The role of androgens in autoimmune liver diseases

• Applicants: Professor Dr. Christoph Schramm; Dr. Dorothee Schwinge
• Subject Area: Gastroenterology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 429191104

The autoimmune liver diseases autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) exhibit some of the highest female predominance among all autoimmune diseases. The underlying reasons remain unknown but there is evidence that androgens play an important role in mediating sex differences in immunity. To analyse the effects of androgens on immune cells, we recruited different human cohorts: transgender people before and during gender-affirming hormone therapy (GAHT) and age-matched cis women with PBC, AIH and healthy controls and performed detailed analyses of immune cells. We found that testosterone affects CD4+ T cell function by inhibiting Th1 and Th17 differentiation and by supporting the differentiation into regulatory T (Treg) cells. We noted decreased testosterone serum levels in women with PBC compared to age-matched controls, supporting a potential role of androgens for T cell dysfunction in this disease. In a trans man with AIH/primary sclerosing cholangitis variant syndrome we observed a markedly improved clinical disease course and profound changes in T cell state using single-cell RNA sequencing during GAHT. We hypothesize that androgens affect T cells directly and that androgen signaling shapes the interaction between T cells and parenchymal cells in the liver. We aim to dissect the cell-specific role of androgens in liver inflammation using conditional knockout mice lacking the androgen receptor AR or/and the membrane-bound androgen receptor ZIP9 in T cells and liver parenchymal cells such as cholangiocytes. To investigate the sex-related immune cell state and the interaction between immune cells and hepatic parenchymal cells, we will analyze a large single-nucleus sequencing dataset derived from human liver samples we obtained from different liver diseases. We will functionally validate findings using established cholangiocyte organoid models (human/mouse). Overall, the elucidation of the role of androgen signaling in the liver may reveal novel treatment targets for autoimmune liver diseases.

• DFG Programme: Research Units
• Subproject of: FOR 5068: Sex differences in immunity