Biliary atresia: cellular dynamics and immune dysregulation

Feldman, Amy G.; Mack, Cara L.

doi:10.1053/j.sempedsurg.2012.05.003

Cited by 72 publications

(55 citation statements)

References 76 publications

(89 reference statements)

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“…Among them, fibrosing cholangiopathies such as primary sclerosing cholangitis (PSC) and biliary atresia (BA) are characterized by cholangiocytic injuries and progressive fibrous obliteration of the biliary tree associated with nonspecific inflammatory cell infiltration [1,2,[9][10][11][12]. Whereas PSC and BA are considered complex disorders involving multiple etiopathogenetic factors, immune system-mediated assaults against the cholangiocytes are regarded a central feature [1,2,[9][10][11][12][13][14][15][16]. Primary biliary cirrhosis (PBC), another form of fibrosing cholangiopathy [17,18], is associated with marked lymphoplasmacytic infiltration around the interlobular ducts (chronic nonsuppurative destructive cholangitis (CNSDC)) and classical autoimmune features including disease specific antimitochondrial antibodies (AMAs) [19].…”

Section: Introductionmentioning

confidence: 99%

Autophagy and senescence in fibrosing cholangiopathies

Nakanuma

Sasaki

Harada

2015

Journal of Hepatology

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Fibrosing cholangiopathy such as primary sclerosing cholangitis (PSC) and biliary atresia (BA) is characterized by biliary epithelial injuries and concentric fibrous obliteration of the biliary tree together with inflammatory cell infiltration. In these diseases, inappropriate innate immunity is reported to contribute more to bile duct pathology as compared with various aspects of "classical" autoimmune diseases. Primary biliary cirrhosis (PBC) is characterized by chronic cholangitis with bile duct loss and classical autoimmune features. Cellular senescence of cholangiocytes and a senescence-associated secretory phenotype lead to the production of proinflammatory cytokines and chemokines that may modify the milieu of the bile duct and then trigger fibroinflammatory responses in PSC and PBC. Furthermore, deregulated autophagy might be involved in cholangiocyte senescence and possibly in the autoimmune process in PBC, and the deregulated innate immunity against enteric microbes or their products that is associated with cholangiocyte senescence might result in the fibrosing cholangitis that develops in PBC and PSC. In BA, innate immunity against double-stranded RNA viruses might be involved in cholangiocyte apoptosis and also in the development of the epithelial-mesenchymal transition of cholangiocytes that results in fibrous obliteration of bile ducts. These recent advances in the understanding of immune-mediated biliary diseases represent a paradigm shift: the cholangiocyte is no longer viewed merely as a passive victim of injury; it is now also considered to function as a potential effector in bile duct pathology.

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Section: Introductionmentioning

confidence: 99%

Autophagy and senescence in fibrosing cholangiopathies

Nakanuma

Sasaki

Harada

2015

Journal of Hepatology

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“…36 The presence of alloreactive T cells can be demonstrated by MLRs. We performed MLRs between the BA mother and the non-BA sibling and compared them to MLRs between the BA mother and the BA daughter who is doing well with almost normal liver function test results (total bilirubin: 0.6 mg/dL, AST: 31 IU/L, ALT: 28 IU/L, GGTP: 41 IU/L, WBC: 6660 cells/ mm 3 , Platelet: 25.3 × 10 4 cells/mm 3 ) and was 9 y old at the time of publication ( Table 2). When the BA daughter plays a role of a stimulator against the BA mother acting as a responder, the stimulation index (SI) was 1.8, whereas the SI was 1.1 between the non-BA sibling acting as a stimulator and the BA mother acting as a responder.…”

Section: Hla In Patients With Ba and The Mothermentioning

confidence: 99%

“…2 Based on the histological similarities of the intrahepatic bile ducts in BA to those seen in immune-mediated hepatic disorders, such as sclerosing cholangitis, liver disorder in graft-vs.-host disease (GvHD), and rejected liver grafts, BA is thought to be a kind of autoimmune disease. 3 During normal human pregnancy, some bidirectional cell trafficking occurs between the mother and the fetus. Since persistent chimeric cells are semiallogeneic, microchimerism can induce GvHD as seen in hematopoietic stem cell transplantation, which manifests as autoimmune disease.…”

Section: Introductionmentioning

confidence: 99%

Maternal microchimerism in biliary atresia

Muraji¹

2014

Chimerism

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“…Investigations into a viral etiology have yielded mixed results, implicating various strains of rotavirus, reovirus, and cytomegalovirus, among others, but there have been inconsistencies in the detection of viruses in patient samples. Preclinical and animal models have identified intriguing contributions to disease progression from various immunological mediators, viruses, and immune cell types, several of which have been demonstrated in human studies [11,21,30,31,33,35,36,37]. Currently, there is a paucity of support for a single viral or immunological insult in the etiopathogenesis of biliary atresia, though these factors certainly may play modifying roles for disease progression.…”

Section: Nongenetic Etiologic Theories Of Biliary Atresiamentioning

confidence: 99%

Genetic Contributors and Modifiers of Biliary Atresia

Mezina

Karpen²

2015

Dig Dis

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To date, the etiology and pathogenic underpinning of the progression of the most prevalent serious neonatal liver disease, biliary atresia, remains elusive. This disease presents as an aggressive form of neonatal cholestasis characterized by the destruction and obliteration of the extrahepatic bile ducts within the first few weeks of life and a rapid progression of biliary fibrosis, likely due to unremitting cholestasis and retention of biliary constituents including bile acids. In ∼5% of patients, biliary atresia is associated with laterality features, suggesting a genetic underpinning to a disease that begins soon after birth. However, biliary atresia does not occur within families and twins are discordant, indicating an absence of strict mendelian inheritance. Despite this, genes related to bile duct dysmorphogenesis/ciliopathies overlapping with features of biliary atresia in both humans and nonhuman model systems have been proposed. Taken together, strict genetic etiologies leading to a common pathway of a neonatal cholangiopathy resulting in biliary atresia remain elusive. Contributions from fibrogenesis- and inflammation-based studies suggest that early engagement of these pathways contributes to disease progression, but a recent double-blind study did not suggest any benefit from early use of corticosteroids. However, there are genetic contributions to the adaptation and response to cholangiopathies and cholestasis that may be present in certain populations that likely impact upon the response to hepatoportoenterostomy and subsequent biliary tract function. Studies utilizing next generation sequencing technologies (e.g., exome analysis) are ongoing in several laboratories around the world; they are expected to provide insights into genetic contributions to biliary atresia outcomes. Altogether, combinations of exome sequencing and large population studies are expected to reveal causative and modifying genes relevant to patients with biliary atresia as a means to provide therapeutic targets and potential opportunities for genetic screening.

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Biliary atresia: cellular dynamics and immune dysregulation

Cited by 72 publications

References 76 publications

Autophagy and senescence in fibrosing cholangiopathies

Autophagy and senescence in fibrosing cholangiopathies

Maternal microchimerism in biliary atresia

Genetic Contributors and Modifiers of Biliary Atresia

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