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Cross linking to tissue transglutaminase and collagen favours gliadin toxicity in coeliac disease

¹ Department of Medicine I, University of Erlangen-Nuernberg, Germany
² Department of Biochemistry, University of Erlangen-Nuernberg, Germany
³ German Research Centre of Food Chemistry, Garching, Germany
⁴ Department of Medicine I, University of Erlangen-Nuernberg, Germany, and Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

Correspondence to:
Correspondence to:
Dr W Dieterich
Department of Medicine I, University of Erlangen-Nuernberg, Glueckstrasse 10, Hofgebäude Labor Prof Schuppan, Erlangen 91054, Germany; walburga.dieterich{at}med1.imed.uni-erlangen.de

Background and aims: Intestinal inflammation in coeliac disease is driven by the gluten fraction of wheat proteins. Deamidation or cross linking of gluten peptides by tissue transglutaminase (tTG), the coeliac disease autoantigen, creates potent T cell stimulatory peptides. Therefore, our aim was to identify the reaction patterns of gluten peptides, intestinal extracellular matrix proteins, and tTG.

Methods: tTG activity was analysed by incorporation of monodansyl cadaverine into gliadins. Fluorescence labelled tTG reactive short gliadin peptides were used to demonstrate their deamidation and explore their cross linking patterns with tTG itself or extracellular matrix proteins. Patient sera and controls were checked for autoantibodies to matrix proteins.

Results: Gliadins 1–11, 1–6, 1–3, and 5 were substrates for tTG. tTG catalysed the cross linking of gliadin peptides with interstitial collagen types I, III, and VI. Coeliac patients showed increased antibody titres against the collagens I, III, V, and VI.

Conclusions: tTG formed high molecular weight complexes with all tested gliadins. As all tested gliadins were substrates for tTG, the tTG catalysed modifications were not restricted to single gliadin types and epitopes. Furthermore, haptenisation and long term immobilisation of gliadin peptides by tTG catalysed binding to abundant extracellular matrix proteins could be instrumental in the perpetuation of intestinal inflammation and some associated autoimmune diseases in coeliac disease.

Abbreviations: ECM, extracellular matrix; ELISA, enzyme linked immunosorbent assay; HLA, human leucocyte antigen; RP-HPLC, reversed phase-high performance liquid chromatography; SDS-PAGE, sodium dodecyl sulphate-polyacrylamide gel electrophoresis; TBS, Tris buffered saline; TRITC, tetramethyl-rhodamine; tTG, tissue transglutaminase

Keywords: coeliac disease; collagens; tissue transglutaminase

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