Gastroenterology
Volume 133, Issue 3 , Pages 1025-1028 , September 2007

Turning Swords Into Plowshares: Transglutaminase to Detoxify Gluten

  • Detlef Schuppan

      Affiliations

    • Corresponding Author InformationAddress requests for reprints to: Detlef Schuppan, MD, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215. fax: (617) 667-2767.
    • ,
  • Yvonne Junker

References 

  1. Schuppan D. Current concepts of celiac disease pathogenesis. Gastroenterology. 2000;119:234–242
  2. Ciclitira PJ, King AL, Fraser JS. AGA technical review on celiac sprue (American Gastroenterological Association). Gastroenterology. 2001;120:1526–1540
  3. Green PH, Jabri B. Coeliac disease. Lancet. 2003;362:383–391
  4. Fasano A, Catassi C. Current approaches to diagnosis and treatment of celiac disease: an evolving spectrum. Gastroenterology. 2001;120:636–651
  5. Maki M, Mustalahti K, Kokkonen J, et al. Prevalence of celiac disease among children in Finland. N Engl J Med. 2003;348:2517–2524
  6. Dieterich W, Ehnis T, Bauer M, et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med. 1997;3:797–801
  7. Lorand L, Graham RM. Transglutaminases: crosslinking enzymes with pleiotropic functions. Nat Rev Mol Cell Biol. 2003;4:140–156
  8. Dieterich W, Esslinger B, Trapp D, et al. Cross linking to tissue transglutaminase and collagen favours gliadin toxicity in coeliac disease. Gut. 2006;55:478–484
  9. Wieser H. Chemistry of gluten proteins. Food Microbiol. 2007;24:115–119
  10. Schuppan D, Dieterich W, Ehnis T, et al. Identification of the autoantigen of celiac disease. Ann N Y Acad Sci. 1998;859:121–126
  11. Arentz-Hansen H, Korner R, Molberg O, et al. The intestinal T cell response to alpha-gliadin in adult celiac disease is focused on a single deamidated glutamine targeted by tissue transglutaminase. J Exp Med. 2000;191:603–612
  12. Molberg O, McAdam SN, Korner R, et al. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat Med. 1998;4:713–717
  13. van de Wal Y, Kooy Y, van Veelen P, et al. Selective deamidation by tissue transglutaminase strongly enhances gliadin-specific T cell reactivity. J Immunol. 1998;161:1585–1588
  14. Sollid LM, Khosla C. Future therapeutic options for celiac disease. Nat Clin Pract Gastroenterol Hepatol. 2005;2:140–147
  15. Logan RF, Rifkind EA, Turner ID, et al. Mortality in celiac disease. Gastroenterology. 1989;97:265–271
  16. Howdle PD, Jalal PK, Holmes GK, et al. Primary small-bowel malignancy in the UK and its association with coeliac disease. QJM. 2003;96:345–353
  17. 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
  18. Hausch F, Shan L, Santiago NA, et al. Intestinal digestive resistance of immunodominant gliadin peptides. Am J Physiol Gastrointest Liver Physiol. 2002;283:G996–G1003
  19. Pyle GG, Paaso B, Anderson BE, et al. Effect of pretreatment of food gluten with prolyl endopeptidase on gluten-induced malabsorption in celiac sprue. Clin Gastroenterol Hepatol. 2005;3:687–694
  20. Koning F, Vader W. Gluten peptides and celiac disease. Science. 2003;299:513–515author reply 513–515
  21. Matysiak-Budnik T, Candalh C, Cellier C, et al. Limited efficiency of prolyl-endopeptidase in the detoxification of gliadin peptides in celiac disease. Gastroenterology. 2005;129:786–796
  22. Cerf-Bensussan N, Matysiak-Budnik T, Cellier C, et al. Oral proteases: a new approach to managing coeliac disease. Gut. 2007;56:157–160
  23. Stepniak D, Spaenij-Dekking L, Mitea C, et al. Highly efficient gluten degradation with a newly identified prolyl endoprotease: implications for celiac disease. Am J Physiol Gastrointest Liver Physiol. 2006;291:G621–G629
