Unique DUOX2(+)ACE2(+) small cholangiocytes are pathogenic targets for primary biliary cholangitis

The aetiology of primary biliary cholangitis (PBC) remains unclear. Here, the authors find that the numbers of DUOX2( +) ACE2 (+) small cholangiocytes in human and mouse livers are inversely associated with disease severity, and present data indicating that they may be the target of polymeric immunoglobulin receptor (pIgR) -mediated humoral responses, suggesting that preservation of these cells and targeting anti-pIgR autoantibodies may be valuable strategies for therapeutic interventions in PBC. Cholangiocytes play a crucial role in bile formation. Cholangiocyte injury causes cholestasis, including primary biliary cholangitis (PBC). However, the etiology of PBC remains unclear despite being characterized as an autoimmune disease. Using single-cell RNA sequencing (scRNA-seq), fluorescence-activated-cell-sorting, multiplex immunofluorescence (IF) and RNAscope analyses, we identified unique DUOX2(+)ACE2(+) small cholangiocytes in human and mouse livers. Their selective decrease in PBC patients was associated with the severity of disease. Moreover, proteomics, scRNA-seq, and qPCR analyses indicated that polymeric immunoglobulin receptor (pIgR) was highly expressed in DUOX2(+)ACE2(+) cholangiocytes. Serum anti-pIgR autoantibody levels were significantly increased in PBC patients, regardless of positive and negative AMA-M2. Spatial transcriptomics and multiplex IF revealed that CD27(+) memory B and plasma cells accumulated in the hepatic portal tracts of PBC patients. Collectively, DUOX2(+)ACE2(+) small cholangiocytes are pathogenic targets in PBC, and preservation of DUOX2(+)ACE2(+) cholangiocytes and targeting anti-pIgR autoantibodies may be valuable strategies for therapeutic interventions in PBC.

Automated summary

The numbers of DUOX2(+)ACE2(+) small cholangiocytes are inversely associated with disease severity in PBC. They may be the target of pIgR-mediated humoral responses. Protecting these cells and targeting anti-pIgR autoantibodies could be valuable strategies for therapeutic interventions in PBC.