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Current Infectious Disease Reports

, Volume 15, Issue 1, pp 14–24 | Cite as

Potential Roles for Infectious Agents in the Pathophysiology of Primary Biliary Cirrhosis: What’s New?

  • Daniel S. Smyk
  • Eirini I. Rigopoulou
  • Dimitrios P. BogdanosEmail author
Intra-abdominal Infections, Hepatitis, and Gastroenteritis (D Bobak, Section Editor)

Abstract

Primary biliary cirrhosis (PBC) is a progressive cholestatic liver disease serologically characterized by the presence of high-titer antimitochondrial antibodies and, histologically by chronic nonsuppurative cholangitis and granulomata. The aetiology of the disease remains elusive, although genetic, epigenetic, environmental, and infectious factors have been considered important for the induction of the disease in genetically prone individuals. The disease shows a striking female predominance and becomes clinically overt at the fourth to sixth decade. These characteristics have prompted investigators to consider infections that predominate in women at these ages as the likely candidates for triggering the disease. Recurrent urinary tract infections due to Escherichia coli were the first infections to be considered pathogenetically relevant. Over the years, several other microorganisms have been linked to the pathogenesis of PBC owing to epidemiological, immunological, microbiological, or experimental findings in animal models. Recent studies have provided data supporting the pathogenic role of Novosphingobium aromaticivorans and betaretroviruses. Several reports have linked other organisms to the induction of the disease and/or the maintenance of the auto-aggressive responses that are perpetuated over the course of the disease. This review highlights the findings of the most recent studies investigating the link between infections and PBC. We also discuss the close interplay of the infectious agents with other environmental and genetic factors, which may explain the multifaceted nature of this puzzling disease.

Keywords

Autoantibody Autoimmune Cholestasis Infection Liver disease E. coli Urinary tract infection Viruses 

Notes

Disclosure

No potential conflicts of interest relevant to this article were reported.

References

Papers of particular interest, published recently, have been highlighted as:• Of importance •• Of major importance

