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Search Results: 1 - 10 of 30 matches for " Yasuni Nakanuma "
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Tutorial Review for Understanding of Cholangiopathy
Yasuni Nakanuma
International Journal of Hepatology , 2012, DOI: 10.1155/2012/547840
Abstract: The biliary tree consists of intrahepatic and extrahepatic bile ducts and is lined by biliary epithelial cells (or cholangiocytes). There are also peribiliary glands around the intrahepatic large bile ducts and extrahepatic bile ducts. The biliary tree is a conduit of bile secreted by hepatocytes and biliary epithelial cells and also of the peribiliary glands and has several physiological roles. A number of diseases affect mainly the intrahepatic and extrahepatic biliary tree, and, in this special issue, these cholangiopathies are reviewed in detail with respect to genetics, pathogenesis, and pathology. In this paper, the anatomy and physiology of the biliary tree, basic injuries to biliary epithelial cells from stress and bile duct damage, and representative cholangiopathies are briefly reviewed.
Tutorial Review for Understanding of Cholangiopathy
Yasuni Nakanuma
International Journal of Hepatology , 2012, DOI: 10.1155/2012/547840
Abstract: The biliary tree consists of intrahepatic and extrahepatic bile ducts and is lined by biliary epithelial cells (or cholangiocytes). There are also peribiliary glands around the intrahepatic large bile ducts and extrahepatic bile ducts. The biliary tree is a conduit of bile secreted by hepatocytes and biliary epithelial cells and also of the peribiliary glands and has several physiological roles. A number of diseases affect mainly the intrahepatic and extrahepatic biliary tree, and, in this special issue, these cholangiopathies are reviewed in detail with respect to genetics, pathogenesis, and pathology. In this paper, the anatomy and physiology of the biliary tree, basic injuries to biliary epithelial cells from stress and bile duct damage, and representative cholangiopathies are briefly reviewed. 1. Introduction A number of diseases affect the biliary tree (cholangiopathies), though the pathological mechanisms involved and the anatomical level of the biliary tree affected vary [1]. For example, small interlobular bile ducts are mainly affected by a Th1-dominated microenvironment and cell-mediated immune response in PBC [2], while a Th2-dominated microenvironment and increased numbers of regulatory T cells are the major features of IgG4-related sclerosing cholangitis which affects mainly the extrahepatic bile ducts [3]. Ischemic damage to the biliary tree is a serious complication in liver transplantations [4]. In this special issue, cholangiopathy with respect to genetics, pathogenesis, and pathology will be discussed in detail. Herein, the anatomy and physiology of the biliary tree, basic injuries to biliary epithelial cells, basic forms of bile duct damage, and etiological classifications of cholangiopathy are reviewed. This tutorial review will be helpful for a better understanding of cholangiopathy. 2. Anatomy and Characteristics of the Biliary Tree 2.1. Anatomy The biliary tree is composed of extrahepatic and intrahepatic bile ducts [5]. The former include the right and left hepatic ducts and their confluence and the common hepatic and bile ducts, while the latter include the bile ducts proximal to the right or left hepatic duct. The intrahepatic branching of the bile ducts is best visualized on a cholangiograph or biliary injection cast (Figures 1 and 2). The extrahepatic bile duct is lined by high columnar epithelial cells, and its wall is composed of dense collagenous tissue harboring scattered smooth muscular elements. Figure 1: Biliary cast of normal liver. C: common hepatic duct, L: left hepatic duct, and R: right hepatic duct. Figure 2:
Cholangiopathy with Respect to Biliary Innate Immunity
Kenichi Harada,Yasuni Nakanuma
International Journal of Hepatology , 2012, DOI: 10.1155/2012/793569
Abstract: Biliary innate immunity is involved in the pathogenesis of cholangiopathies in cases of biliary disease. Cholangiocytes possess Toll-like receptors (TLRs) which recognize pathogen-associated molecular patterns (PAMPs) and play a pivotal role in the innate immune response. Tolerance to bacterial PAMPs such as lipopolysaccharides is also important to maintain homeostasis in the biliary tree, but tolerance to double-stranded RNA (dsRNA) is not found. Moreover, in primary biliary cirrhosis (PBC) and biliary atresia, biliary innate immunity is closely associated with the dysregulation of the periductal cytokine milieu and the induction of biliary apoptosis and epithelial-mesenchymal transition (EMT), forming in disease-specific cholangiopathy. Biliary innate immunity is associated with the pathogenesis of various cholangiopathies in biliary diseases as well as biliary defense systems.
