Does JAGGED 1 Have a Role in the Pathogenesis of Biliary Atresia?

Does JAGGED 1 Have a Role in the Pathogenesis of Biliary Atresia? The significance of JAGGED 1 mutations detected in severe cases of extrahepatic biliary atresia. Kohsaka T, Yuan Z, Guo S, Tagawa M, Nakamura A, Nakano M, Kawasasaki H, Inomatat Y, Tanaka K, and Miyauchi J. Hepatology 2002;36:904–12. Summary: Mutations of human JAGGED 1 (JAG 1) genes are found in 70% of patients with Alagille syndrome. The gene encodes a ligand for the Notch signaling pathway, which is involved in cell fate determination. The similar phenotypes found in patients with Alagille syndrome and extrahepatic biliary atresia (EHBA) and the role of JAG 1 on the bile duct formation process suggested that an evaluation of the frequency of JAG 1 mutations in patients with EHBA should be evaluated. The aims of this study were to clarify the roles of the JAG 1 gene in the pathogenesis of EHBA and to suggest a possible mechanism by which the abnormal JAG 1 protein might relate to the inflammatory process in patients with EHBA. One hundred two patients with EHBA were studied. EHBA was confirmed by identifying fibrosis and obliteration of the extrahepatic ducts on liver biopsies. Sequence analysis of the JAG 1 gene was performed with cloned DNA fragments from blood or liver biopsy specimens. Nine patients (8.8%) had missense mutations of JAG 1, causing a single amino acid replacement. The mutations found in the EHBA patients were not found in 100 control volunteers without liver disease. To exclude the diagnosis of Alagille syndrome, the patients with JAG 1 mutations were screened for facial, vertebral, cardiac, and ophthalmologic abnormalities, and none were found. The outcome of the patients was analyzed with respect to their JAG 1 mutation status. Six of 28 patients requiring liver transplantation before aged 5 years had the JAG 1 mutation compared with only 3 of 72 patients who, at the time of the report, had had Kasai portoenterostomy only. Consanguinity analysis revealed that the ratio of detection of the JAG 1 mutation in the former group was significantly higher than that of the latter group (P < 0.05). The authors concluded that the role of the JAG 1 mutation in patients with EHBA might be an aggravation factor. Based on the authors' personal experience indicating that JAG 1 proteins suppress the tumor necrosis factor (TNF)-α–induced production of interleukin (IL)-8 by Huh 7 hepatoma cells, they next tried to determine if the missense mutations in patients with EHBA were promoting biliary inflammation as a result of dysfunction of the JAG 1 protein. To test this possibility, three JAG 1 missense mutations were made from a cDNA clone of full-length JAG 1. These mutants were then transfected into 3T3 cells with an expression vector. The 3T3-transfected cells were cultured for 48 hours. The supernatant from the culture or the cells themselves were cocultured with Huh 7 cells. Cocultured cells were stimulated with TNF-α and compared with unstimulated cells. The concentration of IL-8 in supernatants from the cocultures was measured. Wild-type JAG 1 resulted in suppression of IL-8 production. Two of the three constructed missense mutations showed half of the suppressive activity compared with wild-type JAG 1. The third mutant suppressed IL-8 production to a degree equal to wild-type JAG 1. The authors concluded that the poor outcome seen in EHBA patients with JAG 1 mutations might be a result of insufficient regulation of inflammatory cytokines caused by dysfunction of the JAG 1–Notch pathway. Comment: This provocative study is the first to show a potential relationship between the JAGGED 1 gene and biliary atresia. The authors concluded that the presence of JAGGED 1 mutants in biliary atresia was associated with a worse prognosis, which might be related to more rapid inflammatory destruction of bile ducts. Several confounding factors need to be considered in interpreting these findings. First, is it possible that the nine patients with JAG 1 mutations had atypical cases of Alagille syndrome? The authors put forth a strong argument against this possibility because these patients had none of the cardiac, ophthalmologic, or musculoskeletal manifestations of Alagille syndrome. However, it is now clear that not all patients with JAG 1 mutations present with the entire clinical spectrum of Alagille disease. For example, some patients have solely cardiac disease without any liver involvement (1). The authors believed that the histologic findings of liver biopsies taken at the time of the Kasai operation were characteristic of EHBA and clearly distinguishable