Transglutaminase and the pathogenesis of coeliac disease

Transglutaminase-catalyzed reactions. During calcium-induced activation, the concealed thiol group of the active site cysteine of the zymogen is unmasked and becomes reactive. A thio-ester intermediate is formed between the activated thiol and a specific glutamine residue in, for example, gliadin. In the presence of a protein-bound lysine residue, transamidation takes place. In the absence of an amine, hydrolysis occurs. In transamidation, the formation of the thio-ester is rate-limiting. Conversely, in hydrolysis, the second step is rate-limiting, making the concentration of the intermediary thio-ester comparatively high.

The effect of calcium and zinc ions on the affinity between TG2 and antibodies from healthy controls (C1–C3) and patients with coeliac disease (P1–P7) expressed as relative absorbance in an ELISA. Calcium chloride and zinc acetate were added during the coating of the antigen (guinea pig liver TG) onto the ELISA plates. As can be seen, increasing concentrations of zinc ions reduce the calcium-dependent affinity in a dose-dependent manner.

The effect of coeliac antibodies on TG2 activity illustrated by a crossed immunoelectrophoretogram stained for TG activity [41]. After one-way electrophoresis of commercial guinea pig liver TG, areas with TG activity were transferred to another gel containing 10% human serum and a new electrophoresis was performed. a: Serum from a patient with CD; b: normal serum. The immunoprecipitate from the coeliac patient displays full TG activity. (Printed with permission from Taylor & Francis.)

A proposed pathway for the pathogenesis of coeliac disease.