The Pathogenesis of Biliary Atresia: Evidence for a Virus-Induced Autoimmune Disease

Cara L. Mack

doi:10.1055/s-2007-985068

Seminars in Liver Disease, Table of Contents

Semin Liver Dis 2007; 27(3): 233-242
DOI: 10.1055/s-2007-985068

The Pathogenesis of Biliary Atresia: Evidence for a Virus-Induced Autoimmune Disease

Cara L. Mack¹

¹Pediatric Liver Center and Liver Transplant Program, Section of Pediatric Gastroenterology, Hepatology, and Nutrition, The Children's Hospital, University of Colorado at Denver-Health Sciences Center, Denver, Colorado

Abstract

ABSTRACT

Biliary atresia is a mystifying cause of neonatal cholestasis, manifested by progressive inflammation and fibrosis of both the extrahepatic and intrahepatic bile ducts. It is a devastating disease that leads to cirrhosis and the need for liver transplantation in the majority of children. The etiology is unknown, and one theory is that it may involve a primary perinatal hepatobiliary viral infection and a secondary generation of an autoimmune-mediated bile duct injury. This review will outline the evidence from both human and murine studies supporting a potential cholangiotropic viral infection as the initiator of bile duct injury in biliary atresia and the role of the adaptive immune response and autoimmunity in progression of disease. Delineating the pathways of immune and autoimmune-mediated bile duct injury within biliary atresia could stimulate development of new medical interventions aimed at suppressing the specific immune response, decreasing the inflammatory damage to bile ducts, and delaying or negating the need for liver transplantation.

