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Semin Liver Dis 2012; 32(04): 307-316
DOI: 10.1055/s-0032-1329899
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Clues to the Etiology of Bile Duct Injury in Biliary Atresia

Cara L. Mack
1   Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado School of Medicine, and Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado
,
Amy G. Feldman
1   Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado School of Medicine, and Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado
,
Ronald J. Sokol
1   Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado School of Medicine, and Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado
› Author Affiliations
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Publication History

Publication Date:
08 February 2013 (online)

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Abstract

Biliary atresia (BA) is an infantile obstructive cholangiopathy of unknown etiology with suboptimal therapy, which is responsible for 40 to 50% of all pediatric liver transplants. Although the etiology of bile duct injury in BA in unknown, it is postulated that a pre- or perinatal viral infection initiates cholangiocyte apoptosis and release of antigens that trigger a Th1 immune response that leads to further bile duct injury, inflammation, and obstructive fibrosis. Humoral immunity and activation of the innate immune system may also play key roles in this process. Moreover, recent investigations from the murine BA model and human data suggest that regulatory T cells and genetic susceptibility factors may orchestrate autoimmune mechanisms. What controls the coordination of these events, why the disease only occurs in the first few months of life, and why a minority of infants with perinatal viral infections develop BA are remaining questions to be answered.

Keywords

neonatal cholestasis - adaptive immunity - innate immunity - humoral immunity
 

  • References

  • 1 Mack CL, Sokol RJ. Unraveling the pathogenesis and etiology of biliary atresia. Pediatr Res 2005; 57 (5 Pt 2) 87R-94R
    CrossrefPubMedSearch in Google Scholar
  • 2 Sokol RJ, Mack C, Narkewicz MR, Karrer FM. Pathogenesis and outcome of biliary atresia: current concepts. J Pediatr Gastroenterol Nutr 2003; 37 (1) 4-21
    Search in Google Scholar
  • 3 Hartley JL, Davenport M, Kelly DA. Biliary atresia. Lancet 2009; 374 (9702) 1704-1713
    CrossrefPubMedSearch in Google Scholar
  • 4 Petersen C. Pathogenesis and treatment opportunities for biliary atresia. Clin Liver Dis 2006; 10 (1) 73-88 , vi vi
    CrossrefPubMedSearch in Google Scholar
  • 5 Bessho K, Bezerra JA. Biliary atresia: will blocking inflammation tame the disease?. Annu Rev Med 2011; 62: 171-185
    CrossrefPubMedSearch in Google Scholar
  • 6 Lien TH, Chang MH, Wu JF , et al; Taiwan Infant Stool Color Card Study Group. Effects of the infant stool color card screening program on 5-year outcome of biliary atresia in Taiwan. Hepatology 2011; 53 (1) 202-208
    CrossrefPubMedSearch in Google Scholar
  • 7 Desmet VJ. Congenital diseases of intrahepatic bile ducts: variations on the theme “ductal plate malformation”. Hepatology 1992; 16 (4) 1069-1083
    CrossrefPubMedSearch in Google Scholar
  • 8 Tan CE, Driver M, Howard ER, Moscoso GJ. Extrahepatic biliary atresia: a first-trimester event? Clues from light microscopy and immunohistochemistry. J Pediatr Surg 1994; 29 (6) 808-814
    CrossrefPubMedSearch in Google Scholar
  • 9 Riepenhoff-Talty M, Gouvea V, Evans MJ , et al. Detection of group C rotavirus in infants with extrahepatic biliary atresia. J Infect Dis 1996; 174 (1) 8-15