  24. Di Cagno R, De Angelis M, Lavermicocca P, et al. Proteolysis by sourdough lactic acid bacteria: effects on wheat flour protein fractions and gliadin peptides involved in human cereal intolerance. Appl Environ Microbiol. 2002;68:623–633
  25. Di Cagno R, De Angelis M, Auricchio S, et al. Sourdough bread made from wheat and nontoxic flours and started with selected lactobacilli is tolerated in celiac sprue patients. Appl Environ Microbiol. 2004;70:1088–1096
  26. Kiyosaki T, Matsumoto I, Asakura T, et al. Gliadain, a gibberellin-inducible cysteine proteinase occurring in germinating seeds of wheat, Triticum aestivum L., specifically digests gliadin and is regulated by intrinsic cystatins. FEBS J. 2007;274:1908–1917
  27. Siegel M, Bethune MT, Gass J, et al. Rational design of combination enzyme therapy for celiac sprue. Chem Biol. 2006;13:649–658
  28. Vader LW, Stepniak DT, Bunnik EM, et al. Characterization of cereal toxicity for celiac disease patients based on protein homology in grains. Gastroenterology. 2003;125:1105–1113
  29. Spaenij-Dekking L, Kooy-Winkelaar Y, van Veelen P, et al. Natural variation in toxicity of wheat: potential for selection of nontoxic varieties for celiac disease patients. Gastroenterology. 2005;129:797–806
  30. Watts T, Berti I, Sapone A, et al. Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats. Proc Natl Acad Sci U S A. 2005;102:2916–2921
  31. Schuppan D, Hahn EG. Biomedicine (Gluten and the gut-lessons for immune regulation). Science. 2002;297:2218–2220
  32. Choi K, Siegel M, Piper JL, et al. Chemistry and biology of dihydroisoxazole derivatives: selective inhibitors of human transglutaminase 2. Chem Biol. 2005;12:469–475
  33. Kim CY, Quarsten H, Bergseng E, et al. Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease. Proc Natl Acad Sci U S A. 2004;101:4175–4179
  34. Salvati VM, Mazzarella G, Gianfrani C, et al. Recombinant human interleukin 10 suppresses gliadin dependent T cell activation in ex vivo cultured coeliac intestinal mucosa. Gut. 2005;54:46–53
  35. Villadsen LS, Schuurman J, Beurskens F, et al. Resolution of psoriasis upon blockade of IL-15 biological activity in a xenograft mouse model. J Clin Invest. 2003;112:1571–1580
  36. Gianfrani C, Siciliano RA, Facchiano AM, et al. Transamidation of wheat flour inhibits the response to gliadin of intestinal T cells in celiac disease. Gastroenterology. 2007;133:780–789
  37. Anderson RP, Degano P, Godkin AJ, et al. In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope. Nat Med. 2000;6:337–342
  38. Shan L, Molberg O, Parrot I, et al. Structural basis for gluten intolerance in celiac sprue. Science. 2002;297:2275–2279
  39. Pasternack R, Dorsch S, Otterbach JT, et al. Bacterial pro-transglutaminase from Streptoverticillium mobaraense—purification, characterisation and sequence of the zymogen. Eur J Biochem. 1998;257:570–576
  40. Yokoyama K, Nio N, Kikuchi Y. Properties and applications of microbial transglutaminase. Appl Microbiol Biotechnol. 2004;64:447–454
  41. Vader W, Kooy Y, Van Veelen P, et al. The gluten response in children with celiac disease is directed toward multiple gliadin and glutenin peptides. Gastroenterology. 2002;122:1729–1737
  42. 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

 The authors’ work on CD is supported by grant 1R21DK073254-02 from the National Institutes of Health and a grant from the German Ministry for Education and Research to D.S.

PII: S0016-5085(07)01437-0

doi: 10.1053/j.gastro.2007.07.039

Gastroenterology
Volume 133, Issue 3 , Pages 1025-1028 , September 2007

Article Tools

* Image Usage & Resolution