Expression of the interferon-induced Mx proteins in biliary atresia

Al-Masri, Abdul Nasser; Flemming, Peer; Rodeck, Burkhard; Melter, Michael; Leonhardt, Johannes; Petersen, Claus

doi:10.1016/j.jpedsurg.2006.02.022

Cited by 31 publications

(26 citation statements)

References 31 publications

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“…In addition, BECs produced antiviral products (IFN-␤ and MxA) on exposure to a synthetic analog of viral dsRNA, poly(I:C). Al-Masri et al 32 reported the increased expression of MxA in bile ducts of patients with BA, suggesting that biliary innate immunity against any virus in vivo is associated with the pathogenesis of BA and supporting the current results obtained using cultured human BECs. In contrast, cytosolic receptors for intracellular dsRNA such as RIG-I and MDA-5 are essential for innate immune responses to intracellular viral replication.…”

Section: Discussionsupporting

confidence: 85%

Innate immune response to double-stranded RNA in biliary epithelial cells is associated with the pathogenesis of biliary atresia

et al. 2007

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B iliary atresia (BA) is characterized by a progressive, inflammatory, and sclerosing cholangiopathy. Little is known about the etiology and pathogenesis of BA, but recent studies have demonstrated the presence of Reoviridae (type 3 reovirus and type C rotavirus) having a double-strand RNA (dsRNA) in liver tissue of patients with BA, although conflicting results have been reported. [1][2][3][4][5] Moreover, the infection of newborn Balb/cmice with Reoviridae including type A rhesus rotavirus and type 3 reovirus (Abney) leads to cholestasis and biliary obstruction resembling human BA. 6,7 However, the role of these viruses in the pathogenesis of cholangiopathies in patients with BA is still unknown.Toll-like receptors (TLRs) are innate immune-recognition receptors that recognize pathogen-associated molecular patterns (PAMPs), and TLR3 recognizes dsRNA including dsRNA viruses. 8 The stimulation of TLR3 by dsRNA transduces signals to activate the transcription factors nuclear factor-B (NF-B) and interferon regulatory factor 3 (IRF3) via Toll-interleukin-1 receptor do-

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Section: Discussionsupporting

confidence: 85%

Innate immune response to double-stranded RNA in biliary epithelial cells is associated with the pathogenesis of biliary atresia

et al. 2007

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“…In a previous publication [3], we hypothesised that the expression of Mx protein, classically triggered by IFN alpha, could be a sign of viral infection during BA [30]. This hypothesis is in line with several in vivo studies that have shown the ability of MxA to inhibit a broad spectrum of negative and positive strand RNA viruses and the upregulation of Mx proteins during viral infections [10,18,25].…”

Section: Discussionsupporting

confidence: 65%

“…Mx proteins were strongly expressed in the livers of almost all (92%) BA patients, compared to a reported incidence of 28% in a comparable control group [3]. In a previous publication [3], we hypothesised that the expression of Mx protein, classically triggered by IFN alpha, could be a sign of viral infection during BA [30].…”

Section: Discussionmentioning

confidence: 84%

“…Since then, several observations have pointed towards a potential cross-link between viral infection and the development of BA, such as the development of a mouse model of BA, induced by neonatal viral infection and an immune response in BA patients that mimics the response to viral infections, i.e. a high expression of Mx protein, induction of Th1 and upregulation of Toll-like receptor (TLR) 3 and 7 [3,6,20,30]. Based on Landing's theory, several studies were performed to identify the potential viral source of BA.…”

Section: Discussionmentioning

confidence: 99%

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Incidence of hepatotropic viruses in biliary atresia

et al. 2008

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Biliary atresia (BA) is the most frequent indication for paediatric liver transplantation. We tested the hypothesis of a viral aetiology of this disease by screening liver samples of a large number of BA patients for the common human hepatotropic viruses. Moreover, we correlated our findings to the expression of Mx protein, which has been shown to be significantly up-regulated during viral infections. Seventy-four liver biopsies (taken during Kasai portoenterostomy) were tested by polymerase chain reaction (PCR) for DNA viruses (herpes simplex virus [HSV], Epstein-Barr virus [EBV], varicella zoster virus [VZV], cytomegalovirus [CMV], adenovirus, parvovirus B19 and polyoma BK) and RNA viruses (enteroviruses, rotavirus and reovirus 3). Mx protein expression was assessed by immunohistochemistry. Virus DNA/RNA was found in less than half of the biopsies (8/74 CMV, 1/74 adenovirus; 21/64 reovirus, 1/64 enterovirus). A limited number presented with double infection. Patients that had detectable viral RNA/DNA in their liver biopsies were significantly older than virus-free patients (P = 0.037). The majority (54/59) of the liver biopsies showed expression of Mx proteins in hepatocytes, bile ducts and epithelium. Our data suggest that the known hepatotropic viruses do not play a major role in the aetiology and progression of BA. Their incidence appears to be, rather, a secondary phenomenon. Nonetheless, the inflammatory response in the livers of BA patients mimics that observed during viral infections.

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“…Based on the theory that a hepatotropic virus could be one potential agent triggering BA, several studies have investigated the inflammatory reaction in patients for potential signs of a virally induced disease [10,13,15]. In a recently published study, the MxA protein, as a sensitive marker for interferon type I activity and with an antiviral function, was found to be upregulated in all liver specimens of patients with BA in contrast to controls [1]. However, we and others could show that the detection of Mx proteins in liver biopsies of children with BA was independent of an infection with hepatotropic viruses [6,7,14].…”

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confidence: 99%

Functional Mx Protein Does Not Prevent Experimental Biliary Atresia in Balb/c Mice

Wehrmann

Kuebler²,

Wienecke³

et al. 2008

Eur J Pediatr Surg

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Biliary atresia (BA) is a rare cholestatic disease, which manifests itself in the form of inflammation of the liver and bile ducts in newborns, with an unknown etiology and a poor outcome. Mx proteins, which are mediators of innate, antiviral resistance induced by type I interferon, were recently detected in the livers of children with BA. Therefore, the aim of this study was to examine whether the expression of Mx protein could affect the course of experimental BA in mice. A total of 185 newborn Balb/c mice (expressing dysfunctional Mx protein) and Balb/c-Mx+-A2G mice (with functional Mx protein) were intraperitoneally infected with rhesus rotavirus (RRV) or injected with saline solution as controls. They were sacrificed if they showed signs of cholestasis or at three weeks after infection. The expression of hepatic Mx protein was detected by immunostaining (POX) and the hepatic virus load was determined. There was no significant difference in the incidence of cholestasis between wild-type Balb/c mice and Balb/c-Mx+-A2G mice (67 % vs. 65 %). However, Mx protein was highly expressed in Balb/c-Mx+-A2G mice with BA phenotype, but not in wild type Balb/c mice or disease-free Balb/c-Mx+-A2G mice despite RRV infection. The difference in the hepatic virus load was not statistically significant in mice with BA. In conclusion, Mx protein does not prevent newborn Balb/c mice from developing biliary atresia after RRV infection. However, the expression of Mx protein is independent of the hepatic virus load and could be used as a marker of BA in humans, as well as in the RRV model.

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Expression of the interferon-induced Mx proteins in biliary atresia

Cited by 31 publications

References 31 publications

Innate immune response to double-stranded RNA in biliary epithelial cells is associated with the pathogenesis of biliary atresia

Innate immune response to double-stranded RNA in biliary epithelial cells is associated with the pathogenesis of biliary atresia

Incidence of hepatotropic viruses in biliary atresia

Functional Mx Protein Does Not Prevent Experimental Biliary Atresia in Balb/c Mice

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