    CrossrefPubMedSearch in Google Scholar
  • 10 Morecki R, Glaser JH, Cho S, Balistreri WF, Horwitz MS. Biliary atresia and reovirus type 3 infection. N Engl J Med 1982; 307 (8) 481-484
    CrossrefPubMedSearch in Google Scholar
  • 11 Jevon GP, Dimmick JE. Biliary atresia and cytomegalovirus infection: a DNA study. Pediatr Dev Pathol 1999; 2 (1) 11-14
    CrossrefPubMedSearch in Google Scholar
  • 12 Sokol RJ, Mack C. Etiopathogenesis of biliary atresia. Semin Liver Dis 2001; 21 (4) 517-524
    Thieme ConnectPubMedSearch in Google Scholar
  • 13 Mack CL. The pathogenesis of biliary atresia: evidence for a virus-induced autoimmune disease. Semin Liver Dis 2007; 27 (3) 233-242
    Thieme ConnectPubMedSearch in Google Scholar
  • 14 Harpavat S, Finegold MJ, Karpen SJ. Patients with biliary atresia have elevated direct/conjugated bilirubin levels shortly after birth. Pediatrics 2011; 128 (6) e1428-e1433
    CrossrefPubMedSearch in Google Scholar
  • 15 Landing BH. Considerations of the pathogenesis of neonatal hepatitis, biliary atresia and choledochal cyst—the concept of infantile obstructive cholangiopathy. Prog Pediatr Surg 1974; 6: 113-139
    PubMedSearch in Google Scholar
  • 16 al-Masri AN, Werfel T, Jakschies D, von Wussow P. Intracellular staining of Mx proteins in cells from peripheral blood, bone marrow and skin. Mol Pathol 1997; 50 (1) 9-14
    PubMedSearch in Google Scholar
  • 17 Huang YH, Chou MH, Du YY , et al. Expression of toll-like receptors and type 1 interferon specific protein MxA in biliary atresia. Lab Invest 2007; 87 (1) 66-74
    CrossrefPubMedSearch in Google Scholar
  • 18 Rauschenfels S, Krassmann M, Al-Masri AN , et al. Incidence of hepatotropic viruses in biliary atresia. Eur J Pediatr 2009; 168 (4) 469-476
    CrossrefPubMedSearch in Google Scholar
  • 19 Domiati-Saad R, Dawson DB, Margraf LR, Finegold MJ, Weinberg AG, Rogers BB. Cytomegalovirus and human herpesvirus 6, but not human papillomavirus, are present in neonatal giant cell hepatitis and extrahepatic biliary atresia. Pediatr Dev Pathol 2000; 3 (4) 367-373
    CrossrefPubMedSearch in Google Scholar
  • 20 Drut R, Drut RM, Gómez MA, Cueto Rúa E, Lojo MM. Presence of human papillomavirus in extrahepatic biliary atresia. J Pediatr Gastroenterol Nutr 1998; 27 (5) 530-535
    CrossrefPubMedSearch in Google Scholar
  • 21 Mahjoub F, Shahsiah R, Ardalan FA , et al. Detection of Epstein Barr virus by chromogenic in situ hybridization in cases of extra-hepatic biliary atresia. Diagn Pathol 2008; 3: 19
    CrossrefPubMedSearch in Google Scholar
  • 22 Fischler B, Ehrnst A, Forsgren M, Orvell C, Nemeth A. The viral association of neonatal cholestasis in Sweden: a possible link between cytomegalovirus infection and extrahepatic biliary atresia. J Pediatr Gastroenterol Nutr 1998; 27 (1) 57-64
    CrossrefPubMedSearch in Google Scholar
  • 23 Tyler KL, Sokol RJ, Oberhaus SM , et al. Detection of reovirus RNA in hepatobiliary tissues from patients with extrahepatic biliary atresia and choledochal cysts. Hepatology 1998; 27 (6) 1475-1482
    CrossrefPubMedSearch in Google Scholar
  • 24 Stanley NF, Dorman DC, Ponsford J. Studies on the pathogenesis of a hitherto undescribed virus (hepato-encephalomyelitis) producing unusual symptoms in suckling mice. Aust J Exp Biol Med Sci 1953; 31 (2) 147-159
    PubMedSearch in Google Scholar
  • 25 Papadimitriou JM. The biliary tract in acute murine reovirus 3 infection. Light and electron microscopic study. Am J Pathol 1968; 52 (3) 595-611
    PubMedSearch in Google Scholar
