Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-βreceptor II dominant-negative mice

Sabine Oertelt, Zhe Xiong Lian, Chun Mei Cheng, Ya Hui Chuang, Kerstien A. Padgett, Xiaosong He, William M. Ridgway, Aftab A. Ansari, Ross L. Coppel, Ming O. Li, Richard A. Flavell, Mitchell Kronenberg, Ian R. Mackay, M. Eric Gershwin

Research output: Contribution to journalArticlepeer-review

213 Scopus citations


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-β receptor type II (dnTGFβRII), 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-βRII 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.

Original languageEnglish (US)
Pages (from-to)1655-1660
Number of pages6
JournalJournal of Immunology
Issue number3
StatePublished - Aug 1 2006

ASJC Scopus subject areas

  • Immunology


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