KEYWORDS

Reovirus - rotavirus - cholangitis - adaptive immunity - neonatal immunity

Full Text

References

REFERENCES

1 Chen S M, Chang M H, Du J C et al.. Screening for biliary atresia by infant stool color card in Taiwan. Pediatrics. 2006; 117 1147-1154
2 Hung P Y, Chen C C, Chen W J et al.. Long-term prognosis of patients with biliary atresia: a 25 year summary. J Pediatr Gastroenterol Nutr. 2006; 42 190-195
3 Sokol R J, Mack C L. Etiopathogenesis of biliary atresia. Semin Liver Dis. 2001; 21 517-524
4 Balistreri W F, Grand R, Hoofnagle J et al.. Biliary atresia: current concepts and research directions. Summary of a symposium. Hepatology. 1996; 23 1682-1692
5 Gosseye S, Otte J B, De Meyer R, Maldague P. A histological study of extrahepatic biliary atresia. Acta Paediatr Belg. 1977; 30 85-90
6 Ohya T, Fujimoto T, Shimomura H et al.. Degeneration of intrahepatic bile duct with lymphocyte infiltration into biliary epithelial cells in biliary atresia. J Pediatr Surg. 1995; 30 515-518
7 Sokol R J, Mack C L, Narkewicz M R, Karrer F M. Pathogenesis and outcome of biliary atresia: current concepts. J Pediatr Gastroenterol Nutr. 2003; 37 4-21
8 Lykavieris P, Chardot C, Sokhn M et al.. Outcome in adulthood of biliary atresia: a study of 63 patients who survived for over 20 years with their native liver. Hepatology. 2005; 41 366-371
9 Bucuvalas J C, Ryckman F C, Atherton H et al.. Predictors of cost of liver transplantation in children: a single center study. J Pediatr. 2001; 139 66-74
10 Riepenhoff-Talty M, Houvea V, Evans M J et al.. Detection of group C rotavirus in infants with extrahepatic biliary atresia. J Infect Dis. 1996; 174 8-15
11 Morecki R, Glaser J H, Cho S, Balistreri W F, Horwitz M S. Biliary atresia and reovirus type 3 infection. N Engl J Med. 1982; 307 481-484
12 Tyler K L, Sokol R J, Oberhaus S M et al.. Detection of reovirus RNA in hepatobiliary tissues from patients with extrahepatic biliary atresia and choledochal cysts. Hepatology. 1998; 27 1475-1482
13 Jevon G P, Kimmick J E. Biliary atresia and cytomegalovirus infection: a DNA study. Pediatr Dev Pathol. 1999; 2 11-14
14 Schreiber R A, Kleinman R E. Genetics, immunology, and biliary atresia: an opening or a diversion?. J Pediatr Gastroenterol Nutr. 1993; 16 111-113
15 Tan C E, Driver M, Howard E R et al.. Extrahepatic biliary atresia: a first-trimester event? Clues from light microscopy and immunohistochemistry. J Pediatr Surg. 1994; 29 808-814
16 Oldstone M B. Molecular and cellular mechanisms, pathogenesis, and treatment of insulin-dependent diabetes obtained through study of a transgenic model of molecular mimicry. Curr Top Microbiol Immunol. 2005; 296 65-87
17 Marrack P, Kappler J, Kotzin B L. Autoimmune disease: why and where it occurs. Nat Med. 2001; 7 899-905
18 Fujinami R S, Oldstone M B. Amino acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity. Science. 1985; 230 1043-1045
19 Naucler C S, Larsson S, Moller E. A novel mechanism for virus-induced autoimmunity in humans. Immunol Rev. 1996; 152 175-192
20 Fae K C, da Silva D D, Oshiro S E et al.. Mimicry in recognition of cardiac myosin peptides by heart-intralesional T cell clones from rheumatic heart disease. J Immunol. 2006; 176 5662-5670
21 Ellis N M, Li Y, Hildebrand W, Fischetti V A, Cunningham M W. T cell mimicry and epitope specificity of cross-reactive T cell clones from rheumatic heart disease. J Immunol. 2005; 175 5448-5456
22 Poole B D, Scofield R H, Harley J B, James J A. Epstein-Barr virus and molecular mimicry in systemic lupus erythematosus. Autoimmunity. 2006; 39 63-70
23 Wucherpfennig K W, Strominger J L. Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell. 1995; 80 695-705
24 Rao V P, Kajon A E, Spindler K R, Carayanniotis G. Involvement of epitope mimicry in potentiation but not initiation of autoimmune disease. J Immunol. 1999; 162 5888-5893
25 Olson J K, Croxford J L, Calenoff M A, Dal Canto M C, Miller S D. A virus-induced molecular mimicry model of multiple sclerosis. J Clin Invest. 2001; 108 311-318
26 Zhao Z S, Granucci F, Yeh L, Schaffer P A, Cantor H. Molecular mimicry by herpes simplex virus-type 1: autoimmune disease after viral infection. Science. 1998; 279 1344-1347
27 Beisel K W, Srinivasappa J, Prabhakar B S. Identification of a putative shared epitope between Coxsackie virus B4 and alpha cardiac myosin heavy chain. Clin Exp Immunol. 1991; 86 49-55
28 Drut R, Drut R M, Gomez M A et al.. Presence of human papillomavirus in extrahepatic biliary atresia. J Pediatr Gastroenterol Nutr. 1998; 27 530-535
29 Domiati-Saad R, Dawson D B, Margraf L R et al.. Cytomegalovirus and human herpesvirus 6, but not human papillomavirus, are present in neonatal giant cell hepatitis and extrahepatic biliary atresia. Pediatr Dev Pathol. 2000; 3 367-373
