Defense versus self-destruction

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Every day our immune system protects us from infections by viruses and bacteria. It recognizes and fights invading pathogens by killing them. The body´s own protection mechanisms avoid that our immune system targets ourselves.

Flu season – it is familiar to all of us: it seems as if we were surrounded by sick people and we hope not to get infected and that our immune system successfully fights the pathogens. The immune system consists of a diverse set of specialized cell types which are trained to distinguish foreign from self and to target invaders.

But what if our immune system is the cause of a disease? What went wrong in this scenario? In the case of so called autoimmune diseases, such as rheumatoid arthritis or diabetes mellitus type 1, the immune system targets the body´s own parts (connective tissue, fibers [rheumatoid arthritis] or pancreatic cells [diabetes]) by mistake. The result is inflammation, that destroys cells and tissues.

Nevertheless, autoimmune diseases are relatively rare in comparison to successfully fended infection diseases. This we owe the ´education process´ immune cells pass during their origin. The immune cells get to know which are body´s own parts and that they are supposed not to react to.

Key to this education process is the presentation of body´s own components (self antigens) towards developing T cells (one type of immune cells of the adaptive immune system). This process takes place in the thymus, an organ in our chest. The presentation is done by a specialized cell type in the thymus tissue, the thymic epithelial cells (mTECs). Developing T cells (thymocytes) that are reactive towards self get sorted out by induced cell death, thus avoiding autoimmune reactions in the periphery of the body.

The diversity of body´s own peptides that our immune system has to learn about is huge. The basic principle of our body is the specialization of cells which allows highly diverse cells with different functions. In general each cell contains the complete genome, the sum of all genes, encoding the information to build up all parts of our body. However, the specialized cells, which make up our brain, intestine or heart differ in the fraction of genes that are used to form the cell. Each cell reads just the genes which are necessary for its specific cell program. This mechanism ensures that a cell in the brain just decodes those information which are needed for the generation of a brain cell. Our genome consists of approximately 23 thousand genes, encoding all information required to build such a complex system as the human body. Though, a single cell is not able to read out all information of the genome and build all proteins encoded by the genes and then decide afterwards which ones to use and which not. This would not just take way too long to fulfill, it would also simply require an amount of energy that is not available. Due to this fact the specific usage and decoding of necessary gene information in each cell is tightly controlled.

The medullary thymic epithelial cells are characterized by: I) their capability to express a wide variety of self-peptides and II) that they present those towards developing immune cells thus establishing self tolerance.

For this purpose mTECs annul the otherwise effective mechanism of specialization and express in addition to their cell type specific program a diverse set of peptides normally only expressed in cells of the brain, intestine, lung and many more. It has long been discussed by experts in the field how mTECs might achieve the expression of so many diverse components of other cell types. Nowadays we know that not each single mTEC is expressing the whole set, rather they express about one to three percent of the full repertoire at any given time point, leading to the so called mosaic expression pattern, in which the mTECs differ in the sets of expressed genes. This mechanism maximizes the spectrum of presented self-peptides towards developing thymocytes. However it remained puzzling how these expression patterns evolve mechanistically.

One hypothesis would be that each mTEC randomly expresses parts of the genes in addition to their specific program. Based on the variance, that results out of the random selection the mosaic expression pattern would occur.

Another potential mechanism would be a common regulatory mechanism underlying the gene expression in mTECs. In such a scenario the expression pattern in mTECs would result out of specific regulatory factors (transcription factors) which target defined sets of genes and regulate their expression.

The mosaic expression of just one to three percent of the self peptides in each mTEC leads to a high degree of diversity (high heterogeneity) between all the cells of the population. This fact made studies in this field difficult so far. Recent new technologies that allow genome wide studies of low cell numbers led to new findings.

Detailed knowledge of the regulatory mechanism underlying the expression patterns of self peptides is important for us in order to be able to understand, if for instance in the case of an autoimmune disease a certain gen did not get expressed in a patient and thus the immune system did never learn to identify that component as body´s own (self). Just at the point where we understand the functioning of self tolerance of the immune system we will be able to tell what is different from these processes in patients with autoimmune diseases and thus ultimately apply personalized treatments in future.

Therefore, we hope to better understand the regulation of the production of body´s own peptides in the thymus and thus the mechanisms of central tolerance (thymic self tolerance) soon. The latest research results are promising as they report on highly organized and tightly regulated expression patterns, which would be of great advantage in the context of potential treatments, as it would be feasible to target such a mechanism whereas expression patterns based on a random process would be hardly manipulable.

Thus, when our immune system again successfully protects us from infections by viruses or bacteria it at the same time also spared us from self attacking. Maybe knowing that our immune system always has to find the balance between defense and carefully avoid harming ourselves, will help you to fell a little better next time you are facing a cold. This secure mechanism might eventually give the opportunity to the one or other pathogen to infect us.



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