Role of autoreactive Natural Killer cells in the pathogenesis of Primary Biliary Cholangitis

Primary biliary cholangitis (PBC) is a chronic liver disease characterized by progressive destruction of intra-hepatic bile ducts. PBC is characterized by immune dysregulation and, although the adaptive immune response has long been implicated in PBC pathogenesis, increasing evidence suggests that also innate immune cells play an active role in the disease. Natural killer (NK) cells are increased in the liver of PBC patients and could play a role in the destruction of biliary epithelial cells (BECs). In this study we aimed to investigate the pathogenic role of NK cells and characterize the mechanisms of NK cell-mediated BEC destruction in PBC. We analyzed single-cell RNA sequencing data of peripheral blood mononuclear cells isolated from PBC patients and healthy donors (HDs). We identified a cluster of CD56br NK cells, enriched in PBC patients, and several clusters of CD56dim NK cells. NK cells from PBC patients expressed higher levels of markers related to NK cell activation (including CD69, FOS, JUNB) and cytotoxicity (including GNLY, NKG7) compared with HDs. In particular, NK cells from advanced-stage PBC patients were still active, but to a lower extent than early-stage PBC patients. In conclusion, circulating NK cells in PBC patients showed an activated phenotype that may exacerbate bile duct damage. Further studies are needed to investigate whether circulating NK cells can re-circulate from the liver or have a different origin, and whether they may be used as a predictive marker of disease progression.