30 Fjaer R B, Bruu A L, Nordbo S A. Extrahepatic bile duct atresia and viral involvement. Pediatr Transplant. 2005; 9 68-73
31 Glaser J H, Balistreri W F, Morecki R. Role of reovirus type 3 in persistent infantile cholestasis. J Pediatr. 1984; 105 912-915
32 Richardson S C, Bishop R F, Smith A L. Reovirus serotype 3 infection in infants with extrahepatic biliary atresia or neonatal hepatitis. J Gastroenterol Hepatol. 1994; 9 264-268
33 Steele M I, Marshall C M, Lloyd R E, Randolph V E. Reovirus 3 not detected by reverse transcriptase-mediated polymerase chain reaction analysis of preserved tissue from infants with cholestatic liver disease. Hepatology. 1995; 21 697-702
34 Saito T, Shinozaki K, Matsunaga T et al.. Lack of evidence for reovirus infection in tissues from patients with biliary atresia and congenital dilatation of the bile duct. J Hepatol. 2004; 40 203-211
35 Papadimitriou J M. The biliary tract in acute murine reovirus 3 infection. Am J Pathol. 1968; 52 595-611
36 Bangaru B, Morecki R, Glaser J H, Gartner L M, Horwitz M S. Comparative studies of biliary atresia in the human newborn and reovirus-induced cholangitis in weanling mice. Lab Invest. 1980; 43 456-462
37 Parashar K, Tarlow M J, McCrae M A. Experimental reovirus type 3-induced murine biliary tract disease. J Pediatr Surg. 1992; 27 843-847
38 Wilson G A, Morrison L A, Fields B N. Association of the reovirus S1 gene with serotype 3-induced biliary atresia in mice. J Virol. 1994; 68 6458-6465
39 Barton E S, Youree B E, Ebert D H et al.. Utilization of sialic acid as a coreceptor is required for reovirus-induced biliary disease. J Clin Invest. 2003; 111 1823-1833
40 Rosenberg D P, Morecki R, Lollini L O, Glaser J, Cornelius C E. Extrahepatic biliary atresia in a rhesus monkey (Macaca mulatta). Hepatology. 1983; 3 577-580
41 Gilger M A, Matson D O, Conner M E et al.. Extraintestinal rotavirus infections in children with immunodeficiency. J Pediatr. 1992; 120 912-917
42 Qiao H, Zhaori G, Jiang Z et al.. Detection of group C rotavirus antigen in bile duct and liver tissues of an infant with extrahepatic biliary atresia. Chin Med J (Engl). 1999; 112 93-95
43 Bobo L, Ojeh C, Chiu D et al.. Lack of evidence for rotavirus by polymerase chain reaction/enzyme immunoassay of hepatobiliary samples from children with biliary atresia. Pediatr Res. 1997; 41 229-234
44 Riepenhoff-Talty M, Schaekel K, Clark H F et al.. Group A rotaviruses produce extrahepatic biliary obstruction in orally inoculated newborn mice. Pediatr Res. 1993; 33 394-399
45 Petersen C, Biermanns D, Kuske M et al.. New aspects in a murine model for extrahepatic biliary atresia. J Pediatr Surg. 1997; 32 1190-1195
46 Petersen C, Grassholl S, Luciano L. Diverse morphology of biliary atresia in an animal model. J Hepatol. 1998; 28 603-607
47 Czech-Schmidt G, Verhagen W, Szavay P et al.. Immunological gap in the infectious animal model for biliary atresia. J Surg Res. 2001; 101 62-67
48 Mack C L, Tucker R M, Sokol R J, Kotzin B L. Armed CD4⁺ effector cells and activated macrophages participate in bile duct injury in murine biliary atresia. Clin Immunol. 2005; 115 200-209
49 Allen S R, Jafri M, Donnelly B et al.. Effect of rotavirus strain on the murine model of biliary atresia. J Virol. 2007; 81 1671-1679
50 Ko H M, Kim K S, Park J W et al.. Congenital cytomegalovirus infection: three autopsy case reports. J Korean Med Sci. 2000; 15 337-432
51 Martelius T, Krogerus L, Hockerstedt K, Bruggeman C, Lautenschlager I. Cytomegalovirus infection is associated with increased inflammation and severe bile duct damage in rat liver allografts. Hepatology. 1998; 27 996-1002
52 Evans P C, Coleman N, Wreghitt T G, Wight D G, Alexandder G J. Cytomegalovirus infection of bile duct epithelial cells, hepatic artery and portal venous endothelium in relation to chronic rejection of liver grafts. J Hepatol. 1999; 31 913-920
53 De Tommaso A M, Andrade P D, Costa S, Escanhoela C, Hessel G. High frequency of human cytomegalovirus DNA in the liver of infants with extrahepatic neonatal cholestasis. BMC Infect Dis. 2005; 5 108
54 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 57-64
55 Dillon P W, Belchis D, Minnick K, Tracy T. Differential expression of the major histocompatibility antigens and ICAM-1 on bile duct epithelial cells in biliary atresia. Tohoku J Exp Med. 1997; 181 33-40
56 Broome 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; 26 857-862
57 Davenport M, Gonde C, Redkar R et al.. Immunohistochemistry of the liver and biliary tree in extrahepatic biliary atresia. J Pediatr Surg. 2001; 36 1017-1025
