Download PDF
Semin Liver Dis 2006; 26(1): 003-021
DOI: 10.1055/s-2006-933559
Copyright © 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Etiopathogenesis of Primary Sclerosing Cholangitis

Christine A. O'Mahony1 , John M. Vierling2
  • 1Departments of Surgery, Baylor Liver Health, Baylor College of Medicine, Houston, Texas
  • 2Departments of Medicine, Baylor Liver Health, Baylor College of Medicine, Houston, Texas
Further Information

Publication History

Publication Date:
23 February 2006 (online)

    Permissions and Reprints

ABSTRACT

The etiopathogenesis of primary sclerosing cholangitis (PSC) remains undefined. Immunopathogenetic mechanisms appear to be involved, based on human leukocyte antigen complex susceptibility associations, existence of multiple autoantibodies, and presence of inflammatory bowel disease in > 75% of patients. PSC may represent an autoimmune disease with atypical features or an immune-mediated inflammatory disease, similar to inflammatory bowel disease itself. Immunogenetic susceptibility is closely linked to ligands for innate immune cells and capacity for sustained production of proinflammatory cytokines. Immunopathogenesis involves a multistep process initiated by the activation of cholangiocyte by bacterial pathogen-associated molecular patterns (stimuli of innate immunity) and proinflammatory cytokines in conjunction with aberrant expression of gut-specific chemokines and endothelial cell adhesion molecules in the liver. After recruitment of gut-primed memory T cells into the portal tracts and peribiliary space, additional mechanisms produce focal, fibrous, obliterative lesions. Progressive periductal fibrosis, chronic inflammation, and ischemic atrophy of biliary epithelia result in ductopenia, cholestasis, and obstructive strictures, culminating in secondary biliary cirrhosis.

KEYWORDS

Primary sclerosing cholangitis - biliary - biliary cirrhosis - etiology - pathogenesis - immunology - inflammatory bowel disease - colitis - ulcerative colitis - Crohn colitis

REFERENCES

  • 1 Vierling J M. Primary sclerosing cholangitis-an autoimmune disease?. In: Leuchner U, Broome U, Stiehl A Cholestatic Liver Diseases: Therapeutic Options and Perspectives. Lancaster, UK; Lancaster Publishing 2004: 65-72
    Google Scholar
  • 2 Worthington J, Cullen S, Chapman R. Immunopathogenesis of primary sclerosing cholangitis.  Clin Rev Allergy Immunol. 2005;  28(2) 93-103
    PubMedGoogle Scholar
  • 3 Vierling J M. Hepatobiliary complications in ulcerative colitis and Crohn's disease. In: Zakim D, Boyer TD Hepatology. 4th ed. Philadelphia, PA; WB Saunders 2002: 1221-1272
    Google Scholar
  • 4 Vierling J M, Braun M, Wang H-M. Immunopathogenesis of vanishing bile duct syndromes. In: Alpini G, Alvaro D, Marzioni M, LeSage G, Larusso N The Pathophysiology of Biliary Epithelia. Georgetown, TX; Landes Bioscience 2004: 330-356
    Google Scholar
  • 5 Mayer L. Redefining autoimmunity.  Gastroenterology. 2003;  125(6) 1574
    CrossrefPubMedGoogle Scholar
  • 6 Kamradt T, Mitchison N A. Tolerance and autoimmunity.  N Engl J Med. 2001;  344(9) 655-664
    PubMedGoogle Scholar
  • 7 Chapman R W. Autoimmunity and primary sclerosing cholangitis. Available at: http://videocast nih gov/PastEvents NIDDK Research Workshop on Primary Sclerosing Cholangitis 2005 Accessed December 2005
    Google Scholar
  • 8 Alpini G, McGill J M, Larusso N F. The pathobiology of biliary epithelia.  Hepatology. 2002;  35(5) 1256-1268
    CrossrefPubMedGoogle Scholar
  • 9 Batts K P. Ischemic cholangitis.  Mayo Clin Proc. 1998;  73(4) 380-385
    CrossrefPubMedGoogle Scholar
  • 10 Fickert P, Fuchsbichler A, Wagner M et al.. Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice.  Gastroenterology. 2004;  127(1) 261-274
    CrossrefPubMedGoogle Scholar
  • 11 Mathison J. Innate immunity.  J Pediatr Gastroenterol Nutr. 2005;  40(suppl 1) S13-S15
    PubMedGoogle Scholar
  • 12 Staros E B. Innate immunity: New approaches to understanding its clinical significance.  Am J Clin Pathol. 2005;  123(2) 305-312
