Compromised Immunocompetence Results in Mild Liver Fibrosis in ALGS

JAGGED1 mutation in Alagille syndrome (ALGS) blunts the immune response, resulting in mild liver fibrosis, according to a poster presentation at the European Association for the Study of the Liver (EASL) Congress in Vienna, Austria, this June. 

Scientists have been puzzled by the relative lack of severe fibrosis and cancer in patients with ALGS, despite the prominence of recurring infections. This is likely due to gaps in the knowledge regarding how mutations in the Notch ligand JAGGED1 regulates immune system development and liver disease progression. 

Mašek and colleagues sought to understand how liver and immune system development are affected in a model of ALGS. They assessed fibrosis and liver cancer prevalence in Jag1^Ndr/Ndr mice and analyzed liver cell populations in an ALGS mouse model using single-cell transcriptomics, as well as in the liver, thymus, and spleen using flow cytometry. 

The research team also tested immune cell function using adaptive immune cell transplantation in 3 groups of Rag1^-/- mice, each modeling conditions similar to ulcerative colitis, hepatocellular cholestasis, or biliary cholestasis. 

Read more about ALGS etiology 

Mašek et al. discovered that none of the Jag1^Ndr/Ndr mice developed liver tumors; instead, these mice developed mild hepatocellular fibrosis typically seen in ALGS, as well as delayed hepatocyte differentiation with blunted inflammation. Jag1^Ndr/Ndr mice were also found to have decreased CD4+ T-cell infiltration into the liver. The CD4+ to CD8+ T-cell ratio in the spleen was raised, as were regulatory T-cell numbers. 

The researchers found that transplanted Jag1^Ndr/Ndr lymphocytes were less reactive in the ulcerative colitis mice model; there was also less activation of the CD4+ and CD8+ T-cells. Finally, Jag1^Ndr/Ndr lymphocyte-transplanted Rag1^-/- mice induced with biliary cholestasis demonstrated 3-fold less periportal fibrosis compared with Rag1^-/- mice transplanted with Jag1^+/+. 

In conclusion, this study shows that the immune system interacts with liver disease to modulate fibrosis in ALGS. In addition, compromised immunocompetence explains the frequent reports of infection in patients with this disorder. 

Reference

Mašek J, Filipovic I, Hankeová S, et al. Immune cell incompetence and hepatocyte differentiation defects explain mild fibrosis in a model of Alagille syndrome. Presented at: European Association for the Study of the Liver (EASL) Congress 2023, Vienna, Austria; June 21-24, 2023. Abstract THU-255.