  • 26 Bangaru B, Morecki R, Glaser JH, Gartner LM, Horwitz MS. Comparative studies of biliary atresia in the human newborn and reovirus-induced cholangitis in weanling mice. Lab Invest 1980; 43 (5) 456-462
    PubMedSearch in Google Scholar
  • 27 Phillips PA, Keast D, Papadimitriou JM, Walters MN, Stanley NF. Chronic obstructive jaundice induced by reovirus type 3 in weanling mice. Pathology 1969; 1 (3) 193-203
    CrossrefPubMedSearch in Google Scholar
  • 28 Wilson GA, Morrison LA, Fields BN. Association of the reovirus S1 gene with serotype 3-induced biliary atresia in mice. J Virol 1994; 68 (10) 6458-6465
    PubMedSearch in Google Scholar
  • 29 Parashar K, Tarlow MJ, McCrae MA. Experimental reovirus type 3-induced murine biliary tract disease. J Pediatr Surg 1992; 27 (7) 843-847
    CrossrefPubMedSearch in Google Scholar
  • 30 Barton ES, Youree BE, Ebert DH , et al. Utilization of sialic acid as a coreceptor is required for reovirus-induced biliary disease. J Clin Invest 2003; 111 (12) 1823-1833
    CrossrefPubMedSearch in Google Scholar
  • 31 Harada K, Sato Y, Itatsu K , et al. Innate immune response to double-stranded RNA in biliary epithelial cells is associated with the pathogenesis of biliary atresia. Hepatology 2007; 46 (4) 1146-1154
    CrossrefPubMedSearch in Google Scholar
  • 32 Glaser JH, Balistreri WF, Morecki R. Role of reovirus type 3 in persistent infantile cholestasis. J Pediatr 1984; 105 (6) 912-915
    PubMedSearch in Google Scholar
  • 33 Richardson SC, Bishop RF, Smith AL. Reovirus serotype 3 infection in infants with extrahepatic biliary atresia or neonatal hepatitis. J Gastroenterol Hepatol 1994; 9 (3) 264-268
    CrossrefPubMedSearch in Google Scholar
  • 34 Brown WR, Sokol RJ, Levin MJ , et al. Lack of correlation between infection with reovirus 3 and extrahepatic biliary atresia or neonatal hepatitis. J Pediatr 1988; 113 (4) 670-676
    PubMedSearch in Google Scholar
  • 35 Dussaix E, Hadchouel M, Tardieu M, Alagille D. Biliary atresia and reovirus type 3 infection. N Engl J Med 1984; 310 (10) 658
    PubMedSearch in Google Scholar
  • 36 Steele MI, Marshall CM, Lloyd RE, Randolph VE. Reovirus 3 not detected by reverse transcriptase-mediated polymerase chain reaction analysis of preserved tissue from infants with cholestatic liver disease. Hepatology 1995; 21 (3) 697-702
    CrossrefPubMedSearch in Google Scholar
  • 37 Riepenhoff-Talty M, Schaekel K, Clark HF , et al. Group A rotaviruses produce extrahepatic biliary obstruction in orally inoculated newborn mice. Pediatr Res 1993; 33 (4 Pt 1) 394-399
    PubMedSearch in Google Scholar
  • 38 Czech-Schmidt G, Verhagen W, Szavay P, Leonhardt J, Petersen C. Immunological gap in the infectious animal model for biliary atresia. J Surg Res 2001; 101 (1) 62-67
    CrossrefPubMedSearch in Google Scholar
  • 39 Mack CL, Tucker RM, Sokol RJ, Kotzin BL. Armed CD4+ Th1 effector cells and activated macrophages participate in bile duct injury in murine biliary atresia. Clin Immunol 2005; 115 (2) 200-209
    CrossrefPubMedSearch in Google Scholar
  • 40 Allen SR, Jafri M, Donnelly B , et al. Effect of rotavirus strain on the murine model of biliary atresia. J Virol 2007; 81 (4) 1671-1679
    CrossrefPubMedSearch in Google Scholar
  • 41 Wang W, Donnelly B, Bondoc A , et al. The rhesus rotavirus gene encoding VP4 is a major determinant in the pathogenesis of biliary atresia in newborn mice. J Virol 2011; 85 (17) 9069-9077
    CrossrefPubMedSearch in Google Scholar
  • 42 Feng N, Sen A, Wolf M, Vo P, Hoshino Y, Greenberg HB. Roles of VP4 and NSP1 in determining the distinctive replication capacities of simian rotavirus RRV and bovine rotavirus UK in the mouse biliary tract. J Virol 2011; 85 (6) 2686-2694