    PubMedGoogle Scholar
  • 13 Podolsky D K. Innate immunity, NOD-2 and primary sclerosing cholangitis. Available at: http://videocast nih gov/PastEvents asp NIDDK Research Workshop on Primary Sclerosing Cholangitis 2005 December 2005
    Google Scholar
  • 14 Delves P J, Roitt I M. The immune system. Second of two parts.  N Engl J Med. 2000;  343(2) 108-117
    CrossrefPubMedGoogle Scholar
  • 15 Delves P J, Roitt I M. The immune system. First of two parts.  N Engl J Med. 2000;  343(1) 37-49
    CrossrefPubMedGoogle Scholar
  • 16 Esche C, Stellato C, Beck L A. Chemokines: key players in innate and adaptive immunity.  J Invest Dermatol. 2005;  125(4) 615-628
    CrossrefPubMedGoogle Scholar
  • 17 Hoebe K, Janssen E, Beutler B. The interface between innate and adaptive immunity.  Nat Immunol. 2004;  5(10) 971-974
    CrossrefPubMedGoogle Scholar
  • 18 Klein J, Sato A. The HLA system. Second of two parts.  N Engl J Med. 2000;  343(11) 782-786
    CrossrefPubMedGoogle Scholar
  • 19 Klein J, Sato A. The HLA system. First of two parts.  N Engl J Med. 2000;  343(10) 702-709
    CrossrefPubMedGoogle Scholar
  • 20 Ulrichs T, Porcelli S A. CD1 proteins: targets of T cell recognition in innate and adaptive immunity.  Rev Immunogenet. 2000;  2(3) 416-432
    PubMedGoogle Scholar
  • 21 Farrar J D, Asnagli H, Murphy K M. T helper subset development: roles of instruction, selection, and transcription.  J Clin Invest. 2002;  109(4) 431-435
    CrossrefPubMedGoogle Scholar
  • 22 Roncarolo M G, Gregori S, Levings M. Type 1 T regulatory cells and their relationship with CD4 + CD25+ T regulatory cells.  Novartis Found Symp. 2003;  252 115-127 , [discussion 127-131]
    PubMedGoogle Scholar
  • 23 van Buul J D, Hordijk P L. Signaling in leukocyte transendothelial migration.  Arterioscler Thromb Vasc Biol. 2004;  24(5) 824-833
    PubMedGoogle Scholar
  • 24 Engelhardt B, Wolburg H. Mini-review: transendothelial migration of leukocytes: through the front door or around the side of the house?.  Eur J Immunol. 2004;  34(11) 2955-2963
    CrossrefPubMedGoogle Scholar
  • 25 Morecki R, Glaser J H, Johnson A B, Kress Y. Detection of reovirus type 3 in the porta hepatis of an infant with extrahepatic biliary atresia: ultrastructural and immunocytochemical study.  Hepatology. 1984;  4(6) 1137-1142
    PubMedGoogle Scholar
  • 26 Phillips P A, Keast D, Papadimitriou J M, Walters M N, Stanley N F. Chronic obstructive jaundice induced by Reovirus type 3 in weanling mice.  Pathology. 1969;  1(3) 193-203
    PubMedGoogle Scholar
  • 27 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(4) 577-580
    PubMedGoogle Scholar
  • 28 Minuk G Y, Rascanin N, Paul R W, Lee P W, Buchan K, Kelly J K. Reovirus type 3 infection in patients with primary biliary cirrhosis and primary sclerosing cholangitis.  J Hepatol. 1987;  5(1) 8-13
    CrossrefPubMedGoogle Scholar
  • 29 Burgart L J. Cholangitis in viral disease.  Mayo Clin Proc. 1998;  73(5) 479-482
    PubMedGoogle Scholar
  • 30 Mehal W Z, Hattersley A T, Chapman R W, Fleming K A. A survey of cytomegalovirus (CMV) DNA in primary sclerosing cholangitis (PSC) liver tissues using a sensitive polymerase chain reaction (PCR) based assay.  J Hepatol. 1992;  15(3) 396-399
    CrossrefPubMedGoogle Scholar
  • 31 Chen X M, Larusso N F. Cryptosporidiosis and the pathogenesis of AIDS-cholangiopathy.  Semin Liver Dis. 2002;  22(3) 277-289
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 Nilsson H O, Taneera J, Castedal M, Glatz E, Olsson R, Wadstrom T. Identification of Helicobacter pylori and other Helicobacter species by PCR, hybridization, and partial DNA sequencing in human liver samples from patients with primary sclerosing cholangitis or primary biliary cirrhosis.  J Clin Microbiol. 2000;  38(3) 1072-1076
    PubMedGoogle Scholar
  • 33 Bjornsson E, Cederborg A, Akvist A, Simren M, Stotzer P O, Bjarnason I. Intestinal permeability and bacterial growth of the small bowel in patients with primary sclerosing cholangitis.  Scand J Gastroenterol. 2005;  40(9) 1090-1094
