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Abstract

The every day response of our immune system is a delicately balanced system between protecting the body of foreign pathogens, such as worms, viruses, infections and other intruding particles on the one side and tolerating the cells of our body on the other side. This balance is conducted by educating the T cells of the immune system during their development in the thymus upon their specific T cell receptors (TCRs) on MHC molecules of the thymic stroma cells. During their development T cells undergo two checkpoints, the positive selection in the cortical part of the thymus on ctecs (corticular thymic epithelial cells) and the negative selection in the medullary part of the thymus on mtecs (medullary thymic epithelial cells). While in the first step the TCR is tested to react at all to self MHC molecules on ctecs, in the second step the TCR is outselected if it reacts too strong to self MCH molecules loaded with self antigens on mtecs. This is an important step in order to make sure that T cells and with them the immune system tolerates self antigens and does not attack the body itself. This way it learns how to discriminate between self and foreign in order to ensure a healthy life of the individual. The peptides loaded to the self MHC molecules on mtecs are called tissue-restricted antigens (TRAs) and represent all tissues of our body. If this presentation and selection procedure is disturbed, the individual suffers of severe autoimmune diseases, in which the immune system attacks the body. Therefore the study of TRAs is most important for the medical study of autoimmunity. In former times it was thought that TRAs are located on chromosomes in a random fashion and are also randomly presented upon surface molecules on mtecs such as MHC molecules. In this thesis we could prove that the localization on a chromosomal level of TRAs is not at all random, but rather organized in so called TRA clusters and furthermore also other genes of a common function are not randomly scattered but ordered in a chromosomal context. We could also show that the gene order is not only due to gene duplication, which was often argued in the past and might give insight into gene regulation in general. One of the regulatory elements of TRA expression is known as the autoimmune regulator (AIRE). We calculated overlaps of AIRE regulated genes with our TRAs and found out that some, but not all TRAs are AIRE regulated, which highly suggests that there might be more transcription factors besides AIRE involved in the formation of central self tolerance. With this thesis I could contribute to the elucidation of more knowledge about central self tolerance, tissue-restricted antigens, gene order and gene expression in terms of chromosomal clustering of functionally related genes in general and TRA-DB is a useful tool which can also be used in the development of an immune therapy against cancer, since the problem of autoimmunity is a severe danger in the immunotherapy treatment in cancer patients.