from Alagille syndrome because hyperplasia of intrahepatic bile ducts was marked in all nine patients. However, it is known that bile duct proliferation may be found in liver biopsies of patients with Alagille syndrome in early stages of the disease (2). The authors believed that the histologic finding of obliteration of the lumen of the extrahepatic bile ducts by granulation, fibrosis, and inflammation was diagnostic of EHBA. However, in patients with Alagille syndrome, the extrahepatic ducts may be so small that a cholangiogram may suggest obstruction proximally in up to 37% of patients (3). The authors did find severe inflammation and fibrosis of the extrahepatic ducts in all nine patients with JAG 1 mutations. This histologic finding is not characteristic of Alagille syndrome and supports the unequivocal diagnosis of EHBA. Second, but less likely, is that atypical Alagille syndrome (without extrahepatic manifestations) and EHBA simultaneously occurred in these nine patients. Certainly, there are reports of patients and members of the same family in whom EHBA and Alagille syndrome coexist (4). Finally, these nine patients could be carriers of JAGGED 1 missense mutations and be clinically unaffected. This scenario has been reported in relatives of Alagille syndrome patients (3). Six of the nine patients with the JAG 1 mutation had a worse prognosis reflected in their earlier need for liver transplantation. The authors proposed that the poor prognosis was a correlate of the JAG 1 mutation. However, there was no documentation that they had explored other risk factors that might have been responsible for the rapid progression of disease. Specifically, the authors did not provide data on the age of the patients at the time of Kasai portoenterostomy. The description of the nine patients with JAG 1 mutation at the time of initial examination suggested that they might have been older at the time of operation than the other patients. They were said to have a “progressively worsening clinical course.... and acholic stools around 3 months of age.” Could it be that the poor prognosis was a result of late presentation and delayed palliative surgery after 12 weeks of age? Although the authors state that the success rate of the Kasai procedure is 72% at their hospital, almost all other series report a success rate of less than 20% in patients aged 12 weeks or older when operated (5). The raw data on age at the time of Kasai portoenterostomy are necessary to interpret these findings. The authors describe an elegant in vitro method to test whether the JAG 1 missense mutations alter the inflammatory environment in patients with biliary atresia. The relationship between the JAG 1–Notch transcription signals and cytokine production involves a negative feedback system, in which the nuclear factor κB (NF-κB) plays a major role (6). NF-κB plays multiple, crucial roles in inflammatory and immune responses. Regulation of cell survival, proliferation, and cytokine production are some of the many functions attributed to NF-κB. NF-κB induces upregulation of JAG 1 protein expression. JAG 1 signals to the receiving cell, activating and upregulating Notch-1. Notch-1 then inhibits NF-κB with the resultant downregulation of cytokine production. The authors have shown that the ability of JAGGED 1 to suppress IL-8 production is reduced approximately 50% (i.e., more IL-8 was produced) in two of three missense mutants of this gene. This is an intriguing finding and warrants further investigation with in vitro studies to elucidate other pathways that may be inhibited or stimulated by JAGGED 1–Notch interactions. The authors hypothesize that persistent inflammation in the nine patients with EHBA and JAG 1 mutants may lead to a more rapid progression to cirrhosis. This speculation may be supported by comparing the intrahepatic portal tract inflammation at age 1 year (liver biopsy) in EHBA patients with and without JAG 1 mutations. This provocative article raises the possibility that there is a relationship between EHBA and Alagille syndrome. Could JAG 1 mutations cause or be a gene modifier for certain patients with EHBA? Is there a new, severe form of Alagille syndrome limited to the biliary tree without extrahepatic manifestations? Could other genes in the Notch signaling pathway be involved in the etiology or progression of EHBA? The novel clinical findings of Kohsaka et al. will now need to be replicated at other centers to help answer these questions. Cara L. Mack The Children's Hospital and University of Colorado Health Sciences Center Denver, Colorado, U.S.A.

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.