Self-destructive immune cells cause fatty liver hepatitis
Fatty liver hepatitis can cause severe liver damage and liver cancer. A research team from the Technical University of Munich (TUM) has now discovered that self-destructive, so-called auto-aggressive cells of the immune system are responsible for the disease. This knowledge can help develop new forms of therapy to prevent the consequences of fatty liver hepatitis.
Excessive obesity is often associated with fatty liver inflammation. So far, it was largely unknown how the disease came about. The team led by the immunologist Prof. Percy Knolle from TUM has researched this process step by step in model systems on mice – and thus provides trend-setting insights into the development of fatty liver hepatitis in humans. “We were also able to observe all the steps that we saw in model systems in patients,” emphasizes Knolle. The team published the results in the renowned journal “Nature”.
Auto-aggressive immune cells destroy liver tissue
The immune system protects us from bacteria and viruses and from malignant tumors from developing. So-called killer CD8 T cells are particularly important here. They specifically recognize infected body cells and eliminate them. In fatty liver hepatitis, the CD8 T cells have lost this ability to specifically switch off. “We have discovered that the immune cells in fatty liver hepatitis are not activated by certain pathogens but by metabolic signals,” explains Michael Dudek, first author of the study. “The T cells activated in this way then indiscriminately destroy all cells in the liver.”
Gradual activation of T cells
Until then, the immune cells go through a unique, step-by-step cell activation that was previously unknown. Only when inflammatory signals and products of lipid metabolism act on the immune cells in the right order do they develop their destructive ability. “Similar to entering a security code to open a safe, the T cells are only ‘armed’ through the defined sequence of activation signals,” says Knolle, who is Professor of Molecular Immunology at TUM. The international research team identified an actually harmless metabolite as the trigger for the killing of tissue cells: the energy carrier ATP, which must be located outside the cells for this. Auto-aggressive CD8 T cells in the liver that reacted with ATP
Auto-aggression, but not autoimmunity
The destruction of tissue by auto-aggressive immune cells discovered by the researchers differs from conventional autoimmune diseases. Cells of the immune system specifically target certain body cells. However, tissue-destroying auto-aggressive T cells may also play a role in autoimmune diseases, although this is not yet known, according to the authors.
New therapies for fatty liver hepatitis
So far, fatty liver hepatitis can only be reversed if the triggering factors – obesity and a high-calorie diet – are eliminated, i.e. the patients change their lifestyle. The knowledge that fatty liver hepatitis is caused by activated immune cells is now providing impetus for the development of new therapies. “The destructive auto-aggressive form of the immune response can be clearly separated from the protective T-cell immune response against viruses and bacteria,” says Knolle. He is confident that targeted immunotherapies can be researched that only prevent tissue destruction.
Featured image: Prof. Percy Knolle and an international research team have discovered that immune cells are stimulated by certain signals to attack healthy liver cells and thus trigger fatty liver Hepatitis. Image: Andreas Heddergott
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, F. 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. Auto-aggressive CXCR6 + CD8 T cells cause liver immune pathology in NASH. Nature (2021). DOI: 10.1038 / s41586-021-03233-8 .
Provided by TUM