title: Escherichia coli infection induces autoimmune cholangitis and anti-mitochondrial antibodies in non-obese diabetic (NOD).B6 (Idd10/Idd18) mice.
abstract: Several epidemiological studies have demonstrated that patients with primary biliary cirrhosis (PBC) have a higher incidence of urinary tract infections (UTI) and there is significant homology of the immunodominant mitochondrial autoantigen, the E2 component of the pyruvate dehydrogenase complex (PDC-E2), between mammals and bacteria. Previous work has demonstrated that non-obese diabetic (NOD).B6 Idd10/Idd18 infected with Novosphingobium aromaticivorans developed liver lesions similar to human PBC. It was postulated that the biliary disease was dependent upon the presence of the unique N. aro glycosphingolipids in activating natural killer T (NK T) cells. To address this issue, we infected NOD.B6 Idd10/Idd18 mice with either Escherichia coli, N. aro or use of a phosphate-buffered saline (PBS) vehicle control and serially followed animals for the appearance of liver pathology and anti-mitochondrial autoantibodies (AMA). Of striking importance, the biliary disease of E. coli-infected mice was more severe than N. Aro-infected mice and the titre of AMA was higher in E. coli-infected mice. Furthermore, the immunopathology did not correlate with the ability of bacterial extracts to produce antigen-dependent activation of NK T cells. Our data suggest that the unique glycosphingolipids of N. aro are not required for the development of autoimmune cholangitis. Importantly, the data highlight the clinical significance of E. coli infection in a genetically susceptible host, and we suggest that the appearance of autoimmune cholangitis is dependent upon molecular mimicry. These data highlight that breach of tolerance to PDC-E2 is probably the first event in the natural history of PBC in genetically susceptible hosts.
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Wang
authors.forename: G-X
authors.initials: GX
authors.lastname: Yang
authors.forename: W C
authors.initials: WC
authors.lastname: Zhang
authors.forename: L
authors.initials: L
authors.lastname: Lu
authors.forename: K
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: M
authors.initials: M
authors.lastname: Kronenberg
authors.forename: J L
authors.initials: JL
authors.lastname: Véla
authors.forename: M
authors.initials: M
authors.lastname: Lopez-Hoyos
authors.forename: X-S
authors.initials: XS
authors.lastname: He
authors.forename: W M
authors.initials: WM
authors.lastname: Ridgway
authors.forename: P S C
authors.initials: PS
authors.lastname: Leung
authors.forename: M E
authors.initials: ME
authors.lastname: Gershwin
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology / Q000382:microbiology; D002761:Cholangitis / Q000276:immunology* / Q000382:microbiology; D051047:Dihydrolipoyllysine-Residue Acetyltransferase / Q000276:immunology*; D004926:Escherichia coli / Q000276:immunology; D004927:Escherichia coli Infections / Q000276:immunology*; D005260:Female; D006028:Glycosphingolipids / Q000378:metabolism; D008099:Liver / Q000382:microbiology; D008100:Liver Abscess / Q000382:microbiology; D008105:Liver Cirrhosis, Biliary / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D008928:Mitochondria / Q000276:immunology*; D024101:Mitochondrial Proteins / Q000276:immunology*; D055611:Natural Killer T-Cells / Q000276:immunology; D042301:Sphingomonadaceae / Q000276:immunology*
chemical_list: D000906:Antibodies; D001323:Autoantibodies; D001324:Autoantigens; D006028:Glycosphingolipids; D024101:Mitochondrial Proteins; C052359:DLAT protein, human; D051047:Dihydrolipoyllysine-Residue Acetyltransferase
keywords: anti-mitochondrial autoantibodies; cholangitis; immune tolerance; microbial aetiology; primary biliary cirrhosis