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Cellular and Molecular Life Sciences

, Volume 66, Issue 20, pp 3375–3385 | Cite as

Celiac disease IgA modulates vascular permeability in vitro through the activity of transglutaminase 2 and RhoA

  • Essi Myrsky
  • Sergio Caja
  • Zsofi Simon-Vecsei
  • Ilma R. Korponay-Szabo
  • Cristina Nadalutti
  • Russell Collighan
  • Alexandre Mongeot
  • Martin Griffin
  • Markku Mäki
  • Katri Kaukinen
  • Katri LindforsEmail author
Research Article

Abstract

Celiac disease is characterized by the presence of specific autoantibodies targeted against transglutaminase 2 (TG2) in untreated patients’ serum and at their production site in the small-bowel mucosa below the basement membrane and around the blood vessels. As these autoantibodies have biological activity in vitro, such as inhibition of angiogenesis, we studied if they might also modulate the endothelial barrier function. Our results show that celiac disease patient autoantibodies increase endothelial permeability for macromolecules, and enhance the binding of lymphocytes to the endothelium and their transendothelial migration when compared to control antibodies in an endothelial cell-based in vitro model. We also demonstrate that these effects are mediated by increased activities of TG2 and RhoA. Since the small bowel mucosal endothelium serves as a “gatekeeper” in inflammatory processes, the disease-specific autoantibodies targeted against TG2 could thus contribute to the pathogenic cascade of celiac disease by increasing blood vessel permeability.

Keywords

Celiac disease Disease-specific autoantibodies Transglutaminase 2 Vascular permeability RhoA activation 

Notes

Acknowledgements

The authors wish to thank Mr. Jorma Kulmala for technical assistance. The Celiac Disease Study Group has been financially supported by the Research Council for Health, the Academy of Finland, the Juselius Foundation, the Paediatric Research Foundation, the Competitive Research Funding of the Pirkanmaa Hospital District, the Research Fund of the Finnish Celiac Society, the Hungarian Scientific Research Fund (OTKA K61868), and the European Commission (contract number MRTN-CT-2006-036032).

