A proposed mechanism in the pathogenesis of
biliary atresia involves an initial virus-induced, progressive T cell-mediated inflammatory obliteration of bile ducts. The aim of this study was to characterize the inflammatory environment present within the liver of infants with
biliary atresia to gain insight into the role of a primary immune-mediated process versus a nonspecific secondary response to biliary obstruction. Frozen liver tissue obtained from patients with
biliary atresia, neonatal
giant cell hepatitis,
total parenteral nutrition (TPN)-related
cholestasis,
choledochal cysts, and normal control subjects was used for fluorescent immunohistochemistry studies of cellular infiltrates,
cytokine mRNA expression, and in situ hybridization for localization of
cytokine-producing cells. Immunohistochemistry revealed increases in CD8(+) and CD4(+) T cells and Kupffer cells (CD68(+)) in the portal tracts of
biliary atresia. Reverse transcription-PCR analysis of
biliary atresia tissue showed a Th1-type
cytokine profile with expression of
IL-2,
interferon-gamma,
tumor necrosis factor-alpha, and
IL-12. This profile was not seen in normal,
neonatal hepatitis or
choledochal cyst livers but was present in TPN-related
cholestasis. In situ hybridization revealed that the Th1
cytokine-producing cells were located in the portal tracts in
biliary atresia and in the parenchyma of TPN-related
cholestasis. A distinctive portal tract inflammatory environment is present in
biliary atresia, involving CD4(+) Th1 cell-mediated immunity. The absence of similar
inflammation in other pediatric cholestatic conditions suggests that the portal tract
inflammation in
biliary atresia is not a secondary response to
cholestasis but rather indicates a specific immune response involved in the pathogenesis of
biliary atresia.