58 Ahmed A F, 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; 193 383-389
59 Mack C L, Tucker R M, Sokol R J et al.. Biliary atresia is associated with CD4⁺ Th1 cell-mediated portal tract inflammation. Pediatr Res. 2004; 56 79-87
60 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; 30 515-518
61 Mack C L, Falta M T, Sullivan A K et al. Oligoclonal expansions of CD4⁺ and CD8⁺ T cells in the target organ of patients with biliary atresia. Gastroenterology. 2007; , doi: 10.1053/j.gastro.2007.04.032
62 Bezerra J A, Tiao G, Ryckman F C et al.. Genetic induction of proinflammatory immunity in children with biliary atresia. Lancet. 2002; 360 1653-1659
63 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 84-89
64 Carvalho E, Liu C, Shivakumar P et al.. Analysis of the biliary transcriptome in experimental biliary atresia. Gastroenterology. 2005; 129 713-717
65 Shivakumar P, Campbell K M, Sabla G E et al.. Obstruction of extrahepatic bile ducts by lymphocytes is regulated by IFN-gamma in experimental biliary atresia. J Clin Invest. 2004; 114 322-329
66 Mohanty S K, Shivakumar P, Sabla G, Bezerra J A. Loss of IL-12 modifies the pro-inflammatory response but does not prevent duct obstruction in experimental biliary atresia. BMC Gastroenterol. 2006; 6 14
67 Tucker R M, Hendrickson R, Mukaida N, Gill R G, Mack C L. Progressive biliary destruction is independent of a functional TNF-α pathway in a rhesus rotavirus-induced murine model of biliary atresia. Viral Immunol. 2007; 20 34-43
68 Hadchouel M, Hugon R N, Odievre M. Immunoglobulin deposits in the biliary remnants of extrahepatic biliary atresia: a study by immunoperoxidase staining in 128 infants. Histopathology. 1981; 5 217-221
69 Vasiliauskas E, Targan S, Cobb L, Vidrich A, Rosenthal P. Biliary atresia: an autoimmune disorder?. Hepatology. 1995; 22 87 (Abstract)
70 Burch J M, Sokol R J, Narkewicz M R et al.. Autoantibodies in mothers of children with neonatal liver disease. J Pediatr Gastroenterol Nutr. 2003; 37 262-267
71 Mack C L, Tucker R M, Lu B R et al.. Cellular and humoral autoimmunity directed at bile duct epithelia in murine biliary atresia. Hepatology. 2006; 44 1231-1239
72 Witebsky E, Rose N R, Terplan K, Paine J R, Egan R W. Chronic thyroiditis and autoimmunization. J Am Med Assoc. 1957; 164 1439-1447
73 Rose N R, Bona C. Defining criteria for autoimmune diseases (Witebsky's postulates revisited). Immunol Today. 1993; 14 426-430
74 Kerkar N, Hadzic N, Davies E et al.. De-novo autoimmune hepatitis after liver transplantation. Lancet. 1998; 351 409-413
75 Gupta P, Hart J, Millis J M, Cronin D, Brady L. De novo hepatitis with autoimmune antibodies and atypical histology: a rare cause of late graft dysfunction after pediatric liver transplantation. Transplantation. 2001; 71 664-668
76 Broome U, Nemeth A, Hultcrantz R et al.. Different expression of HLA-DR and ICAM-1 in livers from patients with biliary atresia and Byler's disease. J Hepatol. 1997; 26 857-862
77 Feng J, Li M, Hu 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 1658-1662
78 Donaldson P T, Clare M, Constantini P K et al.. HLA and cytokine gene polymorphisms in biliary atresia. Liver. 2002; 22 213-219
79 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; 66 295-300
80 A-Kader H H, El-Ayyouti M, Hawas S et al.. HLA in Egyptian children with biliary atresia. J Pediatr. 2002; 141 432-433
81 Dillon P W, Owings E, Cilley R et al.. Immunosuppression as adjuvant therapy for biliary atresia. J Pediatr Surg. 2001; 36 80-85
82 Meyers R L, Book L S, O'Gorman M A et al.. High-dose steroids, ursodeoxycholic acid and chronic intravenous antibiotics improve bile flow after Kasai procedure in infants with biliary atresia. J Pediatr Surg. 2003; 38 406-411
83 Muraji T, Nio M, Ohhama Y et al.. Postoperative corticosteroid therapy for bile drainage in biliary atresia: a nationwide study. J Pediatr Surg. 2004; 39 1803-1805
84 Kobayashi H, Yamataka A, Koga H et al.. Optimum prednisolone useage in patients with biliary atresia post-portoenterostomy. J Pediatr Surg. 2005; 40 327-330
85 Escobar M A, Jay C L, Brooks R M et al.. Effect of corticosteroid therapy on outcomes in biliary atresia after Kasai portoenterostomy. J Pediatr Surg. 2006; 41 99-103
86 Sokol R J. New North American research network focuses on biliary atresia and neonatal liver disease. J Pediatr Gastroenterol Nutr. 2003; 36 1

Cara L MackM.D.

Assistant Professor of Pediatrics, Pediatric Liver Center and Liver Transplant Program, Section of Pediatric Gastroenterology, Hepatology, and Nutrition, The Children's Hospital, University of Colorado at Denver-Health Sciences Center

1056 E. 19th Avenue, Box B290, Denver, CO 80218