title: Impaired indoleamine 2,3-dioxygenase production contributes to the development of autoimmunity in primary biliary cirrhosis.
abstract: The immunomodulatory effects of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) have been elucidated at a cellular level and implicated in the pathogenesis of several complex diseases. Defects within the regulatory T cell compartment are one of the characteristics of primary biliary cirrhosis (PBC), an autoimmune chronic cholestatic liver disease, a phenotype that has also been shown in disease-mimicking animal models of this disease. We hypothesized that IDO dysregulation could lead to altered frequency and/or function of T cells at the level of antigen processing/presentation and we thus investigated IDO in peripheral monocytes and bile duct cells from patients with PBC. Both expression and activation manifested an impaired IFN-gamma response in peripheral monocytes while a peculiar IDO expression profile in bile duct cells characterized early stage PBC. Further, we observed an increased frequency of a gain-of-function SNP within the TGF-beta promoter region, a molecule known to suppress IDO transcription. In conclusion, we submit that an impaired IDO induction characterizes PBC and might represent a contributing factor in disease pathogenesis in association with several specific defects in the target tissue.
authors.affiliation: Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA 95616, USA.
authors.forename: Sabine
authors.initials: S
authors.lastname: Oertelt-Prigione
authors.forename: Tin K
authors.initials: TK
authors.lastname: Mao
authors.forename: Carlo
authors.initials: C
authors.lastname: Selmi
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Aftab A
authors.initials: AA
authors.lastname: Ansari
authors.forename: Ross L
authors.initials: RL
authors.lastname: Coppel
authors.forename: Pietro
authors.initials: P
authors.lastname: Invernizzi
authors.forename: Mauro
authors.initials: M
authors.lastname: Podda
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000503:physiopathology*; D015551:Autoimmunity; D002478:Cells, Cultured; D015536:Down-Regulation; D004847:Epithelial Cells / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000201:enzymology; D008105:Liver Cirrhosis, Biliary / Q000276:immunology* / Q000503:physiopathology*; D009000:Monocytes / Q000201:enzymology; D011817:Rabbits; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma