Ideas on Biliary Atresia

Biliary Atresia -- Mechanism and Outcome
Biliary atresia is the most common indication for liver transplantation in children, yet its cause is elusive. One theory implicates a virus-initiated process that culminates in autoimmune-mediated destruction of bile ducts. New insight has been provided by the rhesus rotavirus (RRV)-induced murine model of biliary atresia that resembles the human disease. In this model, immune-mediated inflammation of bile ducts progresses to biliary obstruction and death by 3 weeks of age.

During the plenary session at this year's AASLD meeting, Mack and colleagues[1] reported the results of a study to test the theory that autoreactive T cells are present in the RRV-model, and thus that transfer of these cells should elicit an autoimmune attack on the bile ducts of a recipient mouse. Liver lymphocytes from RRV-diseased animals were adoptively transferred into immunodeficient mice; this transfer resulted in marked cellular infiltration surrounding the bile ducts of all mice. The infiltrates were composed, in part, of the adoptively transferred CD3+ T cells. This periductular inflammation was not found in the control group and was organ-specific. The T cells migrated to bile duct epithelium in an antigen-specific fashion, suggesting autoreactive T-cell-mediated bile duct injury. Future studies are needed that include T-cell proliferation assays aimed at investigating bile duct epithelium as the target antigen.

Narayanaswamy and colleagues[2] characterized the nature of the inflammatory process in biliary atresia in 21 affected infants. They noted a persistent inflammatory process that involved both a nonpolarized T-helper cell (Th1 and Th2) response, as well as macrophages. The intensity of the inflammatory process correlated directly with outcome. A Th1 commitment also occurs in the murine model. The livers of mice with induced biliary atresia demonstrate increased numbers of T lymphocytes along with high-level expression of Th1-type cytokines (interleukin [IL]-2 and interferon [IFN]-alpha). By 2 weeks post infection, the disease is marked by elevated numbers of macrophages concurrent with high expression of the proinflammatory cytokine TNF-alpha. In mouse models of other inflammatory diseases, TNF- blockade results in rapid recovery or prevention of disease. In view of the similar increase in expression of TNF-alpha at time of diagnosis in infants with biliary atresia, Hendrickson and colleagues[3] hypothesized that elimination of a functional TNF pathway in RRV-infected mice would result in enhanced recovery. Although RRV-infected mice had elevated expression of TNF-alpha, depletion of this cytokine was not sufficient to affect the progression of bile duct inflammation and obstruction. In related murine studies, it has been noted that the absence of IFN-gamma improves cholestasis by decreasing the tropism of lymphocytes to bile ducts. On the basis of previous findings of high levels of expression of the Th1 cytokine IL-12 at the time of duct obstruction, Mohanty and colleagues[4] hypothesized that loss of IL-12 would prevent bile duct obstruction. They found that loss of functional IL-12 did not prevent bile duct obstruction, attenuated -- but did not abolish -- the Th1 response, and induced high expression of type-1 IFNs and infiltration of bile ducts by neutrophils.

Cumulatively, these studies strongly support a role for type-1 IFNs and neutrophils in the pathogenesis of biliary atresia. Additional elucidation of this process may enable specific immunomodulatory therapy for this condition.