Transgenic mice aberrantly expressing pyruvate dehydrogenase complex E2 component on biliary epithelial cells do not show primary biliary cirrhosis

Inamura, Katsuhisa; Tsuji, Hideaki; Nakamoto, Yasunari; Suzuki, Misao; Kaneko, S.

doi:10.1111/j.1365-2249.2006.03090.x

Cited by 12 publications

(7 citation statements)

References 57 publications

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“…The spontaneous animal model of PBC, such as C57BL/6 and MRL/lpr mice, was not stable, and the gene-modified model was not specific enough, and also with technological difficulties in some areas [13]. In 2005, Okada et al [14] established an animal model conforming to PBC in terms of serological and histological characteristics by injecting with polyI:C, an IFN-a inducer, to C57BL/6 mice, and then the model was verified to have an elevated level of Fasassociated death domain-like interleukin-1-b-converting enzyme inhibitory protein L (FLIP L , an anti-apoptotic protein) in hepatic CD4 ?…”

Section: Discussionmentioning

confidence: 98%

Effect of allogeneic bone marrow–derived mesenchymal stem cells transplantation in a polyI:C-induced primary biliary cirrhosis mouse model

et al. 2010

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Primary biliary cirrhosis (PBC) is a slowly progressive autoimmune disease of unknown mechanism. We established a PBC animal model by injecting C57BL/6 mice with polyinosinic-polycytidylic acid sodium (polyI:C) to investigate the therapeutic effect of bone marrow-derived mesenchymal stem cells (BM-MSC) on this model. After 6 weeks of MSC infusion, serum aminotransferase and autoimmune antibodies declined, and histological examination by hematoxylin and eosin staining showed significant amelioration of monocytes infiltration around bile ducts of mice treated with BM-MSC. Interestingly, allogeneic BM-MSC transplantation markedly increased CD4(+)Foxp3(+) regulatory T cells in peripheral blood as well as in lymph nodes when analyzed by flow cytometry. Further examination showed serum TGF-β1 increased but IFN-γ decreased significantly in PBC mice treated with MSC, while with no obvious change in IL-10 expression. Our results for the first time suggested that BM-MSC transplantation could regulate systemic immune response and enhance recovery in liver inflammation of PBC mice, raising the possibility for clinical application of allogeneic MSC in treatment of early-stage PBC patients.

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Section: Discussionmentioning

confidence: 98%

Effect of allogeneic bone marrow–derived mesenchymal stem cells transplantation in a polyI:C-induced primary biliary cirrhosis mouse model

et al. 2010

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“…So far, no causal link between the presence of the auto-ab and the development of PBC has been demonstrated. Notably, inducing aberrant PDC-E2 expression in a transgenic mouse did not cause the disease in animal models [38]. Moreover, reduction in the auto-ab titer of AMA did not improve the disease manifestation [18,38,39].…”

Section: Discussionmentioning

confidence: 93%

Evaluation of Inhibitory Antibodies against the Muscarinic Acetylcholine Receptor Type 3 in Patients with Primary Biliary Cholangitis and Primary Sclerosing Cholangitis

Wilde

Greverath

Steinhagen

et al. 2022

JCM

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Background: Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) constitute rare chronic inflammatory biliary diseases which likely comprise genetic, environmental and autoimmune factors. Specific inhibitory (auto-) antibodies against the muscarinic acetylcholine receptor type 3 (mAChR3 auto-ab) may contribute to the pathogenesis of chronic biliary inflammation by modulating mAChR3− mediated signaling. Aims: The aim of this study was to analyze the prevalence and relevance of inhibitory mAChR3 auto-ab (mAChR3inh+ auto-ab) in a large cohort of PBC patients from two independent tertiary centers in Berlin and Leipzig in comparison to a large PSC cohort. Baseline parameters and response rates to standard treatment with ursodeoxycholic acid (UDCA) were characterized with respect to the individual mAChR3 auto-ab status. Methods: In total, the study population comprised 437 PBC patients, 187 PSC patients and 80 healthy controls. Clinical and laboratory baseline characteristics were retrieved from medical records. The response to ursodeoxycholic acid (UDCA) therapy after 12 months of treatment was available in 176 PBC and 45 PSC patients. Results: The prevalence of mAChR3inh+ auto-ab was significantly higher among PBC patients (11.2%, 49/437; p = 0.008 vs. healthy controls) and PSC patients (33.6%, 63/187; p < 0.0001 vs. healthy controls) compared to healthy controls (2.5%, 2/80), respectively. PBC patients with mAChR3inh+ auto-ab exhibited significantly higher levels of alkaline phosphatase (ALP) and bilirubin, which constitute established parameters for PBC risk stratification. Moreover, mAChR3inh+ PBC patients tended to show decreased response rates to UDCA therapy compared to PBC patients without mAChR3inh+ auto-ab (mAChR3− PBC). In contrast, PSC patients with mAChR3inh+ auto-ab showed no significant differences in laboratory findings compared to mAChR3 auto-ab negative (mAChR3−) PSC patients. Conclusion: MAChR3inh+ auto-ab might be involved in the pathogenesis and treatment response of chronic biliary inflammation in patients with PBC but not in patients with PSC.

