The mechanism responsible for the development of autoimmune diseases is discovered

Academics are researching the development of tolerance against the body’s own tissue

During inflammation processes, cells from our immune system do not only encounter pathogens, but also the remains of dead cells from our body which accumulate from the accompanying tissue damage. In order to prevent an incorrect immune reaction against the body’s own dead cells and, thus, avoid a “horror autotoxicus” and the resulting autoimmune disease, dead cells must be separated from pathogens and “disposed of” appropriately. Until now, it was unclear how to differentiate between the pathogens and dead cells and how to dispose of them separately. Now, for the first time, Dr. Gerhard Krönke’s working group at Medical Clinic 3 – Rheumatology and Immunology at the Erlangen University Hospital (director Prof. Dr. Georg Schett) has identified an enzyme (12/15 lipoxygenase) that controls this basic decision-making process. The results published in the journal “Immunity” showed, amongst other things, that this enzyme’s loss of function leads to incorrect disposal of dead cells and a resulting systemic autoimmune reaction. This has uncovered an essential molecular mechanism in the development of autoimmune diseases, such as lupus erythematosus.

Coordinated separation of waste via the immune system’s macrophages
Every day our immune system has to cope with the difficult task of differentiating between harmful micro-organisms and the harmless remnants of the body’s own cells. The consequences of this decision-making process are far-reaching because the immune reaction against micro-organisms is needed for long-lasting and protective immunity. However, if such an immune reaction takes place against the body’s own cells it can lead to a life-threatening autoimmune disease.

Dr. Stefan Uderhardt and Dr. Gerhard Krönke have now, for the first time, been able to reveal that a special sub-group of macrophages is responsible for disposing of the body’s own dead cells. These tissue macrophages have the ability to dispose of specific dead cells and thus prevent an attack by other parts of the immune system on their remains. At the same time, however, bacteria and other pathogens are recognised and picked up by inflammatory cells from the immune system (monocytes). This process leads to a specific immune reaction. In this way, when faced with inflammations or infections, our immune system performs an early “waste separation” between harmful pathogens and the body’s own dead cells. On the one hand, this is a way of specifically fighting against pathogens and, on the other, prevents an autoimmune reaction and maintains immunological tolerance.

Lipid oxidation as the key to the disposal of dead cells
In addition to identifying this “immunological waste separation” and the sub-grounds of immune cells involved in it, the scientists were also able to discover the underlying molecular mechanisms. They identified a special enzyme in tissue macrophages (12/15 lipoxygenase), which coordinates the separate disposal of dead cells and pathogens. This enzyme, in turn, produces special messenger substances, known as oxidised phospholipids, which control the clean up process via the immune system’s different cells. “However, if this enzyme is missing the disposal of dead cells is disrupted, leading to an autoimmune disease,” explains Dr. Gerhard Krönke, working group leader at Medical Clinic 3. “We were able to show that by adding the oxidised phospholipids generated by the enzyme, proper “waste separation” can be re-established and, thus, an autoimmune reaction prevented”, Krönke continues. In this regard, the work currently being conducted represents essential progress in the development of new and targeted therapies against disorders such as lupus erythematosus.

Over the long-term our body pays for immunological tolerance
Although this oxidation of phospholipids via the enzyme 12/15 lipoxygenase seems essential in maintaining immunological tolerance, sustained and increasing lipid oxidation via this enzyme over many years is also a main cause for the development of arteriosclerosis and vascular calcification and, ultimately, jointly responsible for heart attacks and strokes. These findings therefore indicate that, over the course of our lives, we must “pay” for protection against autoimmune diseases through higher susceptibility to arteriosclerosis and vascular calcification.

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uni | media service | research No. 13/2012 on 16.4.2012