifunctional cross-linking enzymes that stabilize tissues. FASEB J. 5, 3071–3077 (1991).
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).
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).
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).
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).
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).
Aeschlimann, D. & Paulsson, M. Cross-linking of laminin-nidogen complexes by tissue transglutaminase. J. Biol. Chem. 266, 15308–15317 (1991).
Piacentini, M. Tissue transglutaminase: A candidate effector element of physiological cell death. Curr. Top. Microbiol. Immunol. 200, 163–175 (1995).
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).
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).
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).
Ladinser, B., Rossipal, E. & Pittschieler, K. Endomysium antibodies in coeliac disease: An improved method. Gut 35, 776–778 (1994).
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).
Lankisch, P.G. et al. Diagnostic intervals for recognizing celiac disease. Z. Gastroenterol. 34, 473–477 (1996).
Sosroseno, W. A review of the mechanisms of oral tolerance and immunotherapy. J. R. Soc. Med. 88, 14–17 (1995).
Lämmli, U.K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227, 680–685 (1970).
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).
Research Laboratories of ScheringAG, 13342, Berlin, Germany
Istituto di Clinical Medical generale e Terapia Medica, Policlinico S.Orsola, via Massarenti 9, 40138, Bologna, Italy
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