    CrossrefPubMedSearch in Google Scholar
  • 43 Jafri M, Donnelly B, Allen S , et al. Cholangiocyte expression of alpha2beta1-integrin confers susceptibility to rotavirus-induced experimental biliary atresia. Am J Physiol Gastrointest Liver Physiol 2008; 295 (1) G16-G26
    CrossrefPubMedSearch in Google Scholar
  • 44 Bobo L, Ojeh C, Chiu D, Machado A, Colombani P, Schwarz K. Lack of evidence for rotavirus by polymerase chain reaction/enzyme immunoassay of hepatobiliary samples from children with biliary atresia. Pediatr Res 1997; 41 (2) 229-234
    PubMedSearch in Google Scholar
  • 45 Ko HM, Kim KS, Park JW , et al. Congenital cytomegalovirus infection: three autopsy case reports. J Korean Med Sci 2000; 15 (3) 337-342
    CrossrefPubMedSearch in Google Scholar
  • 46 Martelius T, Krogerus L, Höckerstedt K, Bruggeman C, Lautenschlager I. Cytomegalovirus infection is associated with increased inflammation and severe bile duct damage in rat liver allografts. Hepatology 1998; 27 (4) 996-1002
    CrossrefPubMedSearch in Google Scholar
  • 47 Evans PC, Coleman N, Wreghitt TG, Wight DG, Alexander GJ. Cytomegalovirus infection of bile duct epithelial cells, hepatic artery and portal venous endothelium in relation to chronic rejection of liver grafts. J Hepatol 1999; 31 (5) 913-920
    CrossrefPubMedSearch in Google Scholar
  • 48 Chang MH, Huang HH, Huang ES, Kao CL, Hsu HY, Lee CY. Polymerase chain reaction to detect human cytomegalovirus in livers of infants with neonatal hepatitis. Gastroenterology 1992; 103 (3) 1022-1025
    PubMedSearch in Google Scholar
  • 49 Potena L, Valantine HA. Cytomegalovirus-associated allograft rejection in heart transplant patients. Curr Opin Infect Dis 2007; 20 (4) 425-431
    CrossrefPubMedSearch in Google Scholar
  • 50 Dimmick JE. Intrahepatic bile duct paucity and cytomegalovirus infection. Pediatr Pathol 1993; 13 (6) 847-852
    CrossrefPubMedSearch in Google Scholar
  • 51 Xu Y, Yu J, Zhang R , et al. The perinatal infection of cytomegalovirus is an important etiology for biliary atresia in China. Clin Pediatr (Phila) 2012; 51 (2) 109-113
    CrossrefPubMedSearch in Google Scholar
  • 52 Jevon GP, Dimmick JE. Biliary atresia and cytomegalovirus infection: a DNA study. Pediatr Dev Pathol 1999; 2 (1) 11-14
    CrossrefPubMedSearch in Google Scholar
  • 53 Fischler B, Woxenius S, Nemeth A, Papadogiannakis N. Immunoglobulin deposits in liver tissue from infants with biliary atresia and the correlation to cytomegalovirus infection. J Pediatr Surg 2005; 40 (3) 541-546
    CrossrefPubMedSearch in Google Scholar
  • 54 Brindley SM, Lanham AM, Karrer FM, Tucker RM, Fontenot AP, Mack CL. Cytomegalovirus-specific T-cell reactivity in biliary atresia at the time of diagnosis is associated with deficits in regulatory T cells. Hepatology 2012; 55 (4) 1130-1138
    CrossrefPubMedSearch in Google Scholar
  • 55 Shen C, Zheng S, Wang W, Xiao XM. Relationship between prognosis of biliary atresia and infection of cytomegalovirus. World J Pediatr 2008; 4 (2) 123-126
    CrossrefPubMedSearch in Google Scholar
  • 56 Fischler B, Svensson JF, Nemeth A. Early cytomegalovirus infection and the long-term outcome of biliary atresia. Acta Paediatr 2009; 98 (10) 1600-1602
    CrossrefPubMedSearch in Google Scholar
  • 57 Serreze DV, Chapman HD, Varnum DS , et al. B lymphocytes are essential for the initiation of T cell-mediated autoimmune diabetes: analysis of a new “speed congenic” stock of NOD.Ig mu null mice. J Exp Med 1996; 184 (5) 2049-2053
    CrossrefPubMedSearch in Google Scholar
