Immune profiling identifies dysregulated natural killer-cell responses in primary biliary cholangitis patients who fail treatment with ursodeoxycholic acid

Primary biliary cholangitis (PBC) is characterized by variable response to first-line therapy with ursodeoxycholic acid (UDCA). Natural killer (NK) cells have been involved in PBC pathogenesis, yet their contribution to treatment response remains poorly defined. To investigate the involvement of NK cells in PBC and UDCA response.In this study, single-cell RNA sequencing and flow cytometry were combined to profile NK cells in peripheral blood and liver tissue from 60 PBC patients and 34 matched controls.Circulating NK cells were lower in PBC patients than controls, with a relative increase in CD56Bright and decrease in CD56Dim NK cells. These findings were consistent across transcriptomic and flow cytometric analyses. Transcriptomic profiling revealed an activated NK-cell program enriched in genes associated with cytotoxicity and inflammatory responses that was confirmed at the protein level by increased activation and expression of chemokine receptors. NK cells from UDCA non-responders showed higher activation, inflammatory and cytotoxic signatures than responders, indicating an association between NK cell activation and lack of UDCA response. Liver mononuclear cells from end-stage UDCA non-responders were enriched in activated tissue-resident CD56Bright NK cells, suggesting that persistent pro-inflammatory intrahepatic NK cells may contribute to bile duct injury and fibrotic progression.By defining local and systemic NK cell alterations, this study generates new insights into PBC pathogenesis and paves the way for novel therapeutic strategies for the management of UDCA non-responders.