Inhibition of transglutaminase 2 enzymatic activity ameliorates the anti-angiogenic effects of coeliac disease autoantibodies

Objective. Earlier work has demonstrated that serum autoantibodies from coeliac patients targeted against transglutaminase 2 (TG2) inhibit in vitro angiogenesis. The aim of this study was to establish whether coeliac patient-derived monoclonal TG2-targeted antibodies produced by recombination technology exert similar anti-angiogenic effects to serum-derived coeliac autoantibodies. In addition, we studied whether the monoclonal patient autoantibodies modulate endothelial cell TG2 activity and whether such modulation is related to the anti-angiogenic effects. Material and methods. The influence of coeliac patient-derived monoclonal TG2-targeted antibodies on endothelial cell tubule formation was studied using a three-dimensional angiogenic cell culture model. Endothelial cell TG2 enzymatic activity was determined by means of a live-cell enzyme-linked immunosorbent assay. Results. Coeliac patient-derived monoclonal TG2-targeted antibodies produced by recombination technology inhibited endothelial tubule formation and enhanced the crosslinking activity of TG2. When this enzymatic activity was inhibited using site-directed irreversible TG2 inhibitors in the presence of autoantibodies, in vitro angiogenesis reverted to the control level. Conclusions. Since we found a significant negative correlation between endothelial cell angiogenesis and TG2 activity, we suggest that the anti-angiogenic effects of coeliac patient-derived TG2-targeted autoantibodies are exerted by enhanced enzymatic activity of TG2.

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

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.

modern foreign languages classroom:is inclusion of all exclusion in disguise?

The past decade has seen a drive to give all pupils the opportunity to study a Modern Foreign Language (MFL) in schools in England, making the teaching and learning of foreign languages part of the primary school curriculum. The Languages for All: Languages for Life (DfES, 2002) policy was introduced through the National Languages Strategy with an objective to increase the nation’s language capability. Raising the educational standard for all pupils is another government initiative with a strong emphasis on inclusion. As the Languages for All policy stresses the importance and benefits of language learning, and inclusion suggests equality and provision for all, this study examines the inclusion of all key stage 2 pupils in foreign language learning and describes perceptions and experiences of pupils, particularly those identified as having special educational needs (SEN) in their performances and negotiations in learning French. As a small scale, qualitative and ethnographically informed, this research is based on participant observation and semi-structured interviews with pupils, teachers of French, teaching assistants and parents. This study draws upon Nussbaum’s capabilities approach and Bourdieu’s concepts as theoretical foundations to analyse the ‘inclusive’ French classroom. As the capabilities approach takes people as ends not means, and goes beyond a focus on resources, it lends itself to critical thinking on issues around inclusion in education. In this context, this researcher investigates the experiences of pupils who struggle with foreign language learning because of their abilities or disabilities, and frames the discussion around the capabilities approach. The study also focuses on motivation and identity in foreign language learning, and draws upon Bourdieu’s concepts of capital, habitus and field to analyse how the participants make sense of and respond to their own circumstances in relation to their performances in the language learning process. This research thus considers Bourdieu’s concepts for a deeper understanding of issues of inequality in learning French and takes up Nussbaum’s insight that pupils may differ in what learning French means to them, and it is not how they differ, but the difference between their capability to choose and achieve what they value that should matter. The findings indicate that although, initially, the French classroom appears ‘inclusive’ due to the provision and practices of inclusion, a closer look shows it to be exclusionary. In addition, responses from the participants on the usefulness and benefits of foreign language learning are contradictory to the objectives of the Languages for All policy, illustrating the complexity of the ‘inclusive’ MFL classroom. This research concludes that structural and interpersonal practices of inclusion contribute to the disguising of exclusion in a classroom deemed ‘inclusive’. Implications are that an understanding and consideration of other aspect of life such as well-being, interests, needs and values should form a necessary part of the language policy.