  • 58 Chan O, Shlomchik MJ. A new role for B cells in systemic autoimmunity: B cells promote spontaneous T cell activation in MRL-lpr/lpr mice. J Immunol 1998; 160 (1) 51-59
    PubMedSearch in Google Scholar
  • 59 O'Neill SK, Shlomchik MJ, Glant TT, Cao Y, Doodes PD, Finnegan A. Antigen-specific B cells are required as APCs and autoantibody-producing cells for induction of severe autoimmune arthritis. J Immunol 2005; 174 (6) 3781-3788
    PubMedSearch in Google Scholar
  • 60 Yu S, Maiti PK, Dyson M, Jain R, Braley-Mullen H. B cell-deficient NOD.H-2h4 mice have CD4 + CD25+ T regulatory cells that inhibit the development of spontaneous autoimmune thyroiditis. J Exp Med 2006; 203 (2) 349-358
    CrossrefPubMedSearch in Google Scholar
  • 61 Hadchouel M, Hugon RN, Odievre M. Immunoglobulin deposits in the biliary remnants of extrahepatic biliary atresia: a study by immunoperoxidase staining in 128 infants. Histopathology 1981; 5 (2) 217-221
    CrossrefPubMedSearch in Google Scholar
  • 62 Mack CL, Tucker RM, Lu BR , et al. Cellular and humoral autoimmunity directed at bile duct epithelia in murine biliary atresia. Hepatology 2006; 44 (5) 1231-1239
    CrossrefPubMedSearch in Google Scholar
  • 63 Lu BR, Brindley SM, Tucker RM, Lambert CL, Mack CL. α-enolase autoantibodies cross-reactive to viral proteins in a mouse model of biliary atresia. Gastroenterology 2010; 139 (5) 1753-1761
    CrossrefPubMedSearch in Google Scholar
  • 64 Saulot V, Vittecoq O, Charlionet R , et al. Presence of autoantibodies to the glycolytic enzyme alpha-enolase in sera from patients with early rheumatoid arthritis. Arthritis Rheum 2002; 46 (5) 1196-1201
    CrossrefPubMedSearch in Google Scholar
  • 65 Vermeulen N, de Béeck KO, Vermeire S , et al. Identification of a novel autoantigen in inflammatory bowel disease by protein microarray. Inflamm Bowel Dis 2011; 17 (6) 1291-1300
    CrossrefPubMedSearch in Google Scholar
  • 66 Forooghian F, Cheung RK, Smith WC, O'Connor P, Dosch HM. Enolase and arrestin are novel nonmyelin autoantigens in multiple sclerosis. J Clin Immunol 2007; 27 (4) 388-396
    CrossrefPubMedSearch in Google Scholar
  • 67 Fukuda Y, Miyazawa Y, Imoto M , et al. In situ distribution of enolase isozymes in chronic liver disease. Am J Gastroenterol 1989; 84 (6) 601-605
    PubMedSearch in Google Scholar
  • 68 Akisawa N, Maeda T, Iwasaki S, Onishi S. Identification of an autoantibody against alpha-enolase in primary biliary cirrhosis. J Hepatol 1997; 26 (4) 845-851
    CrossrefPubMedSearch in Google Scholar
  • 69 Feldman A, Tucker R, Pelanda R, Mack C. Critical role of B cells in the development of bile duct injury and obstruction in murine biliary atresia. Paper presented at: American Association for the Study of Liver Diseases Annual Meeting; Nov. 4–8, 2011; San Francisco, CA
    PubMed
  • 70 Leonhardt J, Stanulla M, von Wasielewski R , et al. Gene expression profile of the infective murine model for biliary atresia. Pediatr Surg Int 2006; 22 (1) 84-89
    CrossrefPubMedSearch in Google Scholar
  • 71 Carvalho E, Liu C, Shivakumar P, Sabla G, Aronow B, Bezerra JA. Analysis of the biliary transcriptome in experimental biliary atresia. Gastroenterology 2005; 129 (2) 713-717
    CrossrefPubMedSearch in Google Scholar
  • 72 Shivakumar P, Campbell KM, Sabla GE , et al. Obstruction of extrahepatic bile ducts by lymphocytes is regulated by IFN-gamma in experimental biliary atresia. J Clin Invest 2004; 114 (3) 322-329
    CrossrefPubMedSearch in Google Scholar
  • 73 Mohanty SK, Shivakumar P, Sabla G, Bezerra JA. Loss of interleukin-12 modifies the pro-inflammatory response but does not prevent duct obstruction in experimental biliary atresia. BMC Gastroenterol 2006; 6: 14
