Amino Acids

, Volume 36, Issue 4, pp 693–699 | Cite as

Tissue transglutaminase in celiac disease: role of autoantibodies

  • Ivana Caputo
  • Maria Vittoria Barone
  • Stefania Martucciello
  • Marilena Lepretti
  • Carla EspositoEmail author
Review Article


In celiac disease (CD), gluten, the disease-inducing toxic component in wheat, induces the secretion of IgA-class autoantibodies which target tissue transglutaminase (tTG). These autoantibodies are produced in the small-intestinal mucosa, and, during gluten consumption, they can also be detected in patients’ serum but disappear slowly from the circulation on a gluten-free diet. Interestingly, after adoption of a gluten-free diet the serum autoantibodies disappear from the circulation more rapidly than the small-intestinal mucosal autoantibody deposits. The finding of IgA deposits on extracellular tTG in the liver, kidney, lymph nodes and muscles of patients with CD indicates that tTG is accessible to the gut-derived autoantibodies. Although the specific autoantibody response directed against tTG is very characteristic in celiac patients, their role in the immunopathology of the celiac mucosal lesion is a matter of debate. Here we report a brief summary of anti-tTG antibody effects demonstrating that these antibodies are functional and not mere bystanders in the disease pathogenesis. In fact, they inhibit intestinal epithelial cell differentiation, induce intestinal epithelial cell proliferation, increase epithelial permeability and activate monocytes and disturb angiogenesis.


