Anti-Mitochondrial Antibodies and Primary Biliary Cirrhosis in TGF-β 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-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.

Antimitochondrial antibodies in acute liver failure: Implications for primary biliary cirrhosis

“…38 Future studies should address this issue by studying the administration of drugs that induce ALF in the recently described murine models of human PBC. [39][40][41] …”

β-Glucosylceramide ameliorates liver inflammation in murine autoimmune cholangitis

“…This conclusion has been supported by our recent work using a transgenic mouse model in which mice express a dominant negative form of transforming growth factor-b receptor type II specifically in T cells (dnTGF-bRII). dnTGF-bRII mice developed spontaneously periductular aggregates of lymphocytes in liver in association with serum reactivity to the E2 component of pyruvate dehydrogenase complex (PDC-E2), similar to human PBC [8]. Further, the adoptive transfer of CD8 + T cells from dnTGF-bRII mice to Rag1 -/-recipients results in PBC-like liver damage, while CD4 + T cells are less able to cause portal inflammation [9].…”

Long-term bacterial exposure can trigger nonsuppurative destructive cholangitis associated with multifocal epithelial inflammation

“…17 Considering these observations, we speculated that some bacterial components originating from asymptomatic or less apparent chronic bacterial infection might have function(s) in the initiation and/or development of the autoimmune status in patients with PBC, eventually leading to chronic epithelial inflammation in the liver and multiple epithelial inflammation. Recently, a strain with a dominant-negative form of TGFb receptor II, 18 IL-2 receptor a À/À mice, 19 and Ae2 a,b -deficient mice 20 have been reported as spontaneous PBC animal models. However, as these mice are genetically engineered, they might not completely reflect the onset of human PBC.…”