    CrossrefPubMedSearch in Google Scholar
  • 74 Tucker RM, Hendrickson RJ, Mukaida N, Gill RG, Mack CL. Progressive biliary destruction is independent of a functional tumor necrosis factor-alpha pathway in a rhesus rotavirus-induced murine model of biliary atresia. Viral Immunol 2007; 20 (1) 34-43
    CrossrefPubMedSearch in Google Scholar
  • 75 Li J, Bessho K, Shivakumar P , et al. Th2 signals induce epithelial injury in mice and are compatible with the biliary atresia phenotype. J Clin Invest 2011; 121 (11) 4244-4256
    CrossrefPubMedSearch in Google Scholar
  • 76 Davenport M, Gonde C, Redkar R , et al. Immunohistochemistry of the liver and biliary tree in extrahepatic biliary atresia. J Pediatr Surg 2001; 36 (7) 1017-1025
    CrossrefPubMedSearch in Google Scholar
  • 77 Mack CL, Tucker RM, Sokol RJ , et al. Biliary atresia is associated with CD4+ Th1 cell-mediated portal tract inflammation. Pediatr Res 2004; 56 (1) 79-87
    CrossrefPubMedSearch in Google Scholar
  • 78 Ahmed AF, Ohtani H, Nio M , et al. CD8+ T cells infiltrating into bile ducts in biliary atresia do not appear to function as cytotoxic T cells: a clinicopathological analysis. J Pathol 2001; 193 (3) 383-389
    CrossrefPubMedSearch in Google Scholar
  • 79 Shinkai M, Shinkai T, Puri P, Stringer MD. Increased CXCR3 expression associated with CD3-positive lymphocytes in the liver and biliary remnant in biliary atresia. J Pediatr Surg 2006; 41 (5) 950-954
    CrossrefPubMedSearch in Google Scholar
  • 80 Ohya T, Fujimoto T, Shimomura H, Miyano T. Degeneration of intrahepatic bile duct with lymphocyte infiltration into biliary epithelial cells in biliary atresia. J Pediatr Surg 1995; 30 (4) 515-518
    CrossrefPubMedSearch in Google Scholar
  • 81 Bezerra JA, Tiao G, Ryckman FC , et al. Genetic induction of proinflammatory immunity in children with biliary atresia. Lancet 2002; 360 (9346) 1653-1659
    CrossrefPubMedSearch in Google Scholar
  • 82 Whitington PF, Malladi P, Melin-Aldana H, Azzam R, Mack CL, Sahai A. Expression of osteopontin correlates with portal biliary proliferation and fibrosis in biliary atresia. Pediatr Res 2005; 57 (6) 837-844
    CrossrefPubMedSearch in Google Scholar
  • 83 Honsawek S, Vejchapipat P, Chongsrisawat V, Thawornsuk N, Poovorawan Y. Association of circulating osteopontin levels with clinical outcomes in postoperative biliary atresia. Pediatr Surg Int 2011; 27 (3) 283-288
    CrossrefPubMedSearch in Google Scholar
  • 84 Narayanaswamy B, Gonde C, Tredger JM, Hussain M, Vergani D, Davenport M. Serial circulating markers of inflammation in biliary atresia—evolution of the post-operative inflammatory process. Hepatology 2007; 46 (1) 180-187
    CrossrefPubMedSearch in Google Scholar
  • 85 Arikan C, Berdeli A, Kilic M, Tumgor G, Yagci RV, Aydogdu S. Polymorphisms of the ICAM-1 gene are associated with biliary atresia. Dig Dis Sci 2008; 53 (7) 2000-2004
    CrossrefPubMedSearch in Google Scholar
  • 86 Shivakumar P, Sabla G, Mohanty S , et al. Effector role of neonatal hepatic CD8+ lymphocytes in epithelial injury and autoimmunity in experimental biliary atresia. Gastroenterology 2007; 133 (1) 268-277
    CrossrefPubMedSearch in Google Scholar
  • 87 Rose NR, Bona C. Defining criteria for autoimmune diseases (Witebsky's postulates revisited). Immunol Today 1993; 14 (9) 426-430
    CrossrefPubMedSearch in Google Scholar
  • 88 Mack CL, Falta MT, Sullivan AK , et al. Oligoclonal expansions of CD4+ and CD8+ T-cells in the target organ of patients with biliary atresia. Gastroenterology 2007; 133 (1) 278-287
    CrossrefPubMedSearch in Google Scholar
