Effects of Transglutaminase 2 Modulation on Endothelial Cell Biology

Focus on Celiac Disease Pathogenesis

Acta Universitatis Tamperensis No. 1883


By: Cristina Nadalutti
March 2014
Tampere University Press
Distributed by Coronet Books
ISBN: 9789514492945
129 Pages
$105.00 Paper original


In the small intestine villi offers an extensive epithelial surface area for absorptive function and their integrity relies on an appropriate vascular network. In celiac disease (CD), an autoimmune disorder triggered by ingested dietary gluten in susceptible individuals with HLA-DQ2 or DQ8 genotype, the overall mucosal vascular architecture is completely altered. CD is predominately characterized by a strong antibody response targeted against dietary gluten-derived deamidated gliadin peptides and the self-antigen, transglutaminase 2 (TG2). TG2 is a complex multifunctional protein involved in a variety of basic biological processes, including angiogenesis, where its role is still not fully understood. Since our group has previously shown that CD patient derived autoantibodies disturb several steps of angiogenesis, the aim of this thesis project was to deepen our knowledge of TG2 in the endothelium and to clarify the molecular mechanism behind the anti-angiogenic effects exerted by CD antibodies.

This work shed new light on the role of TG2 in the endothelium where the extracellular pool of TG2 is involved in regulating cell-matrix adhesion while the cytoplasmic TG2 is important for cell cycle progression and survival. Furthermore, it was shown that CD IgA antibodies disturb the extracellular function of TG2, thus altering endothelial cell-extracellular matrix (ECM) interactions and thereby affecting endothelial cell adhesion, polarization and motility. Intriguingly, CD IgA promoted the secretion of the redox sensor protein TRX, which probably is needed to keep TG2 in a conformation suitable for the constitutive antibody binding and activation. Thus, this study set up a possible molecular mechanism by which CD antibodies exert their anti-angiogenic functions, which in turn might help to explain the altered small-bowel mucosal microvasculature observed in untreated CD patients.