Innate immunity drives the initiation of a murine model of primary biliary cirrhosis
Journal
PLoS ONE
Journal Volume
10
Journal Issue
3
Pages
e0121320
Date Issued
2015
Author(s)
Abstract
Invariant natural killer T (iNKT) cells play complex roles in bridging innate and adaptive immunity 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-tetracosanoyl-2-amino-1,3,4-nonanetriol (OCH), can influence the development of PBC in a xenobiotic-induced PBC murine model. Groups of mice were treated with either OCH or, as a control, α-galactosylceramide (α-GalCer) and thence serially followed for cytokine production, markers of T cell activation, liver histopathology and anti-mitochondrial antibody responses. 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 inflammation and hepatic fibrosis similar to mice treated with α-GalCer. Further, iNKT cell deficient 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 immunity in the natural history of autoimmune cholangitis. These data have implications for humans with PBC and emphasize that therapeutic strategies must focus not only on suppressing adaptive responses, but also innate immunity. ? 2015 Chang et al.
SDGs
Other Subjects
1 o (alpha dextro galactopyranosyl) n tetracosanoyl 2 amino 1,3,4 nonanetriol; alpha galactosylceramide; chemical compound; gamma interferon; mitochondrion antibody; unclassified drug; alpha-galactosylceramide; CD1d antigen; galactosylceramide; animal experiment; animal model; animal tissue; antibody response; Article; CD-1 mouse; cell count; cell infiltration; cholangitis; controlled study; cytokine production; disease exacerbation; female; hepatitis; histopathology; innate immunity; invariant natural killer T cell; liver fibrosis; mouse; natural killer T cell; nonhuman; primary biliary cirrhosis; T lymphocyte activation; animal; biliary cirrhosis; disease model; drug effects; genetics; immunology; innate immunity; knockout mouse; Murinae; Mus; Animals; Antigens, CD1d; Disease Models, Animal; Galactosylceramides; Immunity, Innate; Liver Cirrhosis, Biliary; Mice; Mice, Knockout; Natural Killer T-Cells
Type
journal article