  • 89 Broomé U, Nemeth A, Hultcrantz R, Scheynius A. Different expression of HLA-DR and ICAM-1 in livers from patients with biliary atresia and Byler's disease. J Hepatol 1997; 26 (4) 857-862
    CrossrefPubMedSearch in Google Scholar
  • 90 Feng J, Li M, Gu W, Tang H, Yu S. The aberrant expression of HLA-DR in intrahepatic bile ducts in patients with biliary atresia: an immunohistochemistry and immune electron microscopy study. J Pediatr Surg 2004; 39 (11) 1658-1662
    CrossrefPubMedSearch in Google Scholar
  • 91 Donaldson PT, Clare M, Constantini PK , et al. HLA and cytokine gene polymorphisms in biliary atresia. Liver 2002; 22 (3) 213-219
    PubMedSearch in Google Scholar
  • 92 Yuasa T, Tsuji H, Kimura S , et al. Human leukocyte antigens in Japanese patients with biliary atresia: retrospective analysis of patients who underwent living donor liver transplantation. Hum Immunol 2005; 66 (3) 295-300
    CrossrefPubMedSearch in Google Scholar
  • 93 Davenport M, Stringer MD, Tizzard SA, McClean P, Mieli-Vergani G, Hadzic N. Randomized, double-blind, placebo-controlled trial of corticosteroids after Kasai portoenterostomy for biliary atresia. Hepatology 2007; 46 (6) 1821-1827
    CrossrefPubMedSearch in Google Scholar
  • 94 Petersen C, Harder D, Melter M , et al. Postoperative high-dose steroids do not improve mid-term survival with native liver in biliary atresia. Am J Gastroenterol 2008; 103 (3) 712-719
    CrossrefPubMedSearch in Google Scholar
  • 95 Sarkhy A, Schreiber RA, Milner RA, Barker CC. Does adjuvant steroid therapy post-Kasai portoenterostomy improve outcome of biliary atresia? Systematic review and meta-analysis. Can J Gastroenterol 2011; 25 (8) 440-444
    PubMedSearch in Google Scholar
  • 96 Sokol RJ. New North American research network focuses on biliary atresia and neonatal liver disease. J Pediatr Gastroenterol Nutr 2003; 36 (1) 1
    PubMedSearch in Google Scholar
  • 97 Grindebacke H, Stenstad H, Quiding-Järbrink M , et al. Dynamic development of homing receptor expression and memory cell differentiation of infant CD4 + CD25 high regulatory T cells. J Immunol 2009; 183 (7) 4360-4370
    CrossrefPubMedSearch in Google Scholar
  • 98 Miethke AG, Saxena V, Shivakumar P, Sabla GE, Simmons J, Chougnet CA. Post-natal paucity of regulatory T cells and control of NK cell activation in experimental biliary atresia. J Hepatol 2010; 52 (5) 718-726
    CrossrefPubMedSearch in Google Scholar
  • 99 Lages CS, Simmons J, Chougnet CA, Miethke AG. Regulatory T cells control the CD8 adaptive immune response at the time of ductal obstruction in experimental biliary atresia. Hepatology 2012; 56 (1) 219-227
    CrossrefPubMedSearch in Google Scholar
  • 100 Krüger DH, Schroeder C, Santibanez-Koref M, Reuter M. Avoidance of DNA methylation. A virus-encoded methylase inhibitor and evidence for counterselection of methylase recognition sites in viral genomes. Cell Biophys 1989; 15 (1-2) 87-95
    PubMedSearch in Google Scholar
  • 101 Ogasawara H, Okada M, Kaneko H, Hishikawa T, Sekigawa I, Hashimoto H. Possible role of DNA hypomethylation in the induction of SLE: relationship to the transcription of human endogenous retroviruses. Clin Exp Rheumatol 2003; 21 (6) 733-738
    PubMedSearch in Google Scholar
  • 102 Lee PP, Fitzpatrick DR, Beard C , et al. A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. Immunity 2001; 15 (5) 763-774
    CrossrefPubMedSearch in Google Scholar
  • 103 Zhang DY, Sabla G, Shivakumar P , et al. Coordinate expression of regulatory genes differentiates embryonic and perinatal forms of biliary atresia. Hepatology 2004; 39 (4) 954-962
