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Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Daniel Aeschlimann, Cardiff University, UK
- Second opponent: Research Director Nadine Cerf-Bensussan, Paris Cité University, France
- Third member and chair of the evaluation committee: Adjunct Professor Johannes Espolin Roksund Hov, University of Oslo
Chair of the Defence
Professor Jan Terje Andersen, University of Oslo
Principal Supervisor
Professor Ludvig M. Sollid, University of Oslo
Summary
Celiac disease is an autoimmune-like disorder of the small intestine driven by the ingestion of gluten proteins. Celiac patients have T-cells that recognize deamidated gluten epitopes presented by disease associated HLA-DQ2.2/HLA-DQ2.5/HLA-DQ8 molecules, which initiates an immune response. The patients also produce antibodies targeting the deamidated gluten epitopes and the endogenous protein transglutaminase 2 (TG2). Formation of anti-TG2 autoantibodies is explained with a Hapten-carrier model. Here, TG2:gluten complexes are internalized by TG2-specific B cells and the gluten peptide is subsequently presented to gluten-specific T cells, leading to activation of both the T-cell and the B-cell. This TG2 enzyme is in addition responsible for the deamidation of the gluten epitopes. This deamidation occurs via formation of a covalent enzyme-substrate intermediate. This intermediate has two potential end products; one where the gluten peptide is cross-linked with a secondary substrate (potentially TG2 itself), the other is that if no secondary substrate is available, the gluten peptide is deamidated. A remaining question in celiac disease pathogenesis is where in the intestine does gluten and TG2 interact.
Here, we present a new model, where pathogenic TG2 is released into the intestinal lumen from shed epithelial cells. In the lumen TG2 will encounter substantial amounts of gluten peptide and a TG2:gluten complex can become readily available to immune cells though Peyer’s patches. We have shown that TG2 with enzymatic potential is readily available from epithelial cells and can drive the collaboration between TG2-specific B cells and gluten-specific T cells. In patients with active celiac disease, we saw an increase in TG2 expression in epithelial cells compared to healthy people, in particular in the cells just about to be shed into the lumen. We also show that the affinity between TG2 and gluten peptides drives the selection of gluten T-cell epitopes, as they have a higher likelihood to be internalized by TG2-specific B-cells and subsequently presented to T-cells. And, that it likely is the TG2:gluten enzyme-substrate intermediate that is internalized by the TG2-specific B cells, at least to a higher extent then when gluten is crosslinked to TG2 acting as a secondary substrate.
Additional information
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