Due to copyright issues, an electronic copy of the thesis must be ordered from the faculty. For the faculty to have time to process the order, the order must be received by the faculty at the latest 2 days before the public defence. Orders received later than 2 days before the defence will not be processed. After the public defence, please address any inquiries regarding the thesis to the candidate.
Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Full Professor Janneke N. Samsom, Erasmus University Rotterdam, The Netherlands
- Second opponent: Researcher Mats Bemark, University of Gothenburg, Sweden
- Third member and chair of the evaluation committee: Professor II Inger Nina Farstad, Faculty of Medicine, University of Oslo
Chair of the Defence
Professor Emeritus Frode Vartdal, University of Oslo
Principal Supervisor
Professor Ludvig Magne Sollid, Faculty of Medicine, University of Oslo
Summary
Celiac disease is an autoimmune disorder driven by ingestion of cereal gluten proteins. There is a strong association of the disease with HLA allotypes DQ2.5, DQ2.2, and DQ8, and celiac disease patients have T cells that recognize deamidated gluten epitopes in the context of these disease-associated HLA molecules. Patients also have B cells and antibodies that recognize the self-protein transglutaminase 2 (TG2), and deamidated gluten peptides. B cell – T cell collaboration seems to have an important role in celiac disease pathogenesis. A hapten-carrier model proposes that TG2-specific T cells take up gluten peptides bound to TG2 and present these to gluten-specific T cells. The mechanism for this dual antigen uptake lies in the enzymatic activity of TG2, which is capable of crosslinking proteins to itself, as well as protein deamidation.
Here, we have genetically modified mice in order to study aspects of adaptive cell – cell interactions relevant to celiac disease in vivo. We have created or acquired mice that express HLA-DQ2.5, knock-in TG2- or gluten peptide-specific B cell receptors, gluten peptide-specific transgenic T cell receptors, and TG2 knock-out mice. Using these mice, we investigated and compared the development of TG2-specific B cells in the presence and absence of cognate antigen, and found no differences in B cell development, suggesting a lack of B cell tolerance induction to TG2, and the possibility that the autoantigen is not readily found extracellularly and available to B cells. We also investigated B cell – T cell interactions in vitro and in vivo to complexes of TG2 and gluten, and characterized HLA-DQ2.5 knock-in and gluten-specific B cell receptor knock-in mice. Because so much is known about celiac disease it is a good candidate for studying autoimmune disease etiology, and the models used in this work were established with that aim in mind.
Additional information
Contact the research support staff.