  1. 1.
    Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl J Med. 2005;353:1261–73.PubMedCrossRefGoogle Scholar
  2. 2.
    Lindor KD, Gershwin ME, Poupon R, et al. Primary biliary cirrhosis. Hepatology. 2009;50:291–308.PubMedCrossRefGoogle Scholar
  3. 3.
    Smyk DS, Rigopoulou EI, Pares A, et al. Sex differences associated with primary biliary cirrhosis. Clin Dev Immunol. 2012;2012:610504.PubMedCrossRefGoogle Scholar
  4. 4.
    Invernizzi P, Alessio MG, Smyk DS, et al. Autoimmune hepatitis type 2 associated with an unexpected and transient presence of primary biliary cirrhosis-specific antimitochondrial antibodies: a case study and review of the literature. BMC Gastroenterol. 2012. in press.Google Scholar
  5. 5.
    Boonstra K, Beuers U, Ponsioen CY. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review. J Hepatol. 2012;56:1181–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Smyk D, Cholongitas E, Kriese S, et al. Primary biliary cirrhosis: family stories. Autoimmune Dis. 2011;2011:189585.PubMedGoogle Scholar
  7. 7.
    Jones DE, Watt FE, Metcalf JV, et al. Familial primary biliary cirrhosis reassessed: a geographically-based population study. J Hepatol. 1999;30:402–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Kim WR, Lindor KD, Locke 3rd GR, et al. Epidemiology and natural history of primary biliary cirrhosis in a US community. Gastroenterology. 2000;119:1631–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Bogdanos DP, Komorowski L. Disease-specific autoantibodies in primary biliary cirrhosis. Clin Chim Acta. 2011;412:502–12.PubMedCrossRefGoogle Scholar
  10. 10.
    Bogdanos DP, Baum H, Vergani D. Antimitochondrial and other autoantibodies. Clin Liver Dis. 2003;7:759–77. vi.PubMedCrossRefGoogle Scholar
  11. 11.
    Bogdanos DP, Invernizzi P, Mackay IR, et al. Autoimmune liver serology: current diagnostic and clinical challenges. World J Gastroenterol. 2008;14:3374–87.PubMedCrossRefGoogle Scholar
  12. 12.
    Muratori L, Granito A, Muratori P, et al. Antimitochondrial antibodies and other antibodies in primary biliary cirrhosis: diagnostic and prognostic value. Clin Liver Dis. 2008;12:261–76. vii.PubMedCrossRefGoogle Scholar
  13. 13.
    Rigopoulou EI, Bogdanos DP, Liaskos C, et al. Anti-mitochondrial antibody immunofluorescent titres correlate with the number and intensity of immunoblot-detected mitochondrial bands in patients with primary biliary cirrhosis. Clinica Chimica Acta Int J Clin Chemist. 2007;380:118–21.CrossRefGoogle Scholar
  14. 14.
    Dahnrich C, Pares A, Caballeria L, et al. New ELISA for detecting primary biliary cirrhosis-specific antimitochondrial antibodies. Clin Chem. 2009;55:978–85.PubMedCrossRefGoogle Scholar
  15. 15.
    Bizzaro N, Covini G, Rosina F, et al. Overcoming a "probable" diagnosis in antimitochondrial antibody negative primary biliary cirrhosis: study of 100 sera and review of the literature. Clin Rev Allergy Immunol. 2012;42:288–97.PubMedCrossRefGoogle Scholar
  16. 16.
    Bogdanos DP, Liaskos C, Rigopoulou EI, et al. Anti-mitochondrial antibodies in patients with systemic lupus erythematosus: revealing the unforeseen. Clin Chim Acta. 2006;373:183–4. author reply 5.PubMedCrossRefGoogle Scholar
  17. 17.
    Metcalf JV, Mitchison HC, Palmer JM, et al. Natural history of early primary biliary cirrhosis. Lancet. 1996;348:1399–402.PubMedCrossRefGoogle Scholar
  18. 18.
    Duarte-Rey C, Bogdanos D, Yang CY, et al. Primary biliary cirrhosis and the nuclear pore complex. Autoimmun Rev. 2012.Google Scholar
  19. 19.
    Itoh S, Ichida T, Yoshida T, et al. Autoantibodies against a 210 kDa glycoprotein of the nuclear pore complex as a prognostic marker in patients with primary biliary cirrhosis. J Gastroenterol Hepatol. 1998;13:257–65.PubMedCrossRefGoogle Scholar
  20. 20.
    Wesierska-Gadek J, Hohenauer H, Hitchman E, et al. Autoantibodies from patients with primary biliary cirrhosis preferentially react with the amino-terminal domain of nuclear pore complex glycoprotein gp210. J Exp Med. 1995;182:1159–62.PubMedCrossRefGoogle Scholar
  21. 21.
    Rigopoulou EI, Davies ET, Pares A, et al. Prevalence and clinical significance of isotype specific antinuclear antibodies in primary biliary cirrhosis. Gut. 2005;54:528–32.PubMedCrossRefGoogle Scholar
  22. 22.
    Bogdanos DP, Liaskos C, Pares A, et al. Anti-gp210 antibody mirrors disease severity in primary biliary cirrhosis. Hepatology. 2007;45:1583. author reply −4.PubMedCrossRefGoogle Scholar
  23. 23.
    Mytilinaiou MG, Meyer W, Scheper T, et al. Diagnostic and clinical utility of antibodies against the nuclear body promyelocytic leukaemia and Sp100 antigens in patients with primary biliary cirrhosis. Clinica Chimica Acta Int J Clin Chemist. 2012;413:1211–6.CrossRefGoogle Scholar
  24. 24.
    Liaskos C, Norman GL, Moulas A, et al. Prevalence of gastric parietal cell antibodies and intrinsic factor antibodies in primary biliary cirrhosis. Clinica Chimica Acta Int J Clin Chemist. 2010;411:411–5.CrossRefGoogle Scholar
