aro glycosphingolipids in activating natural killer T (NK T) cells. The data also suggested that the non-obese diabetic (NOD).B6 insulin-dependent diabetes susceptibility region (Idd10/Idd18) contains the genetic loci that are important in determining the bile duct lesions in the N. aro-infected mice. More recently, Mohammed et al. reported [31] that the Idd10

region in the NOD.B6 Idd10 mice infected with N. aro developed liver lesions similar to PBC, which correlates with the genotype-dependent expression of cd101, a murine type 1 diabetes candidate gene. We have explored this issue in more detail; in particular, a rigorous serial study of Escherichia coli-infected mice. We report herein that E. coli-infected NOD.B6 Idd10/Idd18 develop liver lesions strikingly similar to the portal infiltrates of humans with PBC. N. aro-infected BAY 73-4506 molecular weight mice, as expected, also develop autoimmune cholangitis but, interestingly, the autoantibodies were higher in the E. coli-infected

mice. Our data suggest that infection of a genetically susceptible host with the evolutionarily conserved PDC-E2 has the potential to break tolerance and elicit biliary pathology. These data take on further significance in light of the epidemiological data in humans of urinary infections and subsequent development of PBC. N. aro (ATCC 700278; American Type Culture Collection, Manassas, VA, USA) and E. coli (DH5α, ATCC 25922; American Type Culture Collection) were grown overnight in Mueller Hinton broth (Becton-Dickinson, Franklin Lakes, NJ, USA) and Luria–Bertani broth, respectively, and Ibrutinib molecular weight then inoculated in

fresh medium, grown for 8 h (E. coli at 37°C, N. aro at 30°C) to an optical density (OD) of 0·5 at 600 nm, washed and resuspended in sterile phosphate-buffered saline (PBS) for immediate administration to experimental animals or to prepare sonicates for antigen presentation assays. Sphingomonas yanoikuyae (ATCC 51230; American Type Culture Collection) were grown at 30°C in tryptic soy broth. Female NOD.B6 Idd10/Idd18 (lines 7754) mice were purchased from The Jackson Laboratory (Bar Harbor, ME, USA) and maintained in individually ventilated cages under specific pathogen-free conditions at the University Bcl-w of California at Davis animal facility. All experimental protocols were approved by the University of California Animal Care and Use Committee. The mice were separated into three groups: 13 were infected with N. aro, 13 were infected with E. coli and six were administered with sterile PBS as controls. Briefly, aliquots of 5 × 107 N. aro, or E. coli in 100 μl PBS were administered intravenously (i.v.) into 6-week-old mice through periorbital venous sinus and once more 14 days thereafter. Blood samples were collected every 2 weeks after inoculation. At 26 weeks after inoculation, animals were killed and liver tissues were harvested for histological analysis (Fig. 1). Recombinant human PDC-E2 protein was prepared as described previously [22]. Briefly, overnight E.