References

  1. 1.
    Korponay-Szabo IR, Laurila K, Szondy Z, Halttunen T, Szalai Z, Dahlbom I, Rantala I, Kovacs JB, Fesus L, Maki M (2003) Missing endomysial and reticulin binding of coeliac antibodies in transglutaminase 2 knockout tissues. Gut 52:199–204PubMedCrossRefGoogle Scholar
  2. 2.
    Green PH, Cellier C (2007) Celiac disease. N Engl J Med 357:1731–1743PubMedCrossRefGoogle Scholar
  3. 3.
    Marzari R, Sblattero D, Florian F, Tongiorgi E, Not T, Tommasini A, Ventura A, Bradbury A (2001) Molecular dissection of the tissue transglutaminase autoantibody response in celiac disease. J Immunol 166:4170–4176PubMedGoogle Scholar
  4. 4.
    Korponay-Szabo IR, Halttunen T, Szalai Z, Laurila K, Kiraly R, Kovacs JB, Fesus L, Maki M (2004) In vivo targeting of intestinal and extraintestinal transglutaminase 2 by coeliac autoantibodies. Gut 53:641–648PubMedCrossRefGoogle Scholar
  5. 5.
    Salmi TT, Collin P, Korponay-Szabo IR, Laurila K, Partanen J, Huhtala H, Kiraly R, Lorand L, Reunala T, Maki M, Kaukinen K (2006) Endomysial antibody-negative coeliac disease: clinical characteristics and intestinal autoantibody deposits. Gut 55:1746–1753PubMedCrossRefGoogle Scholar
  6. 6.
    Halttunen T, Maki M (1999) Serum immunoglobulin A from patients with celiac disease inhibits human T84 intestinal crypt epithelial cell differentiation. Gastroenterology 116:566–572PubMedCrossRefGoogle Scholar
  7. 7.
    Barone MV, Caputo I, Ribecco MT, Maglio M, Marzari R, Sblattero D, Troncone R, Auricchio S, Esposito C (2007) Humoral immune response to tissue transglutaminase is related to epithelial cell proliferation in celiac disease. Gastroenterology 132:1245–1253PubMedCrossRefGoogle Scholar
  8. 8.
    Zanoni G, Navone R, Lunardi C, Tridente G, Bason C, Sivori S, Beri R, Dolcino M, Valletta E, Corrocher R, Puccetti A (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
  9. 9.
    Cervio E, Volta U, Verri M, Boschi F, Pastoris O, Granito A, Barbara G, Parisi C, Felicani C, Tonini M, De Giorgio R (2007) Sera of patients with celiac disease and neurologic disorders evoke a mitochondrial-dependent apoptosis in vitro. Gastroenterology 133:195–206PubMedCrossRefGoogle Scholar
  10. 10.
    Boscolo S, Sarich A, Lorenzon A, Passoni M, Rui V, Stebel M, Sblattero D, Marzari R, Hadjivassiliou M, Tongiorgi E (2007) Gluten ataxia: passive transfer in a mouse model. Ann N Y Acad Sci 1107:319–328PubMedCrossRefGoogle Scholar
  11. 11.
    Hadjivassiliou M, Maki M, Sanders DS, Williamson CA, Grunewald RA, Woodroofe NM, Korponay-Szabo IR (2006) Autoantibody targeting of brain and intestinal transglutaminase in gluten ataxia. Neurology 66:373–377PubMedCrossRefGoogle Scholar
  12. 12.
    Myrsky E, Kaukinen K, Syrjanen M, Korponay-Szabo IR, Maki M, Lindfors K (2008) Coeliac disease-specific autoantibodies targeted against transglutaminase 2 disturb angiogenesis. Clin Exp Immunol 152:111–119PubMedCrossRefGoogle Scholar
  13. 13.
    Cooke WT, Holmes GKT (1984) Coeliac disease. Churchill Livingstone, EdinburghGoogle Scholar
  14. 14.
    Myrsky E, Syrjanen M, Korponay-Szabo IR, Maki M, Kaukinen K, Lindfors K (2009) Altered small-bowel mucosal vascular network in untreated coeliac disease. Scand J Gastroenterol 44:162–167PubMedCrossRefGoogle Scholar
  15. 15.
    Ghosh K, Thodeti CK, Dudley AC, Mammoto A, Klagsbrun M, Ingber DE (2008) Tumor-derived endothelial cells exhibit aberrant Rho-mediated mechanosensing and abnormal angiogenesis in vitro. Proc Natl Acad Sci USA 105:11305–11310PubMedCrossRefGoogle Scholar
  16. 16.
    Janiak A, Zemskov EA, Belkin AM (2006) Cell surface transglutaminase promotes RhoA activation via integrin clustering and suppression of the Src-p190RhoGAP signaling pathway. Mol Biol Cell 17:1606–1619PubMedCrossRefGoogle Scholar
  17. 17.
    Wojciak-Stothard B, Potempa S, Eichholtz T, Ridley AJ (2001) Rho and Rac but not Cdc42 regulate endothelial cell permeability. J Cell Sci 114:1343–1355PubMedGoogle Scholar
  18. 18.
    Halttunen T, Marttinen A, Rantala I, Kainulainen H, Maki M (1996) Fibroblasts and transforming growth factor beta induce organization and differentiation of T84 human epithelial cells. Gastroenterology 111:1252–1262PubMedCrossRefGoogle Scholar
  19. 19.
    Birckbichler PJ, Upchurch HF, Patterson MK Jr, Conway E (1985) A monoclonal antibody to cellular transglutaminase. Hybridoma 4:179–186PubMedCrossRefGoogle Scholar
  20. 20.
    Baumgartner W, Golenhofen N, Weth A, Hiiragi T, Saint R, Griffin M, Drenckhahn D (2004) Role of transglutaminase 1 in stabilisation of intercellular junctions of the vascular endothelium. Histochem Cell Biol 122:17–25PubMedCrossRefGoogle Scholar
  21. 21.
    Griffin M, Mongeot A, Collighan R, Saint RE, Jones RA, Coutts IG, Rathbone DL (2008) Synthesis of potent water-soluble tissue transglutaminase inhibitors. Bioorg Med Chem Lett 18:5559–5562PubMedCrossRefGoogle Scholar
  22. 22.
    Korponay-Szabo IR, Vecsei Z, Kiraly R, Dahlbom I, Chirdo F, Nemes E, Fesus L, Maki M (2008) Deamidated gliadin peptides form epitopes that transglutaminase antibodies recognize. J Pediatr Gastroenterol Nutr 46:253–261PubMedCrossRefGoogle Scholar
  23. 23.
    Kiraly R, Vecsei Z, Demenyi T, Korponay-Szabo IR, Fesus L (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
  24. 24.
    Ensari A, Ager A, Marsh MN, Morgan S, Moriarty KJ (1993) Time-course of adhesion molecule expression in rectal mucosa of gluten-sensitive subjects after gluten challenge. Clin Exp Immunol 92:303–307PubMedGoogle Scholar
  25. 25.
    Jelinkova L, Tuckova L, Sanchez D, Krupickova S, Pozler O, Nevoral J, Kotalova R, Tlaskalova-Hogenova H (2000) Increased levels of circulating ICAM-1, E-selectin, and IL-2 receptors in celiac disease. Dig Dis Sci 45:398–402PubMedCrossRefGoogle Scholar
  26. 26.
    Di Sabatino A, Rovedatti L, Rosado MM, Carsetti R, Corazza GR, MacDonald TT (2009) Increased expression of mucosal addressin cell adhesion molecule 1 in the duodenum of patients with active celiac disease is associated with depletion of integrin alpha4beta7-positive T cells in blood. Hum Pathol 40:699–704PubMedCrossRefGoogle Scholar
  27. 27.
    Siegel M, Strnad P, Watts RE, Choi K, Jabri B, Omary MB, Khosla C (2008) Extracellular transglutaminase 2 is catalytically inactive, but is transiently activated upon tissue injury. PLoS ONE 3:e1861.PubMedCrossRefGoogle Scholar
  28. 28.
    Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken EO, Schuppan D (1997) Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med 3:797–801PubMedCrossRefGoogle Scholar
  29. 29.
    Esposito C, Paparo F, Caputo I, Rossi M, Maglio M, Sblattero D, Not T, Porta R, Auricchio S, Marzari R, Troncone R (2002) Anti-tissue transglutaminase antibodies from coeliac patients inhibit transglutaminase activity both in vitro and in situ. Gut 51:177–181PubMedCrossRefGoogle Scholar
  30. 30.
    Anjum N, Baker PN, Robinson NJ, Aplin JD (2009) Maternal celiac disease autoantibodies bind directly to syncytiotrophoblast and inhibit placental tissue transglutaminase activity. Reprod Biol Endocrinol 7:16PubMedCrossRefGoogle Scholar
  31. 31.
    Byrne G, Ryan F, Jackson J, Feighery C, Kelly J (2007) Mutagenesis of the catalytic triad of tissue transglutaminase abrogates coeliac disease serum IgA autoantibody binding. Gut 56:336–341PubMedCrossRefGoogle Scholar
  32. 32.
    Pinkas DM, Strop P, Brunger AT, Khosla C (2007) Transglutaminase 2 undergoes a large conformational change upon activation. PLoS Biol 5:e327PubMedCrossRefGoogle Scholar
  33. 33.
    Noll T, Wozniak G, McCarson K, Hajimohammad A, Metzner HJ, Inserte J, Kummer W, Hehrlein FW, Piper HM (1999) Effect of factor XIII on endothelial barrier function. J Exp Med 189:1373–1382PubMedCrossRefGoogle Scholar
  34. 34.
    Mehta D, Rahman A, Malik AB (2001) Protein kinase C-alpha signals rho-guanine nucleotide dissociation inhibitor phosphorylation and rho activation and regulates the endothelial cell barrier function. J Biol Chem 276:22614–22620PubMedCrossRefGoogle Scholar
  35. 35.
    Holinstat M, Mehta D, Kozasa T, Minshall RD, Malik AB (2003) Protein kinase Calpha-induced p115RhoGEF phosphorylation signals endothelial cytoskeletal rearrangement. J Biol Chem 278:28793–28798PubMedCrossRefGoogle Scholar
  36. 36.
    Singh US, Kunar MT, Kao YL, Baker KM (2001) Role of transglutaminase II in retinoic acid-induced activation of RhoA-associated kinase-2. EMBO J 20:2413–2423PubMedCrossRefGoogle Scholar
  37. 37.
    Breen EC (2007) VEGF in biological control. J Cell Biochem 102:136–1358CrossRefGoogle Scholar
  38. 38.
    Takahashi H, Shibuya M (2005) The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions. Clin Sci (Lond) 109:227–241CrossRefGoogle Scholar
  39. 39.
    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

