title: Genetic induction of proinflammatory immunity in children with biliary atresia.
abstract: BACKGROUND
  Biliary atresia is the commonest cause of pathological jaundice in infants and the leading indication for liver transplantation in children worldwide. The cause and pathogenesis remain largely unknown. Because of clinical heterogeneity and experimental difficulties in addressing molecular mechanisms underlying multifactorial disorders in human beings, we searched for genomic signatures of biliary atresia in affected infants.
  
  
  METHODS
  We generated pools of biotinylated cRNA from livers of 14 infants with biliary atresia and six with neonatal intrahepatic cholestasis (diseased controls) and hybridised the cRNA against oligonucleotide-based gene chips. Immunohistochemistry and reverse transcriptase (RT)-PCR were used to assess the specificity of the findings and functional commitment of lymphocytes in affected livers.
  
  
  RESULTS
  Data filtering, to identify genes that are differentially expressed, and cluster analysis revealed a predominant and coordinated activation of immunity/inflammation genes within the livers of infants with biliary atresia. Most of the genes showed differential lymphocyte function, with activation of osteopontin, a regulator of cell-mediated (T-helper 1 [Th-1]) immunity in T-helper lymphocytes, and suppression of immunoglobulin genes in early stages of disease. These findings were associated with production of interferon gamma in 65% of infants with biliary atresia and no diseased control. However, histologically similar inflammatory infiltrates were present in livers of both groups, implying differential activation states of similar cell types.
  
  
  CONCLUSIONS
  Livers of infants with biliary atresia have a coordinated activation of genes involved in lymphocyte differentiation. Among these genes, the overexpression of osteopontin and interferon gamma points to a potential role of Th-1-like cytokines in disease pathogenesis.
authors.affiliation: Division of Pediatric Gastroenterology, Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA. jorge.bezerra@chmcc.org
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Bezerra
authors.forename: Greg
authors.initials: G
authors.lastname: Tiao
authors.forename: Frederick C
authors.initials: FC
authors.lastname: Ryckman
authors.forename: Maria
authors.initials: M
authors.lastname: Alonso
authors.forename: Gregg E
authors.initials: GE
authors.lastname: Sabla
authors.forename: Benjamin
authors.initials: B
authors.lastname: Shneider
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Sokol
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Aronow
mesh_terms: D001656:Biliary Atresia / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D002779:Cholestasis / Q000235:genetics; D016000:Cluster Analysis; D005786:Gene Expression Regulation; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics; D007223:Infant; D007231:Infant, Newborn; D007567:Jaundice, Neonatal / Q000150:complications; D008099:Liver / Q000473:pathology*