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Adjudication committee
- First opponent: Assistant Professor Barbara E. Stranger, Department of Medicine, University of Chicago, USA
- Second opponent: Professor Eystein Sverre Husebye, Department of Clinical Science, University of Bergen
- Third member and chair of the evaluation committee: Associate Professor Shuo-Wang Qiao, Faculty of Medicine, University of Oslo
Chair of the Defence
Professor II Mathias Toft, Faculty of Medicine, University of Oslo
Principal Supervisor
Professor Benedicte A. Lie, Faculty of Medicine, University of Oslo
Summary
Autoimmune diseases (AIDs) comprise a variety of chronic inflammatory disorders where the immune system attacks the body´s own tissues and organs. Genome-wide association studies have given us a long list of genetic risk variants associated with AIDs, however, the majority of the SNPs are enriched in the non-coding region of the genome, suggesting that they have a regulatory role. Furthermore, AIDs occur due to failure in the immune self-tolerance system. The thymus plays an essential role in the development of immune tolerance, as it is the organ where T-cells with functionally competent T-cell receptors tolerant to the body´s tissues and organs are selected. Today, RNA sequencing of central human thymic cell types, such as the thymic antigen presenting cells (APCs), has yet not been performed.
The first aim of the thesis was to investigate whether risk variants associated with AIDs could influence gene expression levels in human thymus. Genotypes and mRNA levels were investigated in thymic tissue samples from 42 Norwegian patients. In total, nine genetic risk variants were found to correlate with the expression levels of genes in human thymus. These findings suggest that genetic risk variants associated with AIDs can have an influence on thymic gene regulation.
The second aim of the thesis was to compare the transcriptomes of four different human thymic APCs. By performing RNA sequencing, this study showed that the thymic CD141+ dendritic cell is the most active APC in terms of expressing genes involved in antigen processing and human leukocyte antigen (HLA) presentation. The data also supports that mTECs express AIRE, FEZF2 and a high variety of tissue enriched genes. Finally, the APCs also expressed the genes that correlated with AID associated SNPs, suggesting that these SNPs might affect gene regulation in the human thymic APCs.
Taken together, this has given us a better insight into the human thymic transcriptome and its role in genetic predisposition to AIDs.
Additional information
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