Copyright information

© Birkhäuser Verlag, Basel/Switzerland 2009

Authors and Affiliations

  • Essi Myrsky
    • 1
  • Sergio Caja
    • 1
  • Zsofi Simon-Vecsei
    • 2
  • Ilma R. Korponay-Szabo
    • 3
  • Cristina Nadalutti
    • 1
  • Russell Collighan
    • 4
  • Alexandre Mongeot
    • 5
  • Martin Griffin
    • 4
  • Markku Mäki
    • 1
    • 6
  • Katri Kaukinen
    • 1
    • 7
  • Katri Lindfors
    • 1
    Email author
  1. 1.Pediatric Research Center, Medical SchoolUniversity of TampereTampereFinland
  2. 2.Department of Biochemistry and Molecular Biology, Medical and Health Science CenterUniversity of DebrecenDebrecenHungary
  3. 3.Heim Pál Children’s Hospital, Budapest, and Department of Pediatrics, Medical and Health Science CenterUniversity of DebrecenDebrecenHungary
  4. 4.School of Life and Health SciencesAston UniversityBirminghamUK
  5. 5.X LinkNottinghamUK
  6. 6.Department of PediatricsTampere University Hospital, Medical School, University of TampereTampereFinland
  7. 7.Department of Gastroenterology and Alimentary Tract SurgeryTampere University Hospital, Medical School, University of TampereTampereFinland

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