Disease restricted auto-antibody signatures can potentially inform disease pathophysiology. Liver-infiltrating antibody-secreting B cells (ASCs) are reduced in PSC compared to PBC. Cultured liver-infiltrating ASCs in PSC and PBC produce auto-antibodies. Liver-infiltrating ASCs in PBC secrete auto-antibodies to HK1 and PDC-E2. Auto-antibodies from liver-infiltrating ASCs in PSC share reactivity to novel antigen targets.