The cause of PSC is unknown, but genetic studies suggest that the immune system plays a central role in disease development.
Valestrand and colleagues demonstrate in this thesis that bile from patients with chronic liver diseases contains substances that activate the immune cells natural killer T (NKT) cells and mucosa-associated invariant T (MAIT) cells. These immune cells are abundant in the liver and have properties that can regulate immune processes in both protective and harmful directions.
In a mouse model where the common bile duct was ligated, leading to accumulation of bile (cholestasis), the NKT cells were found to be specifically activated. When the common bile duct of mice lacking NKT cells was ligated, these mice developed less liver injury compared to bile duct ligated wild type mice.
This indicates that NKT cells contribute to liver damage during cholestasis. To investigate the role of bile duct cells in NKT cell-related disease progression in cholestasis, a new mouse model was generated with specific loss of CD1d on bile duct cells, a molecule mediating NKT cell activation. By ligating the common bile duct of the novel model with specific loss of CD1d, bile duct cells were not found to be the main contributors to NKT cell related liver injury in acute cholestasis.
These results provide new insight into how the immune system and bile interact in cholestatic liver diseases such as PSC. MAIT and NKT cells represent potential targets for future treatment aimed at protecting the liver and thereby improve the quality of life and survival for patients with these serious liver diseases.
Principal supervisor Professor Espen Melum says “Laura’s thesis is significant fundamental work that sheds light on how the immune system, particularly unconventional T-cells, functions in the context of bile duct inflammation and cholestasis, two processes of crucial importance for primary sclerosing cholangitis (PSC).
We congratulate Dr. Laura Valestrand on successfully defending her thesis. Her work continues at the Department of Pathology at Oslo University Hospital.