Novel Approach to Bile Duct Damage in Primary Biliary Cirrhosis: Participation of Cellular Senescence and Autophagy
Motoko Sasaki,Yasuni Nakanuma
International Journal of Hepatology , 2012, DOI: 10.1155/2012/452143
Abstract: Primary biliary cirrhosis (PBC) is characterized by antimitochondrial autoantibodies (AMAs) in patients' sera and histologically by chronic nonsuppurative destructive cholangitis in small bile ducts, eventually followed by extensive bile duct loss and biliary cirrhosis. The autoimmune-mediated pathogenesis of bile duct lesions, including the significance of AMAs, triggers of the autoimmune process, and so on remain unclear. We have reported that cellular senescence in biliary epithelial cells (BECs) may be involved in bile duct lesions and that autophagy may precede the process of biliary epithelial senescence in PBC. Interestingly, BECs in damaged bile ducts show characteristicsof cellular senescence and autophagy in PBC. A suspected causative factor of biliary epithelial senescence is oxidative stress. Furthermore, senescent BECs may modulate the microenvironment around bile ducts by expressing various chemokines and cytokines called senescence-associated secretory phenotypes and contribute to the pathogenesis in PBC.
IgG4 Cholangiopathy
Yoh Zen,Yasuni Nakanuma
International Journal of Hepatology , 2012, DOI: 10.1155/2012/472376
Abstract: IgG4 cholangiopathy can involve any level of the biliary tree which exhibits sclerosing cholangitis or pseudotumorous hilar lesions. Most cases are associated with autoimmune pancreatitis, an important diagnostic clue. Without autoimmune pancreatitis, however, the diagnosis of IgG4-cholangiopathy is challenging. Indeed such cases have been treated surgically. IgG4-cholangiopathy should be diagnosed based on serological examinations including serum IgG4 concentrations, radiological features, and histological evidence of IgG4
Overview of Hepatocellular Adenoma in Japan
Motoko Sasaki,Yasuni Nakanuma
International Journal of Hepatology , 2012, DOI: 10.1155/2012/648131
Abstract: Hepatocellular adenoma (HCA) is generally a benign hepatocellular tumor arising in a nonfibrotic/cirrhotic liver, and recently four major subgroups were identified based on genotype and phenotype classification from Europe. HCA is rare in Asian countries including Japan, and there have been few studies regarding the subgroups of HCA in Japan. We surveyed subgroups of HCA in 13 patients (7 women) in Japan, based on the phenotypic classification. As results, we identified 2 hepatocyte nuclear factor (HNF) 1α-inactivated HCAs (15%), two β-catenin-activated HCAs (15%), 5 inflammatory HCAs (39%), and 4 unclassified HCAs (29%). The use of oral contraceptives was found only in 2 unclassified HCAs (29%). Rather low percentage of female patients and use of oral contraceptives appear to be common clinicopathological features in Japan and also East Asian countries. Furthermore, a group of possible inflammatory HCAs characterized by strong immunoreactivity for serum amyloid A (SAA) was found in patients with alcoholic cirrhosis. The inflammatory HCA/SAA-positive hepatocellular neoplasm in alcoholic cirrhosis may be a new entity of HCA, which may have potential of malignant transformation. Further studies are needed to clarify genetic changes, monoclonality, and pathogenesis of this new type of hepatocellular neoplasm.