Celiac disease Tissue transglutaminase Autoantibodies Autoimmunity 



Celiac disease


Tissue transglutaminase


Trasforming growth factor β


Gluten ataxia


  1. Aeschlimann D, Thomazy V (2000) Protein crosslinking in assembly and remodelling of extracellular matrices: the role of transglutaminases. Connect Tissue Res 41:1–27PubMedCrossRefGoogle Scholar
  2. Akimov SS, Belkin AM (2001) Cell surface tissue transglutaminase is involved in adhesion and migration of monocytic cells on fibronectin. Blood 98:1567–1576PubMedCrossRefGoogle Scholar
  3. Akimov SS, Krylov D, Fleischman LF et al (2000) Tissue transglutaminase is an integrin-binding adhesion coreceptor for fibronectin. J Cell Biol 148(4):825–838PubMedCrossRefGoogle Scholar
  4. Arentz-Hansen H, Körner R, Molberg O et al (2000) 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 191:603–612PubMedCrossRefGoogle Scholar
  5. Bakker EN, Buus CL, Spaan JA et al (2005) Small artery remodeling depends on tissue-type transglutaminase. Circ Res 96:119–126PubMedCrossRefGoogle Scholar
  6. Balklava Z, Verderio E, Collighan R et al (2002) Analysis of tissue transglutaminase function in the migration of Swiss 3T3 fibroblasts: the active-state conformation of the enzyme does not affect cell motility but is important for its secretion. J Biol Chem 277:16567–16575PubMedCrossRefGoogle Scholar
  7. Barone MV, Caputo I, Ribecco MT et al (2007) Humoral immune response to tissue transglutaminase is related to epithelial cell proliferation in celiac disease. Gastroenterology 132:1245–1253PubMedCrossRefGoogle Scholar
  8. Bergamini CM, Griffin M, Pansini FS (2005) Transglutaminase and vascular biology: physiopathologic implications and perspectives for therapeutic interventions. Curr Med Chem 12:2357–2372PubMedCrossRefGoogle Scholar
  9. Boscolo S, Sarich A, Lorenzon A et al (2007) Gluten ataxia: passive transfer in a mouse model. Ann N Y Acad Sci 1107:319–328PubMedCrossRefGoogle Scholar
  10. Byrne G, Ryan F, Jackson J et al (2007) Mutagenesis of the catalytic triad of tissue transglutaminase abrogates celiac disease serum IgA autoantibody binding. Gut 56:336–341PubMedCrossRefGoogle Scholar
  11. Cervio E, Volta U, Verri M et al (2007) Sera of patients with celiac disease and neurologic disorders evoke a mitochondrial-dependent apoptosis in vitro. Gastroenterology 133:195–206PubMedCrossRefGoogle Scholar
  12. Crovella S, Brandao L, Guimaraes R et al (2007) Speeding up coeliac disease diagnosis in the developing countries. Dig Liver Dis 39:900–902PubMedCrossRefGoogle Scholar
  13. Di Niro R, Sblattero D, Florian F et al (2008) Anti-idiotypic response in mice expressing human autoantibodies. Mol Immunol 45:1782–1791PubMedCrossRefGoogle Scholar
  14. Dieterich W, Ehnis T, Bauer M et al (1997) Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med 3:797–801PubMedCrossRefGoogle Scholar
  15. Dieterich W, Trapp D, Esslinger B et al (2003) Autoantibodies of patients with coeliac disease are insufficient to block tissue transglutaminase activity. Gut 52:1562–1566PubMedCrossRefGoogle Scholar
  16. Esposito C, Caputo I (2005) Mammalian transglutaminases. Identification of substrates as a key to physiological function and physiopathological relevance. FEBS J 272:615–631PubMedCrossRefGoogle Scholar
  17. Esposito C, Paparo F, Caputo I et al (2002) Anti-tissue transglutaminase antibodies from coeliac patients inhibit transglutaminase activity both in vitro and in situ. Gut 51:177–181PubMedCrossRefGoogle Scholar
  18. Esposito C, Paparo F, Caputo I et al (2003) Expression and enzymatic activity of small intestinal tissue transglutaminase in celiac disease. Am J Gastroenterol 98:1813–1820PubMedCrossRefGoogle Scholar
  19. Falasca L, Iadevaia V, Ciccosanti F et al (2005) Transglutaminase type II is a key element in the regulation of the anti-inflammatory response elicited by apoptotic cell engulfment. J Immunol 174(11):7330–7340PubMedGoogle Scholar
  20. Ferrara F, Dal Bo S, Quaglia S et al (2007) Protective role of anti-idiotypic network in celiac disease prone subjects. Gastroenterology 132(supp 1):762Google Scholar
  21. Gentile V, Saydak M, Chiocca EA et al (1991) Isolation and characterization of cDNA clones to mouse macrophage and human endothelial cell tissue transglutaminases. J Biol Chem 266478–266483Google Scholar
  22. Griffin M, Casadio R, Bergamini CM (2002) Transglutaminases: nature’s biological glues. Biochem J 368:377–396PubMedCrossRefGoogle Scholar
  23. Hadjivassiliou M, Mäki M, Sanders DS et al (2006) Autoantibody targeting of brain and intestinal transglutaminase in gluten ataxia. Neurology 66:373–377PubMedCrossRefGoogle Scholar
  24. Halttunen T, Mäki M (1999) Serum immunoglobulin A from patients with celiac disease inhibits human T84 intestinal crypt epithelial cell differentiation. Gastroenterology 116:566–572PubMedCrossRefGoogle Scholar
  25. Hasegawa G, Suwa M, Ichikawa Y et al (2003) A novel function of tissue-type transglutaminase: protein disulphide isomerase. Biochem J 373:793–803PubMedCrossRefGoogle Scholar
  26. Im MJ, Russell MA, Feng JF (1997) Transglutaminase II: a new class of GTP-binding protein with new biological functions. Cell Signal 9:477–482PubMedCrossRefGoogle Scholar
  27. Jabri B, de Serre NP, Cellier C et al (2000) Selective expansion of intraepithelial lymphocytes expressing the HLA-E-specific natural killer receptor CD94 in celiac disease. Gastroenterology 118:867–879PubMedCrossRefGoogle Scholar
  28. Kagnoff MF (2005) Overview and pathogenesis of celiac disease. Gastroenterology 128:S10–S18PubMedCrossRefGoogle Scholar
