Celiac disease IgA modulates vascular permeability in vitro through the activity of transglutaminase 2 and RhoA

Abstract

Celiac disease is characterized by the presence of specific autoantibodies targeted against transglutaminase 2 (TG2) in untreated patients' serum and at their production site in the small-bowel mucosa below the basement membrane and around the blood vessels. As these autoantibodies have biological activity in vitro, such as inhibition of angiogenesis, we studied if they might also modulate the endothelial barrier function. Our results show that celiac disease patient autoantibodies increase endothelial permeability for macromolecules, and enhance the binding of lymphocytes to the endothelium and their transendothelial migration when compared to control antibodies in an endothelial cell-based in vitro model. We also demonstrate that these effects are mediated by increased activities of TG2 and RhoA. Since the small bowel mucosal endothelium serves as a "gatekeeper" in inflammatory processes, the disease-specific autoantibodies targeted against TG2 could thus contribute to the pathogenic cascade of celiac disease by increasing blood vessel permeability.

A single conformational transglutaminase 2 epitope contributed by three domains is critical for celiac antibody binding and effects

“…Celiac antibodies bind well to both the Ca 2þ -bound and Ca 2þ -free TG2 (Fig. S1B) and to open-form TG2 (8) and TG2 transamidates substrates even in the presence of bound celiac antibodies (28). These observations strongly contradict the earlier suggestion (20) that the catalytic triad, situated buried and exposed on the surface just when Ca 2þ and substrates are available, would compose the celiac epitope.…”

Activity-regulating structural changes and autoantibody epitopes in transglutaminase 2 assessed by hydrogen/deuterium exchange

“…TG2-reactive autoantibodies produced in celiac disease could therefore influence TG2 function. Indications of such an effect have been observed by the addition of celiac disease antibodies to cell culture systems (36)(37)(38)(39)(40)(41). The mechanisms underlying the various biological effects reported are not well understood.…”

The role of tissue transglutaminase (TG2) in regulating the tumour progression of the mouse colon carcinoma CT26

“…TG2 activity can influence this process either directly by crosslinking (Chau et al 2005) or indirectly by the crosslinking and activation of matrix-associated latent TGFb . Accumulating reports indicate that TG2-mediated matrix changes can inhibit tumour invasion (Di Giacomo et al 2009;Jones et al 2006;Mangala et al 2005), while a TG2-crosslinked extracellular matrix can also inhibit angiogenesis (Jones et al 2006;Myrsky et al 2009). We recently demonstrated that intratumour injection of TG2 into mice bearing the CT26 tumours led to induction of fibrosis and tumour regression (Jones et al 2006).…”