    CrossrefPubMedSearch in Google Scholar
  • 104 Matthews RP, Eauclaire SF, Mugnier M , et al. DNA hypomethylation causes bile duct defects in zebrafish and is a distinguishing feature of infantile biliary atresia. Hepatology 2011; 53 (3) 905-914
    CrossrefPubMedSearch in Google Scholar
  • 105 Dong R, Zhao R, Zheng S. Changes in epigenetic regulation of CD4+ T lymphocytesin biliary atresia. Pediatr Res 2011; 70 (6) 555-559
    PubMedSearch in Google Scholar
  • 106 Garcia-Barceló MM, Yeung MY, Miao XP , et al. Genome-wide association study identifies a susceptibility locus for biliary atresia on 10q24.2. Hum Mol Genet 2010; 19 (14) 2917-2925
    CrossrefPubMedSearch in Google Scholar
  • 107 Lane T, Lachmann HJ. The emerging role of interleukin-1β in autoinflammatory diseases. Curr Allergy Asthma Rep 2011; 11 (5) 361-368
    CrossrefPubMedSearch in Google Scholar
  • 108 Harada K, Nakanuma Y. Cholangiopathy with respect to biliary innate immunity. Int J Hepatol 2012; 2012 (793569) 793569
    PubMedSearch in Google Scholar
  • 109 Chuang JH, Chou MH, Wu CL, Du YY. Implication of innate immunity in the pathogenesis of biliary atresia. Chang Gung Med J 2006; 29 (3) 240-250
    PubMedSearch in Google Scholar
  • 110 Lövgren T, Eloranta ML, Båve U, Alm GV, Rönnblom L. Induction of interferon-alpha production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG. Arthritis Rheum 2004; 50 (6) 1861-1872
    CrossrefPubMedSearch in Google Scholar
  • 111 Saito T, Hishiki T, Terui K , et al. Toll-like receptor mRNA expression in liver tissue from patients with biliary atresia. J Pediatr Gastroenterol Nutr 2011; 53 (6) 620-626
    PubMedSearch in Google Scholar
  • 112 Tracy Jr TF, Dillon P, Fox ES, Minnick K, Vogler C. The inflammatory response in pediatric biliary disease: macrophage phenotype and distribution. J Pediatr Surg 1996; 31 (1) 121-125 , discussion 125–126
    CrossrefPubMedSearch in Google Scholar
  • 113 Urushihara N, Iwagaki H, Yagi T , et al. Elevation of serum interleukin-18 levels and activation of Kupffer cells in biliary atresia. J Pediatr Surg 2000; 35 (3) 446-449
    CrossrefPubMedSearch in Google Scholar
  • 114 Kobayashi H, Puri P, O'Briain DS, Surana R, Miyano T. Hepatic overexpression of MHC class II antigens and macrophage-associated antigens (CD68) in patients with biliary atresia of poor prognosis. J Pediatr Surg 1997; 32 (4) 590-593
    CrossrefPubMedSearch in Google Scholar
  • 115 Shih HH, Lin TM, Chuang JH , et al. Promoter polymorphism of the CD14 endotoxin receptor gene is associated with biliary atresia and idiopathic neonatal cholestasis. Pediatrics 2005; 116 (2) 437-441
    CrossrefPubMedSearch in Google Scholar
  • 116 Arikan C, Berdeli A, Ozgenc F, Tumgor G, Yagci RV, Aydogdu S. Positive association of macrophage migration inhibitory factor gene-173G/C polymorphism with biliary atresia. J Pediatr Gastroenterol Nutr 2006; 42 (1) 77-82
    CrossrefPubMedSearch in Google Scholar
  • 117 Donn R, Alourfi Z, Zeggini E , et al; British Paediatric Rheumatology Study Group. A functional promoter haplotype of macrophage migration inhibitory factor is linked and associated with juvenile idiopathic arthritis. Arthritis Rheum 2004; 50 (5) 1604-1610
    Search in Google Scholar
  • 118 Nohara H, Okayama N, Inoue N , et al. Association of the -173 G/C polymorphism of the macrophage migration inhibitory factor gene with ulcerative colitis. J Gastroenterol 2004; 39 (3) 242-246
    Search in Google Scholar
  • 119 Glaser SS. Biliary atresia: is lack of innate immune response tolerance key to pathogenesis?. Liver Int 2008; 28 (5) 587-588
    CrossrefPubMedSearch in Google Scholar