    CrossrefPubMedGoogle Scholar
  • 34 Olsson R, Bjornsson E, Backman L et al.. Bile duct bacterial isolates in primary sclerosing cholangitis: a study of explanted livers.  J Hepatol. 1998;  28(3) 426-432
    CrossrefPubMedGoogle Scholar
  • 35 Bjornsson E S, Kilander A F, Olsson R G. Bile duct bacterial isolates in primary sclerosing cholangitis and certain other forms of cholestasis-a study of bile cultures from ERCP.  Hepatogastroenterology. 2000;  47(36) 1504-1508
    PubMedGoogle Scholar
  • 36 ter Borg P C, van Buuren H R, Depla A C. Bacterial cholangitis causing secondary sclerosing cholangitis: a case report.  BMC Gastroenterol. 2002;  2 14-17
    CrossrefPubMedGoogle Scholar
  • 37 Vierling J M. Animal models of primary sclerosing cholangitis. Available at: http://videocast nih gov/PastEvents asp NIDDK Research Workshop on Primary Sclerosing Cholangitis 2005 Accessed December 2005
    Google Scholar
  • 38 Adams D H, Eksteen B, Grant A, Lalor P F, Miles A. long-lived mucosal t cells drive hepatic inflammation in PSC. Available at: http://videocast nih gov/PastEvents asp NIDDK Research Workshop on Primary Sclerosing Cholangitis 2005 Accessed December 2005
    Google Scholar
  • 39 Lichtman S N, Keku J, Clark R L, Schwab J H, Sartor R B. Biliary tract disease in rats with experimental small bowel bacterial overgrowth.  Hepatology. 1991;  13(4) 766-772
    CrossrefPubMedGoogle Scholar
  • 40 Lichtman S N, Okoruwa E E, Keku J, Schwab J H, Sartor R B. Degradation of endogenous bacterial cell wall polymers by the muralytic enzyme mutanolysin prevents hepatobiliary injury in genetically susceptible rats with experimental intestinal bacterial overgrowth.  J Clin Invest. 1992;  90(4) 1313-1322
    CrossrefPubMedGoogle Scholar
  • 41 Vierling J M. Aetiopathogenesis of primary sclerosing cholangitis. In: Manns MP, Chapman RW, Stiehl A, Wiesner RH Primary Sclerosing Cholangitis. London, UK; Kluuten Academic Publishers 1998: 37-45
    Google Scholar
  • 42 Saarinen S, Olerup O, Broome U. Increased frequency of autoimmune diseases in patients with primary sclerosing cholangitis.  Am J Gastroenterol. 2000;  95(11) 3195-3199
    CrossrefPubMedGoogle Scholar
  • 43 Oshitani N, Jinno Y, Sawa Y et al.. Does colitis associated with primary sclerosing cholangitis represent an actual subset of ulcerative colitis?.  Hepatogastroenterology. 2003;  50(54) 1830-1835
    PubMedGoogle Scholar
  • 44 Loftus Jr E V, Harewood G C, Loftus C G et al.. PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis.  Gut. 2005;  54(1) 91-96
    CrossrefPubMedGoogle Scholar
  • 45 Lindor K D, Wiesner R H, Larusso N F, Homburger H A. Enhanced autoreactivity of T-lymphocytes in primary sclerosing cholangitis.  Hepatology. 1987;  7(5) 884-888
    PubMedGoogle Scholar
  • 46 Kilby A E, Krawitt E L, Albertini R J, Chastenay B F, John A. Suppressor T-cell deficiency in primary sclerosing cholangitis. Case and family study.  Dig Dis Sci. 1991;  36(9) 1213-1216
    CrossrefPubMedGoogle Scholar
  • 47 Si L, Whiteside T L, Schade R R, Starzl T E, Van Thiel D H. T-lymphocyte subsets in liver tissues of patients with primary biliary cirrhosis (PBC), patients with primary sclerosing cholangitis (PSC), and normal controls.  J Clin Immunol. 1984;  4(4) 262-272
    CrossrefPubMedGoogle Scholar
  • 48 Whiteside T L, Lasky S, Si L, Van Thiel D H. Immunologic analysis of mononuclear cells in liver tissues and blood of patients with primary sclerosing cholangitis.  Hepatology. 1985;  5(3) 468-474
    PubMedGoogle Scholar
  • 49 Valenski W R, Herrod H G, Williams J W. In vitro evidence for B cell dysfunction in patients with chronic liver disease.  J Clin Lab Immunol. 1989;  28(4) 169-172
    PubMedGoogle Scholar
  • 50 Senaldi G, Donaldson P T, Magrin S et al.. Activation of the complement system in primary sclerosing cholangitis.  Gastroenterology. 1989;  97(6) 1430-1434
    PubMedGoogle Scholar