Biliary Innate Immunity: Function and Modulation
Kenichi Harada,Yasuni Nakanuma
Mediators of Inflammation , 2010, DOI: 10.1155/2010/373878
Abstract: Biliary innate immunity is involved in the pathogenesis of cholangiopathies in patients with primary biliary cirrhosis (PBC) and biliary atresia. Biliary epithelial cells possess an innate immune system consisting of the Toll-like receptor (TLR) family and recognize pathogen-associated molecular patterns (PAMPs). Tolerance to bacterial PAMPs such as lipopolysaccharides is also important to maintain homeostasis in the biliary tree, but tolerance to double-stranded RNA (dsRNA) is not found. In PBC, CD4-positive Th17 cells characterized by the secretion of IL-17 are implicated in the chronic inflammation of bile ducts and the presence of Th17 cells around bile ducts is causally associated with the biliary innate immune responses to PAMPs. Moreover, a negative regulator of intracellular TLR signaling, peroxisome proliferator-activated receptor- (PPAR ), is involved in the pathogenesis of cholangitis. Immunosuppression using PPAR ligands may help to attenuate the bile duct damage in PBC patients. In biliary atresia characterized by a progressive, inflammatory, and sclerosing cholangiopathy, dsRNA viruses are speculated to be an etiological agent and to directly induce enhanced biliary apoptosis via the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Moreover, the epithelial-mesenchymal transition (EMT) of biliary epithelial cells is also evoked by the biliary innate immune response to dsRNA. 1. Introduction Clarification of the molecular mechanisms of innate immunity and significance of innate immune responses to the pathogenesis of immune-mediated diseases as well as to the defense against infections has progressed steadily since the cloning of Tolls in drosophila and Toll-like receptors (TLRs) in mammals including humans [1, 2]. Innate immunity was initially thought to be limited to immunocompetent cells such as dendritic cells and macrophages, but epithelial cells also possess TLRs and proper innate immune systems. Liver and extrahepatic bile ducts consisting of hepatocytes and biliary epithelial cells (BECs) are also exposed to microorganisms and their components originating from the intestines via portal blood and duodenum. In the gastrointestinal tract, TLRs expressed in intestinal epithelial cells may be involved in innate immunity to maintain mucosal homeostasis and also the development of enterocolitis by producing inflammatory molecules [3]. Similar processes using TLRs may operate in the biliary tree. Human bile is sterile under normal conditions, but bacterial components such as lipopolysaccharide (LPS),
Biliary Epithelial Apoptosis, Autophagy, and Senescence in Primary Biliary Cirrhosis
Motoko Sasaki,Yasuni Nakanuma
Hepatitis Research and Treatment , 2010, DOI: 10.1155/2010/205128
Abstract: Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized serologically by the high prevalence of anti-mitochondrial autoantibodies (AMAs) and histologically by the cholangitis of small bile ducts, eventually followed by extensive loss of the small bile duct. An autoimmune pathogenesis is suggested by clinical and experimental studies, but there remain issues regarding the etiology, the significance of AMAs in the pathogenesis of bile duct lesions, and so on. The unique properties of apoptosis in biliary epithelial cells (BECs), in which there is exposure of autoantigen to the effectors of the immune system, are proposed to be a cause of bile duct lesions in PBC. Recent progress disclosed that cellular senescence and autophagy are involved in bile duct lesions in PBC. Senescent BECs may modulate the periductal microenvironment by expressing senescence-associated secretory phenotypes, including various chemokines, and contribute to the pathogenesis of bile duct lesions in PBC. 1. Introduction Primary biliary cirrhosis (PBC) is a chronic, progressive cholestatic liver disease in which autoimmune pathogenesis is suggested [1–4]. It usually affects middle-aged women [1, 5] and often leads to liver failure and liver transplantation [2, 3]. PBC is characterized histologically as cholangitis of small bile ducts (chronic nonsuppurative destructive cholangitis; CNSDC) eventually followed by the extensive loss of small bile ducts [2, 3, 6]. Biliary epithelial cells (BECs) are thought to be the major target of injury in PBC. PBC is serologically characterized by the presence of increased levels of immunoglobulin M (IgM), a high titer of serum antimitochondrial autoantibodies (AMAs), and, in some patients, PBC-specific antinuclear antibodies (ANAs) [1, 2, 7–10]. AMAs are present in about 95% of PBC cases, with disease specificity close to 100%, and are therefore considered the serological hallmark of the disease. The major epitope site for both the B-cell and CD4 and CD8 T-cell response is an inner lipoyl domain of the E2 component of pyruvate dehydrogenase (PDC-E2) [10–13]. There have been many studies on the immunopathological features [10–13], genetic factors [14–17], and environmental factors [5, 18–20], including infectious agents and xenobiotics. The most accepted hypothesis states that PBC results from an environmental insult on a genetically susceptible background. In this scenario, adaptive immunity, both humoral and cellular (CD4 and CD8 T cells), and innate immunity have been proposed as coplayers in immune-mediated liver
IgG4 Cholangiopathy
Yoh Zen,Yasuni Nakanuma
