The problem of self-tolerance versus autoimmune reaction

In vertebrates, the adaptive Immune system has an extraordinary potential for generating receptors that sense and neutralize any foreign antigens entering the body. Efficient recognition of the foreign antigens depends on the regulation of sense and non-sense in Thymus tissue where T cells are selected first positively and negatively. Promiscuous gene expression of Tissue specific antigens (TSA), which is required for negative selection, is introduced to T cells by mature mTEC cells mostly by through the control of Aire gene function in Thymus. Any failure within the function of the Aire gene results in the loss of sense and non-sense separation and thereby, autoimmunity due to improper representation of TSA in Thymus.

De novo evolved genes usually brings novel expression pattern with newly evolved genetic content to specific tissues and therefore, new protein products within the certain cell types. These novel protein products or peptides, which are expressed within the cells and represented by the major histocompatibility complex on the cell surface, have to be introduced to the immune system to avoid autoimmune reaction. Otherwise any tissue having a newly emerged peptide, which is represented on their cell surface, will be considered as foreign antigen and tissue/cells that are having such peptide will be attacked and destroyed by the immune system. Therefore, we propose that de novo evolved protein-coding genes should also be expressed within the thymus tissues to generate self-tolerance.

Based on the analysis from Thymus RNA seq data along with 9 other tissues within the phylogeny of Mus genus, we provide evidence that Thymus plays a very critical role in the evolution of metazoan by controlling birth of a new gene in a specific tissue. Our results indicate a primary role for the Thymus controlling expression of all protein coding genes within both annotated Genic and Non Genic regions. The mechanisms may also be relevant for hybrid incompatibility effects between species and sub-species and thus also of relevance for speciation processes.