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Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Jo Spencer, King's College London, UK
- Second opponent: Professor Oliver Pabst, RWTH Aachen University, Germany
- Third member and chair of the evaluation committee: Professor Inger Nina Farstad, University of Oslo
Chair of the Defence
Professor Emeritus Frode Vartdal, University of Oslo
Principal Supervisor
Professor Ludvig Sollid, University of Oslo
Summary
Celiac disease is a chronic autoimmune disease driven by an aberrant immune response to dietary gluten. The disease is characterized by plasmacytosis of the small intestine with a proportion of the plasma cells recognizing either a deamidated form of gluten or transglutaminase 2 (TG2), the enzyme catalyzing the deamidation process. Celiac disease is dependent on specific allotypes of human leukocyte antigen (HLA) that present deamidated gluten peptides (DGP) to gluten-specific T cells. These T cells provide T-cell help to gluten-specific B cells, but also the TG2-specific B cells that take up complexes of DGP bound to TG2. TG2-DGP-complexes are hypothesized to be formed in the small-intestinal lumen after a gluten-rich meal, with TG2 derived from intestinal epithelial cells that are shed off from the small-intestinal epithelial layer. The aim of this thesis was to investigate the formation of gut plasma cells in response to orally administered gluten and an intestinal epithelial cell-derived TG2-DGP fusion protein formed through interaction with gluten-specific T cells.
To generate celiac disease-relevant plasma-cell responses, we developed a B-cell receptor knock-in mouse expressing DGP-specific B cells and a mouse inducibly expressing a TG2-DGP fusion protein in intestinal epithelial cells. In addition, we utilized mice expressing HLA-DQ2.5, B cells recognizing TG2, and T cells recognizing DGP. Using these mice, we were able to establish gut plasma-cell responses to both orally administered antigens and antigens inducibly expressed in intestinal epithelial cells. We also demonstrated that a TG2-DGP-fusion protein derived from intestinal epithelial cells could drive the interaction between T cells and B cells that is a key component of the autoreactive response in celiac disease. The animal models generated through this work may prove crucial in further investigations into potential disease triggers and mechanisms of disease recall.
Additional information
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