RESEARCH ARTICLE Innate Immunity Drives the Initiation of a Murine Model of Primary Biliary Cirrhosis

Invariant natural killer T (iNKT) cells play complex roles in bridging innate and adaptive im-munity by engaging with glycolipid antigens presented by CD1d. Our earlier work suggested that iNKT cells were involved in the initiation of the original loss of tolerance in primary biliary cirrhosis (PBC). To address this issue in more detail and, in particular, to focus on whether iNKT cells activated by a Th2-biasing agonist (2s,3s,4r)-1-O-(α-D-galactopyranosyl)-N-tet-racosanoyl-2-amino-1,3,4-nonanetriol (OCH), can influence the development of PBC in a xenobiotic-induced PBCmurine model. Groups of mice were treated with either OCH or, as a control, α-galactosylceramide (α-GalCer) and thence serially followed for cytokine produc-tion, markers of T cell activation, liver histopathology and anti-mitochondrial antibody re-sponses. Further, additional groups of CD1d deleted mice were similarly studied. Our data indicate that administration of OCH has a dramatic influence with exacerbation of portal in-flammation and hepatic fibrosis similar to mice treated with α-GalCer. Further, iNKT cell defi-cient CD1d knockout mice have decreased inflammatory portal cell infiltrates and reduced anti-mitochondrial antibody responses. We submit that activation of iNKT cells can occur via overlapping and/or promiscuous pathways and highlight the critical role of innate immu-nity in the natural history of autoimmune cholangitis. These data have implications for hu-mans with PBC and emphasize that therapeutic strategies must focus not only on suppressing adaptive responses, but also innate immunity