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“…Pathogenetical models proposed so far consider as the crucial event the break down of T cell self tolerance to PDC epitopes. The generation of antibodies against PDC by themselves is not enough to damage the biliary ductules,as already mentioned [144] . The molecular mimicry model of self-tolerance breakdown was proposed as a more logical approach compared with the rather obscure concept of autoimmunity [161] .…”

Section: Current Views On the Pathogenesis Of Pbcmentioning

confidence: 94%

“…The results indicated that PDC-E2 expression BECs is not sufficient for the initiation of autoimmunity. Additional factors may be required to establish a model of PBC [144] .…”

Section: The Role Of Apoptosis In Pbcmentioning

confidence: 99%

Primary biliary cirrhosis: From bench to bedside

Notas

2015

WJGPT

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Primary biliary cirrhosis (PBC) is a chronic nonsuppurative destructive intrahepatic cholangitis leading to cirrhosis after a protractive non cirrhotic stage. The etiology and pathogenesis are largely unknown and autoimmne mechanisms have been implicated to explain the pathological lesions. Many epitopes and autoantigens have been reported as crucial in the pathophysiology of the disease and T and B cells abnormalities have been described, the exact pathways leading to the destruction of small intrahepatic ductules are mostly speculative. In this review we examined the various epidemiologal and geoepidemiological data as well as the complex pathogenetic aspects of this disease, focusing on recent in vivo and in vitro studies in this field. Initiation and progression of PBC is believed to be a multifactorial process with strong infuences from the patient's genetic background and by various environmental factors. The role of innate and adaptive immunity, including cytokines, chemokines, macrophages and the involvement of apoptosis and reactive oxygen species are outlined in detailed. The current pathogenetic aspects are presented and a novel pathogenetic theory unifying the accumulated clinical information with in vitro and in vivo data is formulated.A review of clinical manifestations and immunological and pathological diagnosis was presented. Treatment modalities, including the multiple mechanisms of action of ursodeoxycholate were finally discussed. Core tip: Primary biliary cirrhosis (PBC) is a chronic nonsuppurative destructive intrahepatic cholangitis leading to cirrhosis of largely unknown pathophysiology. We examined the epidemiological and geoepidemiological data as well as the pathogenetic aspects of PBC. A novel pathogenetic theory unifying the accumulated clinical information with in vitro and in vivo data is formulated.

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Transgenic mice aberrantly expressing pyruvate dehydrogenase complex E2 component on biliary epithelial cells do not show primary biliary cirrhosis

Abstract: Summary Primary biliary cirrhosis (PBC) is an autoimmune disorder that specifically destroys biliary epithelial cells (BECs

Cited by 12 publications

References 57 publications

Effect of allogeneic bone marrow–derived mesenchymal stem cells transplantation in a polyI:C-induced primary biliary cirrhosis mouse model

Effect of allogeneic bone marrow–derived mesenchymal stem cells transplantation in a polyI:C-induced primary biliary cirrhosis mouse model

Evaluation of Inhibitory Antibodies against the Muscarinic Acetylcholine Receptor Type 3 in Patients with Primary Biliary Cholangitis and Primary Sclerosing Cholangitis

Primary biliary cirrhosis: From bench to bedside

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