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Receptor II Dominant-Negative Mice1
* Division of Rheumatology, Allergy and Clinical Immunology, University of California School of Medicine, Davis, CA 95616;
Division of Internal Medicine, Department of Medicine, Surgery and Dentistry, San Paolo School of Medicine, University of Milan, Milan, Italy;
Division of Rheumatology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322;
¶ Department of Microbiology, Monash University, Melbourne, Australia;
|| Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520;
# La Jolla Institute of Allergy and Immunology, San Diego, CA 92121; and
** Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
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-
receptor type II (dnTGFRII), 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-RII 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.
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  K. Lindor Ursodeoxycholic Acid for the Treatment of Primary Biliary Cirrhosis N. Engl. J. Med., October 11, 2007; 357(15): 1524 - 1529. [Full Text] [PDF]
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 M. Sasaki, H. Ikeda, S. Sawada, Y. Sato, and Y. Nakanuma Naturally-occurring regulatory T cells are increased in inflamed portal tracts with cholangiopathy in primary biliary cirrhosis J. Clin. Pathol., October 1, 2007; 60(10): 1102 - 1107. [Abstract] [Full Text] [PDF]
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