Expression and clinical characteristics of CD161 in primary biliary cholangitis

Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic liver disease lacking noninvasive biomarkers that adequately reflect disease status. CD161 is an immunoregulatory molecule expressed on T and NK cells, but its soluble (sCD161) and membrane-bound (mCD161) forms remain poorly characterized in PBC. We measured serum sCD161 and cellular mCD161 in patients with PBC, patients with post-hepatitis B cirrhosis (PHBC), and healthy controls (HCs), and examined CD161 expression in a PBC mouse model. Serum sCD161 was markedly elevated in patients with PBC compared with both patients with PHBC and HCs. It correlated positively with the Mayo score, total bilirubin, direct bilirubin, and red cell distribution width and negatively with apolipoprotein A1, albumin, and platelet count. ROC analysis yielded an AUC of 0.8851, with 80.88% sensitivity and 86.79% specificity. The AUC for sCD161 was numerically higher than that for GGT but slightly lower than that for ALP. In contrast, mCD161 expression was reduced across multiple peripheral T-cell subsets. CD161 mRNA levels remained unchanged, whereas ADAM10/17 inhibition reduced sCD161 release and increased cell-surface mCD161 expression, supporting a role for proteolytic shedding in these reciprocal alterations. Reduced CD161 expression was also observed in T-cell subsets from the liver and spleen of PBC model mice, and multiplex immunofluorescence showed fewer hepatic CD4⁺CXCR5⁺CD161⁺ cells. These findings support the potential of sCD161 as an adjunctive biomarker for PBC diagnosis and disease assessment.