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. The gene discussed is PIGR; the disease is primary biliary cholangitis.