  • 51 Bodenheimer Jr H C, Larusso N F, Thayer Jr W R, Charland C, Staples P J, Ludwig J. Elevated circulating immune complexes in primary sclerosing cholangitis.  Hepatology. 1983;  3(2) 150-154
    PubMedGoogle Scholar
  • 52 Garred P, Lyon H, Christoffersen P, Mollnes T E, Tranum-Jensen J. Deposition of C3, the terminal complement complex and vitronectin in primary biliary cirrhosis and primary sclerosing cholangitis.  Liver. 1993;  13(6) 305-310
    PubMedGoogle Scholar
  • 53 Minuk G Y, Angus M, Brickman C M et al.. Abnormal clearance of immune complexes from the circulation of patients with primary sclerosing cholangitis.  Gastroenterology. 1985;  88(1 Pt 1) 166-170
    PubMedGoogle Scholar
  • 54 Bloom S, Heryet A, Fleming K, Chapman R W. Inappropriate expression of blood group antigens on biliary and colonic epithelia in primary sclerosing cholangitis.  Gut. 1993;  34(7) 977-983
    PubMedGoogle Scholar
  • 55 Donaldson P T. Genetics of primary sclerosing cholangitis. Available at: http://videocast nih gov/PastEvents asp NIDDK Research Workshop on Primary Sclerosing Cholangitis 2005 Accessed December 2005
    Google Scholar
  • 56 Donaldson P T. Genetics of autoimmune and viral liver diseases; understanding the issues.  J Hepatol. 2004;  41(2) 327-332
    CrossrefPubMedGoogle Scholar
  • 57 Donaldson P T. Genetics of liver disease: immunogenetics and disease pathogenesis.  Gut. 2004;  53(4) 599-608
    CrossrefPubMedGoogle Scholar
  • 58 Norris S, Kondeatis E, Collins R et al.. Mapping MHC-encoded susceptibility and resistance in primary sclerosing cholangitis: the role of MICA polymorphism.  Gastroenterology. 2001;  120(6) 1475-1482
    PubMedGoogle Scholar
  • 59 Wiencke K, Spurkland A, Schrumpf E, Boberg K M. Primary sclerosing cholangitis is associated to an extended B8-DR3 haplotype including particular MICA and MICB alleles.  Hepatology. 2001;  34(4 Pt 1) 625-630
    PubMedGoogle Scholar
  • 60 Hata K, Van Thiel D H, Herberman R B, Whiteside T L. Phenotypic and functional characteristics of lymphocytes isolated from liver biopsy specimens from patients with active liver disease.  Hepatology. 1992;  15(5) 816-823
    PubMedGoogle Scholar
  • 61 Martins E B, Graham A K, Chapman R W, Fleming K A. Elevation of gamma delta T lymphocytes in peripheral blood and livers of patients with primary sclerosing cholangitis and other autoimmune liver diseases.  Hepatology. 1996;  23(5) 988-993
    PubMedGoogle Scholar
  • 62 Abraham L J, Kroeger K M. Impact of the -308 TNF promoter polymorphism on the transcriptional regulation of the TNF gene: relevance to disease.  J Leukoc Biol. 1999;  66(4) 562-566
    PubMedGoogle Scholar
  • 63 Mitchell S A, Grove J, Spurkland A et al.. Association of the tumour necrosis factor alpha -308 but not the interleukin 10 -627 promoter polymorphism with genetic susceptibility to primary sclerosing cholangitis.  Gut. 2001;  49(2) 288-294
    CrossrefPubMedGoogle Scholar
  • 64 Donaldson P T, Norris S. Immunogenetics in PSC.  Best Pract Res Clin Gastroenterol. 2001;  15(4) 611-627
    PubMedGoogle Scholar
  • 65 Ponnuraj E M, Hayward A R. Requirement for TNF-Tnfrsf1 signalling for sclerosing cholangitis in mice chronically infected by Cryptosporidium parvum.  Clin Exp Immunol. 2002;  128(3) 416-420
    CrossrefPubMedGoogle Scholar
  • 66 Holmberg D, Cilio C M, Lundholm M, Motta V. CTLA-4 (CD152) and its involvement in autoimmune disease.  Autoimmunity. 2005;  38(3) 225-233
    CrossrefPubMedGoogle Scholar
  • 67 Eri R, Jonsson J R, Pandeya N et al.. CCR5-Delta32 mutation is strongly associated with primary sclerosing cholangitis.  Genes Immun. 2004;  5(6) 444-450
    CrossrefPubMedGoogle Scholar
  • 68 Satsangi J, Chapman R W, Haldar N et al.. A functional polymorphism of the stromelysin gene (MMP-3) influences susceptibility to primary sclerosing cholangitis.  Gastroenterology. 2001;  121(1) 124-130
    CrossrefPubMedGoogle Scholar
  • 69 Wiencke K, Louka A S, Spurkland A, Vatn M, Schrumpf E, Boberg K M. Association of matrix metalloproteinase-1 and -3 promoter polymorphisms with clinical subsets of Norwegian primary sclerosing cholangitis patients.  J Hepatol. 2004;  41(2) 209-214
