Assessment of the role of the thymic transcriptome in genetic predisposition to autoimmune diseases

Autoimmune disease, like type 1 diabetes and rheumatoid arthritis, are chronic inflammatory disorders caused by an immunological attack against own tissues. Autoimmune diseases are complex genetic diseases with multiple risk factors, affecting about 5% of the population. Several hundred genetic risk variants have been revealed and many factors are overlapping between diseases. The goal of the project is to understand the how these genetic variants influence pathogenesis with focus on thymus, where self-tolerance is established. We have revised and resubmitted a paper where we have revealed ten genetic autoimmune risk variants which influence gene expression levels in thymic tissue. Next, we have isolated a panel of immune cells from thymic tissue to characterize the transcriptome of various thymic T cells (compared with blood from the same individuals), as well as of a spectrum of antigen presenting cells, all by deep RNA sequencing technology. Such studies have never been performed in human samples before (only in mice). These data are currently scrutinized and two large papers are under preparation. In addition, we have performed two separate studies to explore expression levels of antigen-presenting HLA genes, which are the major genetic determinant for autoimmune diseases, but where technically challenges are an obstacle. We have developed qPCR assays as well as a bioinformatics pipeline for RNA sequencing data to obtain reliable expression data from the HLA gene. Biological differences in expression levels of various HLA alleles have also been uncovered. Our data provide a better understanding of the role of thymus in autoimmune diseases and its relation with genetic risk variants.

Autoimmune disease, like type 1 diabetes and rheumatoid arthritis, are chronic inflammatory disorders caused by an immunological attack against own tissues. About 5 % of the population is affected and the social and personal costs are vast. Autoimmune dis eases are complex genetic diseases with multiple risk factors. In the trail of recent genome-wide association studies, upto 100 genetic risk variants have been revealed in specific autoimmune diseases and many factors are overlapping between diseases. A c hallenge ahead is to understand how these genetic variants influence pathogenesis. An interesting feature of the predisposing genes is that they mainly are of an immunological nature, and immune response genes have been shown to possess immense heritable variation in gene expression levels. Our project aims at transforming genetic association signals into functional understanding by applying new deep sequencing technology to explore the impact on transcriptome profiles in thymus. Thymus is a good candidat e for being the biological arena for these common autoimmune risk factors as it has a pivotal role in establishment of a self-tolerant T cell repertoire and hence in avoidance of autoimmunity. We will reveal the transcriptional landscape of thymic tissue and its main cell subsets, as well as identify a new layer of variation, namely DNA-RNA differences. We will correlate these features with autoimmune genetic risk variants to reveal their influence on gene expression levels, alternative splicing and prese nce of novel transcripts. Positive correlations will be replicated in blood cells to investigate whether the mechanisms appear thymus-specific or more widespread. Taken together, our project should give us a better understanding of the role of thymus in a utoimmune diseases. Ultimately, the benefits of unravelling and elucidating genetic risk variants for autoimmune diseases includes increased knowledge about pathogenesis and thereby reveal treatment targets.