title: Identification of potential cytokine pathways for therapeutic intervention in murine primary biliary cirrhosis.
abstract: Primary biliary cirrhosis (PBC) is considered a model autoimmune disease, with the most highly directed and specific autoantibody in both murine and human autoimmunity, the anti-mitochondrial autoantibody (AMA). However, therapeutic advances in this disease have lagged behind. Herein we have taken advantage of our unique model of murine PBC in which mice immunized with 2-octynoic acid coupled to BSA (2OA-BSA), a compound identified by quantitative structure activity relationships (QSAR) of human AMA binding, develop an intense inflammatory cholangitis with striking similarities to humans with PBC. In particular, we have constructed several unique gene-deleted mice, including mice deleted of IL-12p40, IL-12p35, IFN-γ, IL-23p19, IL-17A, IL-17F and IL-22, immunized these animals with 2OA-BSA and followed the natural history of immunopathology to identify key pathways that might provide clues for successful therapy. Our data indicate that whereas both IL-12/Th1 and IL-23/Th17 are involved in cholangitis, it is the IL-12/Th1 signaling pathway that elicits pathology. In fact, deletion of IFN-γ prevents disease and suppresses autoantibodies. Importantly, deletion of the Th17 cytokines IL-17A and IL-22, but not IL-17F, reduces biliary damage; IL-17A-knockout mice have reduced levels of anti-mitochondrial antibody. We further demonstrate that the production of IFN-γ is significantly decreased in the liver of IL-23p19(-/-), IL-17A(-/-) and IL-22(-/-) mice compared with controls. However, the ability of T cells to produce IFN-γ was not affected in Th17 cytokine-deficient mice. Our data indicate that a deficient Th17 pathway suppresses the accumulation of IFN-γ producing cells in liver during the early phase of cholangitis. In conclusion, whereas IFN-γ has a pivotal role in the early events involved in the pathogenesis of autoimmune cholangitis induced by 2OA-BSA, the IL-23/Th17 pathway potentiates the effects of IL-12/IFN-γ-mediated immunopathology.
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, California, United States of America ; Hepatology Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Kawata
authors.forename: Masanobu
authors.initials: M
authors.lastname: Tsuda
authors.forename: Guo-Xiang
authors.initials: GX
authors.lastname: Yang
authors.forename: Weici
authors.initials: W
authors.lastname: Zhang
authors.forename: Hajime
authors.initials: H
authors.lastname: Tanaka
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Patrick
authors.initials: P
authors.lastname: Leung
authors.forename: Xiao-Song
authors.initials: XS
authors.lastname: He
authors.forename: Stuart
authors.initials: S
authors.lastname: Knechtle
authors.forename: Aftab A
authors.initials: AA
authors.lastname: Ansari
authors.forename: Ross L
authors.initials: RL
authors.lastname: Coppel
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis*; D015551:Autoimmunity; D002761:Cholangitis / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry / Q000276:immunology; D005786:Gene Expression Regulation; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage / Q000276:immunology; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D053765:Interleukin-12 Subunit p35 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D020381:Interleukin-17 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D053760:Interleukin-23 Subunit p19 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008105:Liver Cirrhosis, Biliary / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000276:immunology; D012710:Serum Albumin, Bovine / Q000737:chemistry / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D058408:Th1-Th2 Balance; D000097043:Interleukin-22
chemical_list: D001323:Autoantibodies; D005229:Fatty Acids, Monounsaturated; D018796:Immunoconjugates; D007371:Interferon-gamma; D053765:Interleukin-12 Subunit p35; D020381:Interleukin-17; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D012710:Serum Albumin, Bovine; D000097043:Interleukin-22; C060855:2-octynoic acid
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