Non-alcoholic steatohepatitis (NASH), often referred to as ‘fatty liver hepatitis’, can cause severe liver damage and liver cancer. A team of researchers at the Technical University of Munich (TUM) has discovered that this condition is caused by cells invading healthy tissue – what is known as self-aggression. Their findings could help develop new therapies to avoid NASH results.
Fatty liver disease (NASH) is often associated with obesity. However, our understanding of the causes has been very limited. A team working with psychologist Professor Percy Knolle of TUM has now studied this process step-by-step in mouse-based modeling systems – and gained promising insights into the the mechanisms that cause NASH in humans. “We have seen every step seen in the modeling systems in human patients,” says Dr. Knolle. The team ‘s results will be published in Nature.
Self-aggressive immune cells destroy liver tissue
The immune system protects us from bacteria and viruses and the development of cancerous tumors. The so-called CD8 killer T cells play an important role here. In particular, they identify infectious body cells and remove them. With fatty liver hepatitis, the CD8 T cells have lost this ability to target inactivation. “We have found that, at NASH, the immune cells are not activated by specific pathogens, but by metabolic stimuli,” says Michael Dudek, first author of the study. “The T cells activated in this way then kill liver cells of all kinds.”
Continuous activation of T cells.
Until then, the immune cells go through a specific, step-by-step process of action – which was not previously known. The T cells develop their self-aggressive properties only when exposed to inflammatory signals and fat metabolism results in the correct order. “As when we use the combination to release an immune system, the T cells are converted to a‘ lethal mode ’only through the defined set of activation stimuli,” says Dr. Knolle, professor of molecular immunology at TUM. As the reason for killing thin cells, the international team of researchers identified a harmless metabolite: the presence of extracellular ATP cells. When autoimmune CD8 T cells in the liver react with ATP, they destroy nearby cells, thus causing NASH.
Auto-aggression, but not self-defense disorder
Tension destruction through autoimmune immune cells, as the researchers found, is different from cognitive autoimmune disorders, in which immune system cells make specific attacks on specific cells in the body. The authors note, however, that the self-destructing substance-destroying T cells may play a role in as yet undetected autoimmune pathways.
New therapies for fatty liver hepatitis
Until now, the only way to reverse the effects of fatty liver hepatitis was to eliminate the underlying factors – namely obesity and a high-calorie diet. In other words, patients had to change their lifestyles. The understanding that the disease is caused by active immune cells now suggests the potential for the development of new therapies. “The self-destructive form of the immune response is fundamentally different from the T-cell immune response to viruses and bacteria,” says Dr. Knolle. It is encouraging that further research will identify targeted immunotherapies that prevent tissue destruction.
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Published:
M. Dudek, D. Pfister, S. Donakonda, P. Filpe, A. Schneider, M. Laschinger, D. Hartmann, N. Hüser, P. Meiser, F.Bayerl, D. Inverso, J. Wigger, M. Sebode, R. Öllinger, R. Rad, S. Hegenbarth, M. Anton, A. Guillot, A.Bowman, D. Heide, P. Ramadori, V. Leone, F. Müller, C. Garcia-Caceres, T. Gruber, G. Seifert, AM Kabat, J.-P. Malm, S. Reider, M. Effenberger, S. Roth, A. Billeter, B. Müller-Stich, EJ Pearce,. Koch-Nolte, R. Käser, H. Tilg, R. Thimme, T. Böttler, F. Tacke, J.-F. Dufour, D. Haller, PJ Murray, R. Heeren, D. Zehn, JP Böttcher, M. Heikenwälder, PA Knolle. Autoimmune CXCR6 + CD8 T cells cause liver immune pathology in NASH. Nature (2021). DOI: 10.1038 / s41586-021-03233-8.
Further information:
Professor Pery Knolle
https: /
Institute of Molecular Psychology
http: // www.
High resolution images:
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Contact:
Prof. Dr. Percy Knolle
Munich Technical University
Institute of Molecular Psychology
Phone: +49 (0) 89 4140-6921
[email protected]
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