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Tissue transglutaminase in celiac disease: role of autoantibodies

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Abstract

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.

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Abbreviations

CD:

Celiac disease

tTG:

Tissue transglutaminase

TGF β:

Trasforming growth factor β

GA:

Gluten ataxia

References

  • Aeschlimann D, Thomazy V (2000) Protein crosslinking in assembly and remodelling of extracellular matrices: the role of transglutaminases. Connect Tissue Res 41:1–27

    Article  PubMed  CAS  Google Scholar 

  • Akimov SS, Belkin AM (2001) Cell surface tissue transglutaminase is involved in adhesion and migration of monocytic cells on fibronectin. Blood 98:1567–1576

    Article  PubMed  CAS  Google Scholar 

  • Akimov SS, Krylov D, Fleischman LF et al (2000) Tissue transglutaminase is an integrin-binding adhesion coreceptor for fibronectin. J Cell Biol 148(4):825–838

    Article  PubMed  CAS  Google Scholar 

  • 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 191:603–612

    Article  PubMed  CAS  Google Scholar 

  • Bakker EN, Buus CL, Spaan JA et al (2005) Small artery remodeling depends on tissue-type transglutaminase. Circ Res 96:119–126

    Article  PubMed  CAS  Google Scholar 

  • 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 277:16567–16575

    Article  PubMed  CAS  Google Scholar 

  • 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 132:1245–1253

    Article  PubMed  CAS  Google Scholar 

  • Bergamini CM, Griffin M, Pansini FS (2005) Transglutaminase and vascular biology: physiopathologic implications and perspectives for therapeutic interventions. Curr Med Chem 12:2357–2372

    Article  PubMed  CAS  Google Scholar 

  • Boscolo S, Sarich A, Lorenzon A et al (2007) Gluten ataxia: passive transfer in a mouse model. Ann N Y Acad Sci 1107:319–328

    Article  PubMed  CAS  Google Scholar 

  • 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 56:336–341

    Article  PubMed  CAS  Google Scholar 

  • 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 133:195–206

    Article  PubMed  CAS  Google Scholar 

  • Crovella S, Brandao L, Guimaraes R et al (2007) Speeding up coeliac disease diagnosis in the developing countries. Dig Liver Dis 39:900–902

    Article  PubMed  CAS  Google Scholar 

  • Di Niro R, Sblattero D, Florian F et al (2008) Anti-idiotypic response in mice expressing human autoantibodies. Mol Immunol 45:1782–1791

    Article  PubMed  CAS  Google Scholar 

  • Dieterich W, Ehnis T, Bauer M et al (1997) Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med 3:797–801

    Article  PubMed  CAS  Google Scholar 

  • Dieterich W, Trapp D, Esslinger B et al (2003) Autoantibodies of patients with coeliac disease are insufficient to block tissue transglutaminase activity. Gut 52:1562–1566

    Article  PubMed  CAS  Google Scholar 

  • Esposito C, Caputo I (2005) Mammalian transglutaminases. Identification of substrates as a key to physiological function and physiopathological relevance. FEBS J 272:615–631

    Article  PubMed  CAS  Google Scholar 

  • 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 51:177–181

    Article  PubMed  CAS  Google Scholar 

  • Esposito C, Paparo F, Caputo I et al (2003) Expression and enzymatic activity of small intestinal tissue transglutaminase in celiac disease. Am J Gastroenterol 98:1813–1820

    Article  PubMed  CAS  Google Scholar 

  • 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):7330–7340

    PubMed  CAS  Google Scholar 

  • 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):762

    Google Scholar 

  • 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 266478–266483

  • Griffin M, Casadio R, Bergamini CM (2002) Transglutaminases: nature’s biological glues. Biochem J 368:377–396

    Article  PubMed  CAS  Google Scholar 

  • Hadjivassiliou M, Mäki M, Sanders DS et al (2006) Autoantibody targeting of brain and intestinal transglutaminase in gluten ataxia. Neurology 66:373–377

    Article  PubMed  CAS  Google Scholar 

  • Halttunen T, Mäki M (1999) Serum immunoglobulin A from patients with celiac disease inhibits human T84 intestinal crypt epithelial cell differentiation. Gastroenterology 116:566–572

    Article  PubMed  CAS  Google Scholar 

  • Hasegawa G, Suwa M, Ichikawa Y et al (2003) A novel function of tissue-type transglutaminase: protein disulphide isomerase. Biochem J 373:793–803

    Article  PubMed  CAS  Google Scholar 

  • Im MJ, Russell MA, Feng JF (1997) Transglutaminase II: a new class of GTP-binding protein with new biological functions. Cell Signal 9:477–482

    Article  PubMed  CAS  Google Scholar 

  • 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 118:867–879

    Article  PubMed  CAS  Google Scholar 

  • Kagnoff MF (2005) Overview and pathogenesis of celiac disease. Gastroenterology 128:S10–S18

    Article  PubMed  CAS  Google Scholar 

  • 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 122:881–888

    Article  PubMed  Google Scholar 

  • Kim SY, Jeitner TM, Steinert PM (2002) Transglutaminases in disease. Neurochem Int 40:85–103

    Article  PubMed  CAS  Google Scholar 

  • 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 26:278–287

    Article  PubMed  CAS  Google Scholar 

  • Korponay-Szabó IR, Halttunen T, Szalai Z et al (2004) In vivo targeting of intestinal and extraintestinal transglutaminase 2 by celiac autoantibodies. Gut 53:641–648