International Journal of Hepatology , 2012, DOI: 10.1155/2012/472376
Abstract: IgG4 cholangiopathy can involve any level of the biliary tree which exhibits sclerosing cholangitis or pseudotumorous hilar lesions. Most cases are associated with autoimmune pancreatitis, an important diagnostic clue. Without autoimmune pancreatitis, however, the diagnosis of IgG4-cholangiopathy is challenging. Indeed such cases have been treated surgically. IgG4-cholangiopathy should be diagnosed based on serological examinations including serum IgG4 concentrations, radiological features, and histological evidence of IgG4+ plasma cell infiltration. Steroid therapy is very effective even at disease relapse. A Th2-dominant immune response or the activation of regulatory T cells seems to be involved in the underlying immune reaction. It is still unknown why IgG4 levels are specifically elevated in patients with this disease. IgG4 might be secondarily overexpressed by Th2 or regulatory cytokines given the lack of evidence that IgG4 is an autoantibody. 1. Introduction IgG4-related disease is a unique systemic inflammatory condition characterized by tumorous swelling of affected organs and high-serum IgG4 concentrations [1–3]. Autoimmune pancreatitis is a prototype of IgG4 disease as Hamano et al. described in a landmark paper in 2001 [4]. Further studies have confirmed that IgG4-related disease can involve a variety of organs including the salivary glands (chronic sclerosing sialadenitis) [5, 6], lacrimal glands (Mikulicz’s disease) [7, 8], and retroperitoneum (retroperitoneal fibrosis) [9, 10]. The bile duct lesion is called IgG4-related sclerosing cholangitis (IgG4-SC) [11] or IgG4-associated cholangitis [12, 13] (the former is used hereafter). Since we reported that IgG4-SC is a distinct entity which should be differentiated from primary sclerosing cholangitis (PSC) [11], clinical and pathological features have been clarified [12, 13]. In this paper, we describe the concept, pathology, differential diagnosis, and pathogenesis of IgG4-SC. 2. Spectrum of IgG4 Cholangiopathy The relationship between IgG4-SC and autoimmune pancreatitis is summarized in Table 1. IgG4-SC can manifest as diffuse sclerosing cholangitis or a hilar pseudotumourous mass [11]. The former should be differentiated from PSC, whereas the latter radiologically resembles hilar cholangiocarcinoma [14]. Of note is that most case of IgG4-SC are associated with autoimmune pancreatitis. A study by the Mayo Clinic found that only 4 of 53 patients (7.5%) with IgG4 cholangiopathy had cholangitis without autoimmune pancreatitis [13]. Whether or not IgG4-SC can involve only peripheral small bile
Novel Approach to Bile Duct Damage in Primary Biliary Cirrhosis: Participation of Cellular Senescence and Autophagy
Motoko Sasaki,Yasuni Nakanuma
International Journal of Hepatology , 2012, DOI: 10.1155/2012/452143
Abstract: Primary biliary cirrhosis (PBC) is characterized by antimitochondrial autoantibodies (AMAs) in patients' sera and histologically by chronic nonsuppurative destructive cholangitis in small bile ducts, eventually followed by extensive bile duct loss and biliary cirrhosis. The autoimmune-mediated pathogenesis of bile duct lesions, including the significance of AMAs, triggers of the autoimmune process, and so on remain unclear. We have reported that cellular senescence in biliary epithelial cells (BECs) may be involved in bile duct lesions and that autophagy may precede the process of biliary epithelial senescence in PBC. Interestingly, BECs in damaged bile ducts show characteristicsof cellular senescence and autophagy in PBC. A suspected causative factor of biliary epithelial senescence is oxidative stress. Furthermore, senescent BECs may modulate the microenvironment around bile ducts by expressing various chemokines and cytokines called senescence-associated secretory phenotypes and contribute to the pathogenesis in PBC. 1. Introduction Primary biliary cirrhosis (PBC) is a chronic, progressive cholestatic liver disease that affects usually middle-aged women and occasionally leads to liver failure and liver transplantation [1–5]. Autoimmune pathogenesis is suggested in PBC [1–4], because PBC is serologically characterized by a high titer of serum antimitochondrial autoantibodies (AMAs) and by an increased level of immunoglobulin M (IgM). PBC-specific antinuclear antibodies (ANAs), such as anti-gp210 are also detected in some patients [1, 2, 6–9]. AMAs are present in about 95% of patients with PBC, with disease specificity close to 100%. An inner lipoyl domain of the E2-component of pyruvate dehydrogenase (PDC-E2) and other 2-oxo-acid dehydrogenases is a major epitope for both B-cell and CD4 and CD8 T-cell response [9–12]. PBC is characterized histologically by the cholangitis of small bile ducts (chronic nonsuppurative destructive cholangitis; CNSDC), eventually followed by the extensive loss of small bile ducts and biliary cirrhosis [2, 3, 13]. Therefore, a major target of autoimmune-mediated injury has been thought to be biliary epithelial cells (BECs) in PBC. There has been considerable progress in elucidating the immunopathological features [9–12], genetic factors [14–17], and environmental factors such as infectious agents and xenobiotics [5, 18–20] in the pathogenesis of PBC. The most accepted hypothesis states that PBC results from a combination of multiple genetic factors (susceptible genetic background) and superimposed environmental triggers. In
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