    CrossrefPubMedGoogle Scholar
  • 70 Pauli-Magnus C, Kerb R, Fattinger K et al.. BSEP and MDR3 haplotype structure in healthy Caucasians, primary biliary cirrhosis and primary sclerosing cholangitis.  Hepatology. 2004;  39(3) 779-791
    CrossrefPubMedGoogle Scholar
  • 71 Hadj-Rabia S, Baala L, Vabres P et al.. Claudin-1 gene mutations in neonatal sclerosing cholangitis associated with ichthyosis: a tight junction disease.  Gastroenterology. 2004;  127(5) 1386-1390
    CrossrefPubMedGoogle Scholar
  • 72 Sheth S, Shea J C, Bishop M D et al.. Increased prevalence of CFTR mutations and variants and decreased chloride secretion in primary sclerosing cholangitis.  Hum Genet. 2003;  113(3) 286-292
    CrossrefPubMedGoogle Scholar
  • 73 Girodon E, Sternberg D, Chazouilleres O et al.. Cystic fibrosis transmembrane conductance regulator (CFTR) gene defects in patients with primary sclerosing cholangitis.  J Hepatol. 2002;  37(2) 192-197
    CrossrefPubMedGoogle Scholar
  • 74 Blanco P G, Zaman M M, Junaidi O et al.. Induction of colitis in cftr-/- mice results in bile duct injury.  Am J Physiol Gastrointest Liver Physiol. 2004;  287(2) G491-G496
    CrossrefPubMedGoogle Scholar
  • 75 Fox R I, Kang H I. Pathogenesis of Sjogren's syndrome.  Rheum Dis Clin North Am. 1992;  18(3) 517-538
    PubMedGoogle Scholar
  • 76 Kouri T. Etiology of rheumatoid arthritis.  Experientia. 1985;  41(4) 434-441
    CrossrefPubMedGoogle Scholar
  • 77 Vergani D, Mieli-Vergani G. Autoimmune hepatitis.  Minerva Gastroenterol Dietol. 2004;  50(2) 113-123
    PubMedGoogle Scholar
  • 78 Wong F S, Wen L. The study of HLA class II and autoimmune diabetes.  Curr Mol Med. 2003;  3(1) 1-15
    PubMedGoogle Scholar
  • 79 Lio D, Candore G, Romano G C et al.. Modification of cytokine patterns in subjects bearing the HLA-B8,DR3 phenotype: implications for autoimmunity.  Cytokines Cell Mol Ther. 1997;  3(4) 217-224
    PubMedGoogle Scholar
  • 80 Mehal W Z, Lo Y M, Wordsworth B P et al.. HLA DR4 is a marker for rapid disease progression in primary sclerosing cholangitis.  Gastroenterology. 1994;  106(1) 160-167
    PubMedGoogle Scholar
  • 81 Yang X, Cullen S N, Li J H, Chapman R W, Jewell D P. Susceptibility to primary sclerosing cholangitis is associated with polymorphisms of intercellular adhesion molecule-1.  J Hepatol. 2004;  40(3) 375-379
    CrossrefPubMedGoogle Scholar
  • 82 Boberg K M, Spurkland A, Rocca G et al.. The HLA-DR3,DQ2 heterozygous genotype is associated with an accelerated progression of primary sclerosing cholangitis.  Scand J Gastroenterol. 2001;  36(8) 886-890
    PubMedGoogle Scholar
  • 83 Terjung B, Worman H J. Anti-neutrophil antibodies in primary sclerosing cholangitis.  Best Pract Res Clin Gastroenterol. 2001;  15(4) 629-642
    CrossrefPubMedGoogle Scholar
  • 84 Terjung B, Spengler U, Sauerbruch T, Worman H J. Atypical p-ANCA in IBD and hepatobiliary disorders react with a 50-kilodalton nuclear envelope protein of neutrophils and myeloid cell lines.  Gastroenterology. 2000;  119(2) 310-322
    CrossrefPubMedGoogle Scholar
  • 85 Terjung B, Muennich M, Gottwein J et al.. Identification of myleloid-specific tubulin-beta isotype 5 as target antigen of antineutrophil cytoplasmic antibodies in autoimmune liver diseases.  Hepatology. 2005;  42 288A
    PubMedGoogle Scholar
  • 86 Tubulin-beta .isotype 5. Available at: http://www.ncbi.nlm.nih.gov/entrez/queryfcgi?CMD=search&DB=protein Accessed December 21, 2005
    Google Scholar
  • 87 Pokorny C S, Norton I D, McCaughan G W, Selby W S. Anti-neutrophil cytoplasmic antibody: a prognostic indicator in primary sclerosing cholangitis.  J Gastroenterol Hepatol. 1994;  9(1) 40-44
    PubMedGoogle Scholar
  • 88 Bansi D S, Bauducci M, Bergqvist A et al.. Detection of antineutrophil cytoplasmic antibodies in primary sclerosing cholangitis: a comparison of the alkaline phosphatase and immunofluorescent techniques.  Eur J Gastroenterol Hepatol. 1997;  9(6) 575-580