    Article  PubMed  Google Scholar 

  • Lesort M, Attanavanich K, Zhang J et al (1998) Distinct nuclear localization and activity of tissue transglutaminase. J Biol Chem 273:11991–11994

    Article  PubMed  CAS  Google Scholar 

  • Lorand L, Graham RM (2003) Transglutaminases: crosslinking enzymes with pleiotropic functions. Nat Rev Mol Cell Biol 4:140–156

    Article  PubMed  CAS  Google Scholar 

  • Maiuri L, Ciacci C, Ricciardelli I et al (2005) Unexpected role of surface transglutaminase type II in celiac disease. Gastroenterology 129:1400–1413

    Article  PubMed  CAS  Google Scholar 

  • Mangala LS, Mehta K (2005) Tissue transglutaminase (TG2) in cancer biology. Prog Exp Tumor Res 38:125–138

    Article  PubMed  CAS  Google Scholar 

  • Marzari R, Sblattero D, Florian F et al (2001) Molecular dissection of the tissue transglutaminase autoantibody response in celiac disease. J Immunol 166:4170–4176

    PubMed  CAS  Google Scholar 

  • Meresse B, Curran SA, Ciszewski C et al (2006) Reprogramming of CTLs into natural killer-like cells in celiac disease. J Exp Med 203:1343–1355

    Article  PubMed  CAS  Google Scholar 

  • 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 279:23863–23868

    Article  PubMed  CAS  Google Scholar 

  • 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 4:713–717

    Article  PubMed  CAS  Google Scholar 

  • Molberg O, McAdam SN, Sollid LM (2000) Role of tissue transglutaminase in celiac disease. J Pediatr Gastroenterol Nutr 30:232–240

    Article  PubMed  CAS  Google Scholar 

  • Moss SF, Attia L, Scholes JV et al (1996) Increased small intestinal apoptosis in coeliac disease. Gut 39:811–817

    Article  PubMed  CAS  Google Scholar 

  • Myrsky E, Kaukinen K, Syrjänen M et al (2008) Coeliac disease-specific autoantibodies targeted against transglutaminase 2 disturb angiogenesis. Clin Exp Immunol 152:111–119

    PubMed  CAS  Google Scholar 

  • Pinkas DM, Strop P, Brunger AT et al (2007) Transglutaminase 2 undergoes a large conformational change upon activation. PLoS Biol 5:e327

    Article  PubMed  CAS  Google Scholar 

  • Roth EB, Sjöberg K, Stenberg P (2003) Biochemical and immuno-pathological aspects of tissue transglutaminase in celiac disease. Autoimmunity 36:221–226

    Article  PubMed  CAS  Google Scholar 

  • Ruan Q, Johnson GV (2007) Transglutaminase 2 in neurodegenerative disorders. Front Biosci 12:891–904

    Article  PubMed  CAS  Google Scholar 

  • Schuppan D, Dieterich W, Riecken EO (1998) Exposing gliadin as a tasty food for lymphocytes. Nat Med 4:666–667

    Article  PubMed  CAS  Google Scholar 

  • Sollid LM (2000) Molecular basis of celiac disease. Annu Rev Immunol 18:53–81

    Article  PubMed  CAS  Google Scholar 

  • Sollid LM (2002) Coeliac disease: dissecting a complex inflammatory disorder. Nat Rev Immunol 2:647–655

    Article  PubMed  CAS  Google Scholar 

  • Sollid LM, Molberg O, Mc Adam S et al (1997) Autoantibodies in coeliac disease: tissue transglutaminase guilt by association? Gut 41:851–852

    Article  PubMed  CAS  Google Scholar 

  • Stenberg P, Roth EB, Sjöberg K (2008) Transglutaminase and the pathogenesis of coeliac disease. Eur J Intern Med 19:83–91

    Article  PubMed  CAS  Google Scholar 

  • 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 9:6

    Article  PubMed  CAS  Google Scholar 

  • 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 117:297–303

    Article  PubMed  CAS  Google Scholar 

  • Verderio EA, Johnson T, Griffin M (2004) Tissue transglutaminase in normal and abnormal wound healing: review article. Amino Acids 26:387–404

    Article  PubMed  CAS  Google Scholar 

  • 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 102:2916–2921

    Article  PubMed  CAS  Google Scholar 

  • 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:e358

    Article  PubMed  CAS  Google Scholar 

  • Zemskov EA, Janiak A, Hang J et al (2006) The role of tissue transglutaminase in cell-matrix interactions. Front Biosci 11:1057–1076

    Article  PubMed  CAS  Google Scholar 

  • 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 120:3188–3199

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Chemistry, University of Salerno, via Ponte Don Melillo, 84084, Fisciano (SA), Italy

    Ivana Caputo, Stefania Martucciello, Marilena Lepretti & Carla Esposito

  2. Department of Pediatrics and European Laboratory for the Investigation of Food-Induced Diseases, University Federico II, Naples, Italy

    Maria Vittoria Barone

Authors
  1. Ivana Caputo
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  2. Maria Vittoria Barone
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  3. Stefania Martucciello
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  4. Marilena Lepretti
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  5. Carla Esposito
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Corresponding author

Correspondence to Carla Esposito.

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Caputo, I., Barone, M.V., Martucciello, S. et al. Tissue transglutaminase in celiac disease: role of autoantibodies. Amino Acids 36, 693–699 (2009). https://doi.org/10.1007/s00726-008-0120-z

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  • DOI: https://doi.org/10.1007/s00726-008-0120-z

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