Coeliac disease is an autoimmune-mediated disorder triggered by dietary gluten in individuals with genetic susceptibility. In this condition gluten triggers both innate and adaptive immune responses, and leads to small-intestinal mucosal inflammation, crypt hyperplasia and villous atrophy. Coeliac disease is a systemic disorder, since it also manifests itself extra-intestinally, and is associated with a number of complications.

A unique characteristic for coeliac disease among the enteropathies is the production of autoantibodies targeted mainly against transglutaminase 2 (TG2). These autoantibodies are found in patients circulation, but also bound to extracellular TG2 below the epithelial basement membrane and around capillaries in the small-intestinal mucosa and in various coeliac disease-affected extra-intestinal organs. These deposits have been shown to evince biological activity. Furthermore, TG2-targeted autoantibodies have several biological effects in vitro.

In the present study it was shown that the overall architecture of the small-bowel mucosal vasculature is altered, capillary tufts are absent, and both the number and the maturity of the vessels are decreased in the coeliac disease-affected small-intestinal mucosa. This deterioration is clearly gluten-dependent, since after a one-year gluten-free diet the vascular architecture normalised and TG2-targeted small-bowel mucosal autoantibody deposits diminished.

Since TG2 has a role in vascular biology, the possible effects of coeliac autoantibodies on angiogenesis were studied in vitro with vascular endothelial and mesenchymal cells. The results obtained show that patient serum-derived affinity-purified autoantibodies interfere significantly with several steps in angiogenesis, including endothelial and mesenchymal tubule formation and migration. The coeliac autoantibodies and recombinant patient-derived TG2-specific antibodies also reduced endothelial branching in a three-dimensional cell culture model.

It was demonstrated that coeliac disease-specific autoantibodies in vitro increase endothelial permeability to macromolecules and lymphocytes and enhance lymphocyte adhesion on the endothelium.

Live cell enzyme-linked immunosorbent assays (ELISA) showed that in the presence of coeliac patient serum-derived affinity-purified autoantibodies or recombinant TG2-targeted antibodies, TG2 transamidating activity was significantly increased. Moreover, the TG2 enzymatic activity correlated inversely with tubule length in the presence of coeliac antibodies. In vitro the autoantibody-induced altered TG2 activity seemed to be involved in disturbed endothelial function in the presence of coeliac autoantibodies, since pretreatment of the endothelial cultures with TG2 inhibitor could restore the barrier function and diminish lymphocyte adhesion to the endothelium. In addition, coeliac autoantibodies were found to increase in vitro activity of ras homology gene family member A (RhoA), signaling protein involved e.g. in leukocyte transmigration.

It was demonstrated that inactivation of RhoA restored endothelial function and also reduced lymphocyte adhesion to endothelial cells, suggesting that patient autoantibodies might exert their function partially through the RhoA signaling pathway.

To conclude, the observed distruption of the mucosal vessel network in untreated coeliac disease could lead to lack of mechanical support to the villi, thus contributing to the formation of mucosal lesion. If gluten-triggered coeliac patient autoantibodies could also exert anti-angiogenic effects in vivo, the various vascular alterations seen in the active state of coeliac disease could be explained by insufficient angiogenesis due to mucosal TG2-specific IgA deposits. Moreover, if coeliac autoantibodies are able to induce endothelial barrier dysfunction and lymphocyte adhesion on the endothelium, they might in vivo enhance macromolecule and lymphocyte infiltration from the circulation to the small-intestinal mucosa, and thus have a role in the development and maintenance of the mucosal lesion.