    PubMedGoogle Scholar
  • 89 Mulder A H, Horst G, Haagsma E B, Limburg P C, Kleibeuker J H, Kallenberg C G. Prevalence and characterization of neutrophil cytoplasmic antibodies in autoimmune liver diseases.  Hepatology. 1993;  17(3) 411-417
    CrossrefPubMedGoogle Scholar
  • 90 Mizoguchi E, Mizoguchi A, Chiba C, Niles J L, Bhan A K. Antineutrophil cytoplasmic antibodies in T-cell receptor alpha-deficient mice with chronic colitis.  Gastroenterology. 1997;  113(6) 1828-1835
    CrossrefPubMedGoogle Scholar
  • 91 Seibold F, Brandwein S, Simpson S, Terhorst C, Elson C O. pANCA represents a cross-reactivity to enteric bacterial antigens.  J Clin Immunol. 1998;  18(2) 153-160
    CrossrefPubMedGoogle Scholar
  • 92 Schultz H, Schinke S, Weiss J, Cerundolo V, Gross W L, Gadola S. BPI-ANCA in transporter associated with antigen presentation (TAP) deficiency: possible role in susceptibility to Gram-negative bacterial infections.  Clin Exp Immunol. 2003;  133(2) 252-259
    CrossrefPubMedGoogle Scholar
  • 93 Schultz H, Weiss J, Carroll S F, Gross W L. The endotoxin-binding bactericidal/permeability-increasing protein (BPI): a target antigen of autoantibodies.  J Leukoc Biol. 2001;  69(4) 505-512
    PubMedGoogle Scholar
  • 94 Xu B, Broome U, Ericzon B G, Sumitran-Holgersson S. High frequency of autoantibodies in patients with primary sclerosing cholangitis that bind biliary epithelial cells and induce expression of CD44 and production of interleukin 6.  Gut. 2002;  51(1) 120-127
    CrossrefPubMedGoogle Scholar
  • 95 Nagano O, Saya H. Mechanism and biological significance of CD44 cleavage.  Cancer Sci. 2004;  95(12) 930-935
    CrossrefPubMedGoogle Scholar
  • 96 Wittig B M, Stallmach A, Zeitz M, Gunthert U. Functional involvement of CD44 variant 7 in gut immune response.  Pathobiology. 2002;  70(3) 184-189
    CrossrefPubMedGoogle Scholar
  • 97 Naor D, Nedvetzki S. CD44 in rheumatoid arthritis.  Arthritis Res Ther. 2003;  5(3) 105-115
    PubMedGoogle Scholar
  • 98 Das K M. Relationship of extraintestinal involvements in inflammatory bowel disease: new insights into autoimmune pathogenesis.  Dig Dis Sci. 1999;  44(1) 1-13
    CrossrefPubMedGoogle Scholar
  • 99 Das K M, Vecchi M, Sakamaki S. A shared and unique epitope(s) on human colon, skin, and biliary epithelium detected by a monoclonal antibody.  Gastroenterology. 1990;  98(2) 464-469
    PubMedGoogle Scholar
  • 100 Mandal A, Dasgupta A, Jeffers L et al.. Autoantibodies in sclerosing cholangitis against a shared peptide in biliary and colon epithelium.  Gastroenterology. 1994;  106(1) 185-192
    PubMedGoogle Scholar
  • 101 Angulo P, Peter J B, Gershwin M E et al.. Serum autoantibodies in patients with primary sclerosing cholangitis.  J Hepatol. 2000;  32(2) 182-187
    PubMedGoogle Scholar
  • 102 Sakamaki S, Takayanagi N, Yoshizaki N et al.. Autoantibodies against the specific epitope of human tropomyosin(s) detected by a peptide based enzyme immunoassay in sera of patients with ulcerative colitis show antibody dependent cell mediated cytotoxicity against HLA-DPw9 transfected L cells.  Gut. 2000;  47(2) 236-241
    CrossrefPubMedGoogle Scholar
  • 103 Ludwig J. Histopathology of primary sclerosing cholangitis. In: Manns MP, Chapman RW, Stiehl A, Wiesner RH Primary Sclerosing Cholangitis. Boston, MA; Kluwer Academic 1998: 14-21
    Google Scholar
  • 104 Dienes H P, Lohse A W, Gerken G et al.. Bile duct epithelia as target cells in primary biliary cirrhosis and primary sclerosing cholangitis.  Virchows Arch. 1997;  431(2) 119-124
    CrossrefPubMedGoogle Scholar
  • 105 Broome U, Hultcrantz R, Scheynius A. Lack of concomitant expression of ICAM-1 and HLA-DR on bile duct cells from patients with primary sclerosing cholangitis and primary biliary cirrhosis.  Scand J Gastroenterol. 1993;  28(2) 126-130
    PubMedGoogle Scholar
  • 106 Ponsioen C Y, Kuiper H, Ten Kate F J, van Milligen de W M, van Deventer S J, Tytgat G N. Immunohistochemical analysis of inflammation in primary sclerosing cholangitis.  Eur J Gastroenterol Hepatol. 1999;  11(7) 769-774
