title: Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor II dominant-negative mice.
abstract: Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver, characterized by lymphocytic infiltrates in portal tracts, selective destruction of biliary epithelial cells, and anti-mitochondrial Abs (AMAs). The elucidation of early events in the induction of tissue inflammation and autoimmunity in PBC has been hampered by the cryptic onset of the disease, the practical limitations in accessing the target tissue, and the lack of a suitable animal model. We demonstrate in this study that a mouse transgenic for directed expression of a dominant-negative form of TGF-beta receptor type II (dnTGFbetaRII), under the direction of the CD4 promoter, mimics several key phenotypic features of human PBC, including spontaneous production of AMAs directed to the same mitochondrial autoantigens, namely PDC-E2, BCOADC-E2, and OGDC-E2. The murine AMAs also inhibit PDC-E2 activity. Moreover, there is lymphocytic liver infiltration with periportal inflammation analogous to the histological profile in human PBC. Additionally, the serum cytokine profile of affected mice mimics data in human PBC. The concomitant presence of these immunopathological features in the transgenic mice suggests that the TGF-betaRII pathway is implicated in the pathogenesis of PBC. Finally, these data point away from initiation of autoimmunity by mechanisms such as molecular mimicry and more toward activation of an intrinsically self-reactive T cell repertoire in which necessary regulatory T cell influences are lacking.
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California School of Medicine, Davis, CA 95616, USA.
authors.forename: Sabine
authors.initials: S
authors.lastname: Oertelt
authors.forename: Zhe-Xiong
authors.initials: ZX
authors.lastname: Lian
authors.forename: Chun-Mei
authors.initials: CM
authors.lastname: Cheng
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Chuang
authors.forename: Kerstien A
authors.initials: KA
authors.lastname: Padgett
authors.forename: Xiao-Song
authors.initials: XS
authors.lastname: He
authors.forename: William M
authors.initials: WM
authors.lastname: Ridgway
authors.forename: Aftab A
authors.initials: AA
authors.lastname: Ansari
authors.forename: Ross L
authors.initials: RL
authors.lastname: Coppel
authors.forename: Ming O
authors.initials: MO
authors.lastname: Li
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Mitchell
authors.initials: M
authors.lastname: Kronenberg
authors.forename: Ian R
authors.initials: IR
authors.lastname: Mackay
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis*; D001652:Bile Ducts / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D008099:Liver / Q000276:immunology / Q000473:pathology; D008105:Liver Cirrhosis, Biliary / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D016131:Lymphocyte Subsets / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000276:immunology*; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency* / Q000235:genetics*; D013045:Species Specificity
chemical_list: D001323:Autoantibodies; D016207:Cytokines; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II