  29. Kaukinen K, Halme L, Collin P et al (2002) Celiac disease in patients with severe liver disease: gluten-free diet may reverse hepatic failure. Gastroenterology 122:881–888PubMedCrossRefGoogle Scholar
  30. Kim SY, Jeitner TM, Steinert PM (2002) Transglutaminases in disease. Neurochem Int 40:85–103PubMedCrossRefGoogle Scholar
  31. Király R, Vecsei Z, Deményi T et al (2006) Coeliac autoantibodies can enhance transamidating and inhibit GTPase activity of tissue transglutaminase: dependence on reaction environment and enzyme fitness. J Autoimmun 26:278–287PubMedCrossRefGoogle Scholar
  32. Korponay-Szabó IR, Halttunen T, Szalai Z et al (2004) In vivo targeting of intestinal and extraintestinal transglutaminase 2 by celiac autoantibodies. Gut 53:641–648PubMedCrossRefGoogle Scholar
  33. Lesort M, Attanavanich K, Zhang J et al (1998) Distinct nuclear localization and activity of tissue transglutaminase. J Biol Chem 273:11991–11994PubMedCrossRefGoogle Scholar
  34. Lorand L, Graham RM (2003) Transglutaminases: crosslinking enzymes with pleiotropic functions. Nat Rev Mol Cell Biol 4:140–156PubMedCrossRefGoogle Scholar
  35. Maiuri L, Ciacci C, Ricciardelli I et al (2005) Unexpected role of surface transglutaminase type II in celiac disease. Gastroenterology 129:1400–1413PubMedCrossRefGoogle Scholar
  36. Mangala LS, Mehta K (2005) Tissue transglutaminase (TG2) in cancer biology. Prog Exp Tumor Res 38:125–138PubMedCrossRefGoogle Scholar
  37. Marzari R, Sblattero D, Florian F et al (2001) Molecular dissection of the tissue transglutaminase autoantibody response in celiac disease. J Immunol 166:4170–4176PubMedGoogle Scholar
  38. Meresse B, Curran SA, Ciszewski C et al (2006) Reprogramming of CTLs into natural killer-like cells in celiac disease. J Exp Med 203:1343–1355PubMedCrossRefGoogle Scholar
  39. Mishra S, Murphy LJ (2004) Tissue transglutaminase has intrinsic kinase activity: identification of transglutaminase 2 as an insulin-like growth factor-binding protein-3 kinase. J Biol Chem 279:23863–23868PubMedCrossRefGoogle Scholar
  40. Molberg O, Mcadam SN, Körner R et al (1998) Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat Med 4:713–717PubMedCrossRefGoogle Scholar
  41. Molberg O, McAdam SN, Sollid LM (2000) Role of tissue transglutaminase in celiac disease. J Pediatr Gastroenterol Nutr 30:232–240PubMedCrossRefGoogle Scholar
  42. Moss SF, Attia L, Scholes JV et al (1996) Increased small intestinal apoptosis in coeliac disease. Gut 39:811–817PubMedCrossRefGoogle Scholar
  43. Myrsky E, Kaukinen K, Syrjänen M et al (2008) Coeliac disease-specific autoantibodies targeted against transglutaminase 2 disturb angiogenesis. Clin Exp Immunol 152:111–119PubMedGoogle Scholar
  44. Pinkas DM, Strop P, Brunger AT et al (2007) Transglutaminase 2 undergoes a large conformational change upon activation. PLoS Biol 5:e327PubMedCrossRefGoogle Scholar
  45. Roth EB, Sjöberg K, Stenberg P (2003) Biochemical and immuno-pathological aspects of tissue transglutaminase in celiac disease. Autoimmunity 36:221–226PubMedCrossRefGoogle Scholar
  46. Ruan Q, Johnson GV (2007) Transglutaminase 2 in neurodegenerative disorders. Front Biosci 12:891–904PubMedCrossRefGoogle Scholar
  47. Schuppan D, Dieterich W, Riecken EO (1998) Exposing gliadin as a tasty food for lymphocytes. Nat Med 4:666–667PubMedCrossRefGoogle Scholar
  48. Sollid LM (2000) Molecular basis of celiac disease. Annu Rev Immunol 18:53–81PubMedCrossRefGoogle Scholar
  49. Sollid LM (2002) Coeliac disease: dissecting a complex inflammatory disorder. Nat Rev Immunol 2:647–655PubMedCrossRefGoogle Scholar
  50. Sollid LM, Molberg O, Mc Adam S et al (1997) Autoantibodies in coeliac disease: tissue transglutaminase guilt by association? Gut 41:851–852PubMedCrossRefGoogle Scholar
  51. Stenberg P, Roth EB, Sjöberg K (2008) Transglutaminase and the pathogenesis of coeliac disease. Eur J Intern Med 19:83–91PubMedCrossRefGoogle Scholar
  52. Stenman SM, Lindfors K, Korponay-Szabo IR et al (2008) Secretion of celiac disease autoantibodies after in vitro gliadin challenge is dependent on small-bowel mucosal transglutaminase 2-specific IgA deposits. BMC Immunol 9:6PubMedCrossRefGoogle Scholar
  53. Ventura A, Magazzù G, Greco L (1999) 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 117:297–303PubMedCrossRefGoogle Scholar
  54. Verderio EA, Johnson T, Griffin M (2004) Tissue transglutaminase in normal and abnormal wound healing: review article. Amino Acids 26:387–404PubMedCrossRefGoogle Scholar
  55. Watts T, Berti I, Sapone A et al (2005) Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats. Proc Natl Acad Sci 102:2916–2921PubMedCrossRefGoogle Scholar
  56. Zanoni G, Navone R, Lunardi C et al (2006) In celiac disease, a subset of autoantibodies against transglutaminase binds toll-like receptor 4 and induces activation of monocytes. PLoS Med 3:e358PubMedCrossRefGoogle Scholar
  57. Zemskov EA, Janiak A, Hang J et al (2006) The role of tissue transglutaminase in cell-matrix interactions. Front Biosci 11:1057–1076PubMedCrossRefGoogle Scholar
  58. Zemskov EA, Mikhailenko I, Strickland DK et al (2007) Cell-surface transglutaminase undergoes internalization and lysosomal degradation: an essential role for LRP1. J Cell Sci 120:3188–3199PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Ivana Caputo
    • 1
  • Maria Vittoria Barone
    • 2
  • Stefania Martucciello
    • 1
  • Marilena Lepretti
    • 1
  • Carla Esposito
    • 1
    Email author
  1. 1.Department of ChemistryUniversity of SalernoFisciano (SA)Italy
  2. 2.Department of Pediatrics and European Laboratory for the Investigation of Food-Induced DiseasesUniversity Federico IINaplesItaly

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