    PubMedGoogle Scholar
  • 107 Adams D H, Afford S C. The role of cholangiocytes in the development of chronic inflammatory liver disease.  Front Biosci. 2002;  7 e276-e285
    PubMedGoogle Scholar
  • 108 Morland C M, Fear J, McNab G, Joplin R, Adams D H. Promotion of leukocyte transendothelial cell migration by chemokines derived from human biliary epithelial cells in vitro.  Proc Assoc Am Physicians. 1997;  109(4) 372-382
    PubMedGoogle Scholar
  • 109 Sasatomi K, Noguchi K, Sakisaka S, Sata M, Tanikawa K. Abnormal accumulation of endotoxin in biliary epithelial cells in primary biliary cirrhosis and primary sclerosing cholangitis.  J Hepatol. 1998;  29(3) 409-416
    CrossrefPubMedGoogle Scholar
  • 110 Beaussier M, Wendum D, Fouassier L et al.. Adaptative bile duct proliferative response in experimental bile duct ischemia.  J Hepatol. 2005;  42(2) 257-265
    PubMedGoogle Scholar
  • 111 Benninger J, Grobholz R, Oeztuerk Y et al.. Sclerosing cholangitis following severe trauma: description of a remarkable disease entity with emphasis on possible pathophysiologic mechanisms.  World J Gastroenterol. 2005;  11(27) 4199-4205
    PubMedGoogle Scholar
  • 112 Ludwig J, Kim C H, Wiesner R H, Krom R A. Floxuridine-induced sclerosing cholangitis: an ischemic cholangiopathy?.  Hepatology. 1989;  9(2) 215-218
    CrossrefPubMedGoogle Scholar
  • 113 Parangi S, Oz M C, Blume R S et al.. Hepatobiliary complications of polyarteritis nodosa.  Arch Surg. 1991;  126(7) 909-912
    PubMedGoogle Scholar
  • 114 Doppman J L, Girton M E. Bile duct scarring following ethanol embolization of the hepatic artery: an experimental study in monkeys.  Radiology. 1984;  152(3) 621-626
    PubMedGoogle Scholar
  • 115 Washington K, Clavien P A, Killenberg P. Peribiliary vascular plexus in primary sclerosing cholangitis and primary biliary cirrhosis.  Hum Pathol. 1997;  28(7) 791-795
    PubMedGoogle Scholar
  • 116 Patel T. Aberrant local renin-angiotensin II responses in the pathogenesis of primary sclerosing cholangitis.  Med Hypotheses. 2003;  61(1) 64-67
    CrossrefPubMedGoogle Scholar
  • 117 Probert C S, Christ A D, Saubermann L J et al.. Analysis of human common bile duct-associated T cells: evidence for oligoclonality, T cell clonal persistence, and epithelial cell recognition.  J Immunol. 1997;  158(4) 1941-1948
    PubMedGoogle Scholar
  • 118 Eksteen B, Grant A J, Miles A et al.. Hepatic endothelial CCL25 mediates the recruitment of CCR9+ gut-homing lymphocytes to the liver in primary sclerosing cholangitis.  J Exp Med. 2004;  200(11) 1511-1517
    CrossrefPubMedGoogle Scholar
  • 119 Grant A J, Lalor P F, Salmi M, Jalkanen S, Adams D H. Homing of mucosal lymphocytes to the liver in the pathogenesis of hepatic complications of inflammatory bowel disease.  Lancet. 2002;  359(9301) 150-157
    CrossrefPubMedGoogle Scholar
  • 120 Klugewitz K, Adams D H, Emoto M, Eulenburg K, Hamann A. The composition of intrahepatic lymphocytes: shaped by selective recruitment?.  Trends Immunol. 2004;  25(11) 590-594
    CrossrefPubMedGoogle Scholar
  • 121 Broome U, Grunewald J, Scheynius A, Olerup O, Hultcrantz R. Preferential V beta3 usage by hepatic T lymphocytes in patients with primary sclerosing cholangitis.  J Hepatol. 1997;  26(3) 527-534
    CrossrefPubMedGoogle Scholar
  • 122 Viney J L, Jones S, Chiu H H et al.. Mucosal addressin cell adhesion molecule-1: a structural and functional analysis demarcates the integrin binding motif.  J Immunol. 1996;  157(6) 2488-2497
    PubMedGoogle Scholar
  • 123 Hillan K J, Hagler K E, MacSween R N et al.. Expression of the mucosal vascular addressin, MAdCAM-1, in inflammatory liver disease.  Liver. 1999;  19(6) 509-518
    PubMedGoogle Scholar
  • 124 Grant A J, Lalor P F, Hubscher S G, Briskin M, Adams D H. MAdCAM-1 expressed in chronic inflammatory liver disease supports mucosal lymphocyte adhesion to hepatic endothelium (MAdCAM-1 in chronic inflammatory liver disease).  Hepatology. 2001;  33(5) 1065-1072
