Mouse mammary tumor virus in anti-mitochondrial antibody producing mouse models

Zhang, Guangzhi; Chen, Min; Graham, Don; Subsin, Benchamas; McDougall, Chelsea; Gilady, Suzanna; Kneteman, Mark; Law, Lok Man J.; Swain, Mark G.; Trauner, Michael; Wrzesinski, Stephen H.; Flavell, Richard A.; Wasilenko, Shawn; Mason, Andrew L.

doi:10.1016/j.jhep.2011.01.037

Cited by 36 publications

(62 citation statements)

References 23 publications

(49 reference statements)

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“…In the setting of immunodeficiency, these mice express mouse mammary tumor virus related to the betaretrovirus characterized in PBC; these viral proteins are located in biliary epithelium or lymphoid tissues that also display aberrant mitochondrial PDC-E2 expression, providing a mechanism for production of AMA. 97–99 Other stimuli, including xenobiotics 100 and bacteria, 101 have also been shown to trigger AMA production in mouse models. With regard to the known genetic risk factors for PBC, conflicting results have been derived in a spontaneous mouse model of PBC, where mice lacking IL-12 p35 or IL-12 p40 developed either increased hepatic fibrosis or diminished autoimmune cholangitis, respectively.…”

Section: Animal Models Of Cholestasis Parallel Genomic Effortsmentioning

confidence: 99%

The Genetics of Complex Cholestatic Disorders

et al. 2013

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Cholestatic liver diseases are caused by a range of hepatobiliary insults and involve complex interactions among environmental and genetic factors. Little is known about the pathogenic mechanisms of specific cholestatic diseases, which has limited our ability to manage patients with these disorders. However, recent genome-wide studies have provided insight into the pathogenesis of gallstones, primary biliary cirrhosis, and primary sclerosing cholangitis. A lithogenic variant in the gene that encodes the hepatobiliary transporter ABCG8 has been identified as a risk factor for gallstone disease; this variant has been associated with altered cholesterol excretion and metabolism. Other variants of genes encoding transporters that affect the composition of bile have been associated with cholestasis, namely ABCB11, which encodes the bile salt export pump, and ABCB4, which encodes hepatocanalicular phosphatidylcholine floppase. Many genes associated with gallstones have also been linked with vanishing bile duct syndromes and other cholestatic disorders. In contrast, studies have associated primary biliary cirrhosis and primary sclerosing cholangitis with genes encoding major histocompatibility complex proteins and identified loci associated with microbial sensing and immune regulatory pathways outside this region, such as genes encoding IL12, STAT4, IRF5, IL2 and its receptor (IL2R), CD28, and CD80. These discoveries have raised interest in the development of reagents that target these gene products. We review recent findings from genetic studies of patients with cholestatic liver disease. Future characterization of genetic variants in animal models, stratification of risk alleles by clinical course, and identification of interacting environmental factors will increase our understanding of these complex cholestatic diseases.

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Section: Animal Models Of Cholestasis Parallel Genomic Effortsmentioning

confidence: 99%

The Genetics of Complex Cholestatic Disorders

et al. 2013

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“…On and above demonstrating proviral integration in the bile ducts of patients with PBC, an ELISA is being constructed to determine the seroprevalence of HBRV infection in a large cohort of patients with liver disease. Also, mouse models are being used to demonstrate how infection with the closely related MMTV triggers autoimmune biliary disease [52]. These animal models are being used to validate combination antiviral treatments to inhibit betaretrovirus infection and ongoing clinical trials are investigating whether anti-retroviral therapy can improve histological, biochemical and clinical endpoints in patients with PBC [6,53,54].…”

Section: Pathophysiology Of Recurrent Pbc and De Novo Aihmentioning

confidence: 99%

“…As such, further characterization of the role of cyclophilins in the betaretrovirus life cycle would be beneficial both in vitro and in mouse models of PBC with MMTV infection. [52] Such studies are encouraged as they would serve the dual purpose of characterizing the mechanism of cyclophilin inhibitors in blocking HBRV production and for identifying novel management strategies for patients with PBC.…”

Section: Prospectusmentioning

confidence: 99%

Is there a Role for Cyclophilin Inhibitors in the Management of Primary Biliary Cirrhosis?

Wasilenko

Montano‐Loza

Mason

2013

Viruses

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Autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) are poorly understood autoimmune liver diseases. Immunosuppression is used to treat AIH and ursodeoxycholic acid is used to slow the progression of PBC. Nevertheless, a proportion of patients with both disorders progress to liver failure. Following liver transplantation, up to a third of patients with PBC experience recurrent disease. Moreover a syndrome referred to as “de novo AIH” occurs in a proportion of patients regardless of maintenance immunosuppression, who have been transplanted for disorders unrelated to AIH. Of note, the use of cyclosporine A appears to protect against the development of recurrent PBC and de novo AIH even though it is a less potent immunosuppressive compared to tacrolimus. The reason why cyclosporine A is protective has not been determined. However, a virus resembling mouse mammary tumor virus (MMTV) has been characterized in patients with PBC and AIH. Accordingly, we hypothesized that the protective effect of cyclosporine A in liver transplant recipients may be mediated by the antiviral activity of this cyclophilin inhibitor. Treatment of the MMTV producing MM5MT cells with different antivirals and immunosuppressive agents showed that both cyclosporine A and the analogue NIM811 inhibited MMTV production from the producer cells. Herein, we discuss the evidence supporting the role of MMTV-like human betaretrovirus in the development of PBC and de novo AIH and speculate on the possibility that the agent may be associated with disease following transplantation. We also review the mechanisms of how both cyclosporine A and NIM811 may inhibit betaretrovirus production in vitro.

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“…Although similar, the infectome relates only to those organisms [170,172,256,258,393,394] Novosphingobium aromaticivorans [172,393] Mycobacterium gordonae [395][396][397] Lactobacillus delbrueckii subsp. bulgaricus [250,270] Viruses Betaretrovirus [263,267,398,399] This table provides examples of infectious organisms which have been implicated in the pathogenesis of primary biliary cirrhosis (PBC). Although several organisms have been implicated, we have only included those which appear to have strong evidence base so far, based on multiple studies and case reports.…”

Section: Approaches To Study the Infectomementioning

confidence: 99%

Tracing environmental markers of autoimmunity: introducing the infectome

et al. 2013

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We recently introduced the concept of the infectome as a means of studying all infectious factors which contribute to the development of autoimmune disease. It forms the infectious part of the exposome, which collates all environmental factors contributing to the development of disease and studies the sum total of burden which leads to the loss of adaptive mechanisms in the body. These studies complement genome-wide association studies, which establish the genetic predisposition to disease. The infectome is a component which spans the whole life and may begin at the earliest stages right up to the time when the first symptoms manifest, and may thus contribute to the understanding of the pathogenesis of autoimmunity at the prodromal/asymptomatic stages. We provide practical examples and research tools as to how we can investigate disease-specific infectomes, using laboratory approaches employed from projects studying the "immunome" and "microbiome". It is envisioned that an understanding of the infectome and the environmental factors that affect it will allow for earlier patient-specific intervention by clinicians, through the possible treatment of infectious agents as well as other compounding factors, and hence slowing or preventing disease development.

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Mouse mammary tumor virus in anti-mitochondrial antibody producing mouse models

Cited by 36 publications

References 23 publications

The Genetics of Complex Cholestatic Disorders

The Genetics of Complex Cholestatic Disorders

Is there a Role for Cyclophilin Inhibitors in the Management of Primary Biliary Cirrhosis?

Tracing environmental markers of autoimmunity: introducing the infectome

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