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Autoantibodies from patients with celiac disease inhibit transglutaminase 2 binding to heparin/heparan sulfate and interfere with intestinal epithelial cell adhesion

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Abstract

Autoantibodies from patients with celiac disease (CD) can influence transglutaminase 2 (TG2) activity and its cellular functions, but the exact mechanisms have remained unknown. Our objective was to study whether autoantibodies could modulate TG2 binding to heparin/heparan sulfate (HS) and intestinal epithelial cell attachment to fibronectin-TG2 matrix. Anti-TG2 antibodies were purified by TG2 affinity chromatography from sera of patients with active CD. Serum and antibody effects on TG2 binding to heparin/HS, on transamidase activity of TG2, as well as on Caco-2 cell attachment to fibronectin-TG2 matrix were assessed using microplate assays. Both sera and purified anti-TG2 antibodies from CD patients with high anti-TG2 IgA levels reduced TG2 binding to heparin/HS as compared with those with low anti-TG2 IgA or controls. There was a negative correlation between anti-TG2 IgA levels and TG2 binding to heparin/HS. Treatment of fibronectin-TG2 coated wells with CD patients’ sera or purified anti-TG2 antibodies reduced attachment of Caco-2 cells onto the plate as compared with the control samples. The effect of CD patients’ antibodies on Caco-2 cell attachment to fibronectin-TG2 matrix occurred independently of the inhibition of cell adhesion by Arg-Gly-Asp sequence containing peptides. Anti-TG2 autoantibodies had no effect on transamidase activity of TG2 in vitro. We suggest that modulation of adhesion function of TG2 by autoantibodies from patients with CD could be related to the inhibition of TG2 binding to HS residues of cell surface proteoglycans and could have possible implications for CD pathogenesis.

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Abbreviations

ANOVA:

Analysis of variance

AP:

Alkaline phosphatase

BSA:

Bovine serum albumin

CD:

Celiac disease

DGR:

Asp-Gly-Arg

DMEM:

Dulbecco’s modified Eagle’s medium

ECM:

Extracellular matrix

EDTA:

Ethylenediaminetetraacetic acid

ELISA:

Enzyme linked immunosorbent assay

FN:

Fibronectin

HS:

Heparan sulfate

HSPG:

Heparan sulfate proteoglycan

RGD:

Arg-Gly-Asp

SD:

Standard deviation

SDS-PAGE:

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

TG2:

Transglutaminase 2

References

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

    Article  PubMed  CAS  Google Scholar 

  • Balklava Z, Verderio E, Collighan R, Gross S, Adams J, Griffin M (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, 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 132:1245–1253

    Article  PubMed  CAS  Google Scholar 

  • Bishop JR, Schuksz M, Esko JD (2007) Heparan sulphate proteoglycans fine-tune mammalian physiology. Nature 446:1030–1037

    Article  PubMed  CAS  Google Scholar 

  • Byrne G, Feighery C, Jackson J, Kelly J (2010) Coeliac disease autoantibodies mediate significant inhibition of tissue transglutaminase. Clin Immunol 136:426–431

    Article  PubMed  CAS  Google Scholar 

  • Caputo I, Barone MV, Martucciello S, Lepretti M, Esposito C (2009) Tissue transglutaminase in celiac disease: role of autoantibodies. Amino Acids 36:693–699

    Article  PubMed  CAS  Google Scholar 

  • Caputo I, Barone MV, Lepretti M, Martucciello S, Nista I, Troncone R, Auricchio S, Sblattero D, Esposito C (2010) Celiac anti-tissue transglutaminase antibodies interfere with the uptake of alpha gliadin peptide 31–43 but not of peptide 57–68 by epithelial cells. Biochim Biophys Acta 1802:717–727

    PubMed  CAS  Google Scholar 

  • Di Simone N, Silano M, Castellani R, Di Nicuolo F, D’Alessio MC, Franceschi F, Tritarelli A, Leone AM, Tersigni C, Gasbarrini G, Silveri NG, Caruso A, Gasbarrini A (2010) Anti-tissue transglutaminase antibodies from celiac patients are responsible for trophoblast damage via apoptosis in vitro. Am J Gastroenterol 105:2254–2261

    Article  PubMed  CAS  Google Scholar 

  • 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 3:797–801

    Article  PubMed  CAS  Google Scholar 

  • Dieterich W, Trapp D, Esslinger B, Leidenberger M, Piper J, Hahn E, Schuppan D (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, 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 51:177–181

    Article  PubMed  CAS  Google Scholar 

  • Halttunen T, Maki 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 

  • Hang J, Zemskov EA, Lorand L, Belkin AM (2005) Identification of a novel recognition sequence for fibronectin within the NH2-terminal beta-sandwich domain of tissue transglutaminase. J Biol Chem 280:23675–23683

    Article  PubMed  CAS  Google Scholar 

  • Iismaa SE, Mearns BM, Lorand L, Graham RM (2009) Transglutaminases and disease: lessons from genetically engineered mouse models and inherited disorders. Physiol Rev 89:991–1023

    Article  PubMed  CAS  Google Scholar 

  • Jabri B, Sollid LM (2009) Tissue-mediated control of immunopathology in coeliac disease. Nat Rev Immunol 9:858–870

    Article  PubMed  CAS  Google Scholar 

  • Kainulainen H, Rantala I, Collin P, Ruuska T, Paivarinne H, Halttunen T, Lindfors K, Kaukinen K, Maki M (2002) Blisters in the small intestinal mucosa of coeliac patients contain T cells positive for cyclooxygenase 2. Gut 50:84–89