    CrossrefPubMedGoogle Scholar
  • 125 Grant A J, Goddard S, Ahmed-Choudhury J et al.. Hepatic expression of secondary lymphoid chemokine (CCL21) promotes the development of portal-associated lymphoid tissue in chronic inflammatory liver disease.  Am J Pathol. 2002;  160(4) 1445-1455
    PubMedGoogle Scholar
  • 126 Eksteen B, Miles A E, Grant A J, Adams D H. Lymphocyte homing in the pathogenesis of extra-intestinal manifestations of inflammatory bowel disease.  Clin Med. 2004;  4(2) 173-180
    PubMedGoogle Scholar
  • 127 Lalor P F, Edwards S, McNab G, Salmi M, Jalkanen S, Adams D H. Vascular adhesion protein-1 mediates adhesion and transmigration of lymphocytes on human hepatic endothelial cells.  J Immunol. 2002;  169(2) 983-992
    PubMedGoogle Scholar
  • 128 Mora J R, Bono M R, Manjunath N et al.. Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells.  Nature. 2003;  424(6944) 88-93
    PubMedGoogle Scholar
  • 129 Bo X, Broome U, Remberger M, Sumitran-Holgersson S. Tumour necrosis factor alpha impairs function of liver derived T lymphocytes and natural killer cells in patients with primary sclerosing cholangitis.  Gut. 2001;  49(1) 131-141
    CrossrefPubMedGoogle Scholar
  • 130 Cameron R G, Blendis L M, Neuman M G. Accumulation of macrophages in primary sclerosing cholangitis.  Clin Biochem. 2001;  34(3) 195-201
    CrossrefPubMedGoogle Scholar
  • 131 Kuroe K, Haga Y, Funakoshi O, Mizuki I, Kanazawa K, Yoshida Y. Extraintestinal manifestations of granulomatous enterocolitis induced in rabbits by long-term submucosal administration of muramyl dipeptide emulsified with Freund's incomplete adjuvant.  J Gastroenterol. 1996;  31(2) 199-206
    PubMedGoogle Scholar
  • 132 Yamada S, Ishii M, Liang L S, Yamamoto T, Toyota T. Small duct cholangitis induced by N-formyl L-methionine L-leucine L-tyrosine in rats.  J Gastroenterol. 1994;  29(5) 631-636
    CrossrefPubMedGoogle Scholar
  • 133 Sakisaka S, Kawaguchi T, Taniguchi E et al.. Alterations in tight junctions differ between primary biliary cirrhosis and primary sclerosing cholangitis.  Hepatology. 2001;  33(6) 1460-1468
    CrossrefPubMedGoogle Scholar
  • 134 Hobson C H, Butt T J, Ferry D M, Hunter J, Chadwick V S, Broom M F. Enterohepatic circulation of bacterial chemotactic peptide in rats with experimental colitis.  Gastroenterology. 1988;  94(4) 1006-1013
    CrossrefPubMedGoogle Scholar
  • 135 Watt S M, Fawcett J, Murdoch S J et al.. CD66 identifies the biliary glycoprotein (BGP) adhesion molecule: cloning, expression, and adhesion functions of the BGPc splice variant.  Blood. 1994;  84(1) 200-210
    PubMedGoogle Scholar
  • 136 Riethdorf L, Lisboa B W, Henkel U, Naumann M, Wagener C, Loning T. Differential expression of CD66a (BGP), a cell adhesion molecule of the carcinoembryonic antigen family, in benign, premalignant, and malignant lesions of the human mammary gland.  J Histochem Cytochem. 1997;  45(7) 957-963
    PubMedGoogle Scholar
  • 137 Morales V M, Christ A, Watt S M et al.. Regulation of human intestinal intraepithelial lymphocyte cytolytic function by biliary glycoprotein (CD66a).  J Immunol. 1999;  163(3) 1363-1370
    PubMedGoogle Scholar
  • 138 Grappone C, Pinzani M, Parola M et al.. Expression of platelet-derived growth factor in newly formed cholangiocytes during experimental biliary fibrosis in rats.  J Hepatol. 1999;  31(1) 100-109
    CrossrefPubMedGoogle Scholar
  • 139 Pinzani M. Liver fibrosis.  Springer Semin Immunopathol. 1999;  21(4) 475-490
    PubMedGoogle Scholar
  • 140 Ishii M, Iwai M, Harada Y et al.. A role of mast cells for hepatic fibrosis in primary sclerosing cholangitis.  Hepatol Res. 2005;  31(3) 127-131
    PubMedGoogle Scholar
  • 141 Ishii M, Iwai M, Harada Y et al.. A role of mast cells for hepatic fibrosis in primary sclerosing cholangitis.  Hepatol Res. 2005;  31(3) 127-131
    PubMedGoogle Scholar

John M VierlingM.D. FACP 

Professor of Medicine and Surgery Baylor College of Medicine

1709 Dryden, Suite 1500, Houston, TX 77030

Email: vierling@bcm.tmc.edu