An alternative but complementary concept for loss of self-tolerance in PBC is the idea of underlying immune deficits. This concept is based on clinical and experimental evidence. PBC exhibits clustering with various autoimmune disorders, both within individuals and family. Moreover, in PBC there are reduced levels of Tregs suppressing immune reactions against self [197] . In two genetically manipulated mouse strains, spontaneous occurrence of a PBC-like lymphoid cholangitis together with positivity for anti-PDC-E2 within several weeks of life was reported when either transgenic expression of a dominant negative TGF-β II receptor (dnTGF-β RII) or transgenic disruption of the IL-2 receptor alpha that is highly expressed on Tregs was performed [198, 199] . Interestingly, B cells had a suppressive effect on the inflammatory response in the dnTGF-β RII model of PBC [200] . A role for IL-2 signaling defects in development of PBC was supported by a report of a PBC-like liver disease in a child with inborn deficiency of IL-2 receptor alpha [201] . An additional mouse model of NOD.c3c4 was described to develop autoimmune biliary disease and was found to test AMA-positive [202] . In all models outlined here, the biliary epithelium is infiltrated with CD4 and CD8 T cells, whereas granulomas and eosinophilic infiltration are seen only in NOD.c3c4 mice.