    Article  PubMed  CAS  Google Scholar 

  • 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 26:278–287

    Article  PubMed  CAS  Google Scholar 

  • 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 53:641–648

    Article  PubMed  CAS  Google Scholar 

  • Lewis NR, Scott BB (2006) Systematic review: the use of serology to exclude or diagnose coeliac disease (a comparison of the endomysial and tissue transglutaminase antibody tests). Aliment Pharmacol Ther 24:47–54

    Article  PubMed  CAS  Google Scholar 

  • Lindfors K, Kaukinen K, Maki M (2009) A role for anti-transglutaminase 2 autoantibodies in the pathogenesis of coeliac disease? Amino Acids 36:685–691

    Article  PubMed  CAS  Google Scholar 

  • Liu S, Cerione RA, Clardy J (2002) Structural basis for the guanine nucleotide-binding activity of tissue transglutaminase and its regulation of transamidation activity. Proc Natl Acad Sci USA 99:2743–2747

    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 

  • Mahoney DJ, Whittle JD, Milner CM, Clark SJ, Mulloy B, Buttle DJ, Jones GC, Day AJ, Short RD (2004) A method for the non-covalent immobilization of heparin to surfaces. Anal Biochem 330:123–129

    Article  PubMed  CAS  Google Scholar 

  • Mehta K, Kumar A, Kim HI (2010) Transglutaminase 2: a multi-tasking protein in the complex circuitry of inflammation and cancer. Biochem Pharmacol 80:1921–1929

    Article  PubMed  CAS  Google Scholar 

  • 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 152:111–119

    Article  PubMed  CAS  Google Scholar 

  • Myrsky E, Caja S, Simon-Vecsei Z, Korponay-Szabo IR, Nadalutti C, Collighan R, Mongeot A, Griffin M, Maki M, Kaukinen K, Lindfors K (2009) Celiac disease IgA modulates vascular permeability in vitro through the activity of transglutaminase 2 and RhoA. Cell Mol Life Sci 66:3375–3385

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Ruoslahti E (1996) RGD and other recognition sequences for integrins. Annu Rev Cell Dev Biol 12:697–715

    Article  PubMed  CAS  Google Scholar 

  • Scarpellini A, Germack R, Lortat-Jacob H, Muramatsu T, Billett E, Johnson T, Verderio EA (2009) Heparan sulfate proteoglycans are receptors for the cell-surface trafficking and biological activity of transglutaminase-2. J Biol Chem 284:18411–18423

    Article  PubMed  CAS  Google Scholar 

  • Teesalu K, Uibo O, Kalkkinen N, Janmey P, Uibo R (2001) Increased levels of IgA antibodies against desmin in children with coeliac disease. Int Arch Allergy Immunol 126:157–166

    Article  PubMed  CAS  Google Scholar 

  • Teesalu K, Agardh D, Panarina M, Utt M, Uibo O, Uibo R (2009) A modified ELISA for improved detection of IgA, IgG, and IgM anti-tissue transglutaminase antibodies in celiac disease. Clin Chim Acta 403:37–41

    Article  PubMed  CAS  Google Scholar 

  • Telci D, Wang Z, Li X, Verderio EA, Humphries MJ, Baccarini M, Basaga H, Griffin M (2008) Fibronectin-tissue transglutaminase matrix rescues RGD-impaired cell adhesion through syndecan-4 and beta1 integrin co-signaling. J Biol Chem 283:20937–20947

    Article  PubMed  CAS  Google Scholar 

  • Uibo R, Panarina M, Teesalu K, Talja I, Sepp E, Utt M, Mikelsaar M, Heilman K, Uibo O, Vorobjova T (2011) Celiac disease in patients with type 1 diabetes: a condition with distinct changes in intestinal immunity? Cell Mol Immunol 8:150–156

    Article  PubMed  CAS  Google Scholar 

  • Verderio EA, Telci D, Okoye A, Melino G, Griffin M (2003) A novel RGD-independent cell adhesion pathway mediated by fibronectin-bound tissue transglutaminase rescues cells from anoikis. J Biol Chem 278:42604–42614

    Article  PubMed  CAS  Google Scholar 

  • Verderio EA, Scarpellini A, Johnson TS (2009) Novel interactions of TG2 with heparan sulfate proteoglycans: reflection on physiological implications. Amino Acids 36:671–677

    Article  PubMed  CAS  Google Scholar 

  • 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:e358

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The study was supported by Estonian Science Foundation grant nr. 7749 and target-financed grant nr. 0180035s08 from Estonian Ministry of Education and Science, and by European Union Regional Development Fund. The authors thank Mrs. Anu Kõiveer for her suggestions in culturing Caco-2 cells.

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Authors and Affiliations

  1. Immunology Group, Department of General and Molecular Pathology, University of Tartu, Ravila 19, 50411, Tartu, Estonia

    Kaupo Teesalu, Marina Panarina, Raivo Uibo & Meeme Utt

  2. Department of Pediatrics, University of Tartu, N. Lunini 6, 51014, Tartu, Estonia

    Oivi Uibo

  3. Childrens’ Clinic, Tartu University Hospital, N. Lunini 6, 51014, Tartu, Estonia

    Oivi Uibo

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  1. Kaupo Teesalu
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  2. Marina Panarina
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  3. Oivi Uibo
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  4. Raivo Uibo
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  5. Meeme Utt
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Correspondence to Kaupo Teesalu.

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Teesalu, K., Panarina, M., Uibo, O. et al. Autoantibodies from patients with celiac disease inhibit transglutaminase 2 binding to heparin/heparan sulfate and interfere with intestinal epithelial cell adhesion. Amino Acids 42, 1055–1064 (2012). https://doi.org/10.1007/s00726-011-1020-1

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  • DOI: https://doi.org/10.1007/s00726-011-1020-1

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