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Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Paul Klenerman, University of Oxford, UK
- Second opponent: Professor Katharina Scherf, KIT - Karlsruhe Institute of Technology, Germany
- Third member and chair of the evaluation committee: Professor Ketil Størdal, University of Oslo
Chair of the Defence
Associate Professor Andreas Lossius, University of Oslo
Principal Supervisor
Professor Ludvig Magne Sollid, University of Oslo
Summary
Celiac disease is an autoimmune-like disorder mediated by maladapted T cell responses to gluten proteins. Gluten-reactive CD4+ T cells play the main role in the pathogenesis of celiac disease. These T cells specifically recognize TG2-deamidated gluten peptides in the context of disease predisposing HLA-DQ2.2/HLA-DQ2.5/HLA-DQ8 molecules. These peptides have been extensively studied and several epitopes have been discovered. Of these, only few dominate the immune response across patients and are referred to as immunodominant epitopes. HLA-DQ2.5:gluten tetramers representing these immunodominant epitopes enable specific isolation of gluten-reactive T cells. However, several studies suggests that there exists a large population of gluten-reactive T cells that do not recognize immunodominant or any other known epitopes. Recently, it was demonstrated that these T cells express a very distinct phenotype. Here, we demonstrated that by harnessing the specific phenotype of glutenreactive T cells, we can isolate large numbers of gluten-reactive T cells without the need for HLA- DQ2.5 tetramers. Expectedly, a large number of these gluten-reactive T cells were unreactive to known gluten epitopes. We used these T cells and harnessed the knowledge of characteristic shared features of known gluten epitopes to develop a scalable and effective strategy for the identification of novel epitopes that stimulate pathogenic CD4+ T cells driving the celiac disease. In a relatively small-scale study, we successfully identified five novel gluten epitopes. Lastly, we examined responses and phenotype of disease-relevant CD4+ T cells, CD8+ T cells, and γδ T cells in patients with dermatitis herpetiformis, an extraintestinal manifestation of celiac disease, before and after gluten challenge. We demonstrated that T cells from patients with dermatitis herpetiformis exhibit similar responses to gluten as T cells from patients with classical celiac disease.
Additional information
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