Type 2 Transglutaminase in Coeliac Disease: A Key Player in Pathogenesis, Diagnosis and Therapy

Abstract

Type 2 transglutaminase (TG2) is the main autoantigen in coeliac disease (CD), a widespread inflammatory enteropathy caused by the ingestion of gluten-containing cereals in genetically predisposed individuals. As a consequence, serum antibodies to TG2 represent a very useful marker in CD diagnosis. However, TG2 is also an important player in CD pathogenesis, for its ability to deamidate some Gln residues of gluten peptides, which become more immunogenic in CD intestinal mucosa. Given the importance of TG2 enzymatic activities in CD, several studies have sought to discover specific and potent inhibitors that could be employed in new therapeutical approaches for CD, as alternatives to a lifelong gluten-free diet. In this review, we summarise all the aspects regarding TG2 involvement in CD, including its enzymatic reactions in pathogenesis, the role of anti-TG2 antibodies in disease management, and the exploration of recent strategies to reduce deamidation or to use transamidation to detoxify gluten.

Keywords: TG2 inhibitors; anti-TG2 antibodies; autoimmunity; coeliac disease; gluten; transglutaminases; type 2 transglutaminase.

Figure 1

Scheme of the main events of CD pathogenesis. In gut lumen, gluten/gliadin is partially digested (1) and large fragments cross the intestinal barrier (2), triggering an increased intestinal permeability with zonulin release (3). Antigen presentation by HLA-DQ2/8 APCs (4) elicits an adaptive immune response with the release of pro-inflammatory cytokines (5), the recruitment of cytotoxic T cells (6), and the activation of gliadin-specific B cells (7), with the consequent production of anti-gliadin antibodies (8). All together, these events lead to the loss of mucosal integrity (9), which is slowly recovered with a gluten-free diet (10). This scheme does not show the role of TG2 gluten modifications, which are explained in the next figures.

Figure 2

TG-catalysed acyl transfer reactions. (A). Cross-link formation between the γ-carboxamide group of a Gln residue and the ε-amino group of a Lys residue with the release of ammonia. (B). Reaction of incorporation of a polyamine into a Gln residue. (C). Deamidation of a Gln residue to a Glu residue.

Figure 3

TG2 deamidation of a specific Gln residue in gliadin peptide introduces a net negative charge responsible for better recognition by DQ2/8 molecules on APC cells.

Figure 4

Gliadin peptides deriving from covalent complexes between TG2 and gliadin are presented by TG2-specific B cells, thus activating gliadin-restricted CD4⁺ T helper cells, which, in turn, stimulate plasma cell maturation and autoimmune response against TG2.