  25. 25.
    Muratori P, Muratori L, Guidi M, et al. Anti-Saccharomyces cerevisiae antibodies (ASCA) and autoimmune liver diseases. Clin Exp Immunol. 2003;132:473–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Rigopoulou EI, Roggenbuck D, Smyk DS, et al. Asialoglycoprotein receptor (ASGPR) as target autoantigen in liver autoimmunity: lost and found. Autoimmun Rev. 2012.Google Scholar
  27. 27.
    Wesierska-Gadek J, Penner E, Battezzati PM, et al. Correlation of initial autoantibody profile and clinical outcome in primary biliary cirrhosis. Hepatology. 2006;43:1135–44.PubMedCrossRefGoogle Scholar
  28. 28.
    Rigamonti C, Bogdanos DP, Mytilinaiou MG, et al. Primary biliary cirrhosis associated with systemic sclerosis: diagnostic and clinical challenges. Int J Rheumatol. 2011;2011:976427.PubMedGoogle Scholar
  29. 29.
    Bogdanos DP, Rigamonti C, Smyk D, et al. In: Radstake T, editor. Systemic sclerosis - an update on the aberrant immune system and clinical features. Rijeka, Croatia: Intech; 2012. p. 151–66.Google Scholar
  30. 30.
    Heathcote EJ. Management of primary biliary cirrhosis. The American Association for the Study of Liver Diseases practice guidelines. Hepatology. 2000;31:1005–13.PubMedCrossRefGoogle Scholar
  31. 31.
    Duarte-Rey C, Bogdanos DP, Leung PS, et al. IgM predominance in autoimmune disease: genetics and gender. Autoimmun Rev. 2012;11:A404–12.PubMedCrossRefGoogle Scholar
  32. 32.
    Kikuchi K, Lian ZX, Yang GX, et al. Bacterial CpG induces hyper-IgM production in CD27(+) memory B cells in primary biliary cirrhosis. Gastroenterology. 2005;128:304–12.PubMedCrossRefGoogle Scholar
  33. 33.
    Bogdanos DP, Smyk DS, Rigopoulou EI, et al. Twin studies in autoimmune disease: genetics, gender and environment. J Autoimmun. 2012;38:J156–69.PubMedCrossRefGoogle Scholar
  34. 34.
    Selmi C, Leung PS, Sherr DH, et al. Mechanisms of environmental influence on human autoimmunity: a national institute of environmental health sciences expert panel workshop. J Autoimmun. 2012.Google Scholar
  35. 35.
    Miller FW, Pollard KM, Parks CG, et al. Criteria for environmentally associated autoimmune diseases. J Autoimmun. 2012.Google Scholar
  36. 36.
    Smyk DS, Mytilinaiou MG, Milkiewicz P, et al. Towards systemic sclerosis and away from primary biliary cirrhosis: the case of PTPN22. Autoimmun Highlights. 2012;3:1–9.CrossRefGoogle Scholar
  37. 37.
    Smyk DS, Rigopoulou EI, Bizarro N, et al. Hair dyes as a risk for autoimmunity: from systemic lupus erythematosus to primary biliary cirrhosis. Autoimmun Highlights. 2012. in press.Google Scholar
  38. 38.
    Smyk D, Mytilinaiou MG, Rigopoulou EI, et al. PBC triggers in water reservoirs, coal mining areas and waste disposal sites: from Newcastle to New York. Dis Markers. 2010;29:337–44.PubMedGoogle Scholar
  39. 39.
    Smyk DS, Rigopoulou EI, Lleo A, et al. Immunopathogenesis of primary biliary cirrhosis: an old wives' tale. Immun Ageing. 2011;8:12.PubMedCrossRefGoogle Scholar
  40. 40.
    Rigopoulou EI, Smyk DS, Matthews CE, et al. Epstein-barr virus as a trigger of autoimmune liver diseases. Adv Virol. 2012;2012:987471.PubMedGoogle Scholar
  41. 41.
    Smyk DS, Rigopoulou EI, Muratori L, et al. Smoking as a risk factor for autoimmune liver disease: what we can learn from primary biliary cirrhosis. Ann Hepatol. 2012;11:7–14.PubMedGoogle Scholar
  42. 42.
    Smyk DS, Bogdanos DP, Kriese S, et al. Urinary tract infection as a risk factor for autoimmune liver disease: from bench to bedside. Clin Res Hepatol Gastroenterol. 2012;36:110–21.PubMedCrossRefGoogle Scholar
  43. 43.
    Smyk D, Rigopoulou EI, Baum H, et al. Autoimmunity and environment: am I at risk? Clin Rev Allergy Immunol. 2012;42:199–212.PubMedCrossRefGoogle Scholar
  44. 44.
    Varyani FK, West J, Card TR. An increased risk of urinary tract infection precedes development of primary biliary cirrhosis. BMC Gastroenterol. 2011;11:95.PubMedCrossRefGoogle Scholar
  45. 45.
    Smyk D, Rigopoulou EI, Yoh Z, et al. Infectious triggers of primary biliary cirrhosis: do we know enough? Curr Trends in Immunol. 2010;11:35–49.Google Scholar
  46. 46.
    Shigematsu H, Shimoda S, Nakamura M, et al. Fine specificity of T cells reactive to human PDC-E2 163–176 peptide, the immunodominant autoantigen in primary biliary cirrhosis: implications for molecular mimicry and cross-recognition among mitochondrial autoantigens. Hepatology. 2000;32:901–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Shimoda S, Nakamura M, Shigematsu H, et al. Mimicry peptides of human PDC-E2 163–176 peptide, the immunodominant T-cell epitope of primary biliary cirrhosis. Hepatology. 2000;31:1212–6.PubMedCrossRefGoogle Scholar
  48. 48.
    Shimoda S, Van de Water J, Ansari A, et al. Identification and precursor frequency analysis of a common T cell epitope motif in mitochondrial autoantigens in primary biliary cirrhosis. J Clin Invest. 1998;102:1831–40.PubMedCrossRefGoogle Scholar
  49. 49.
    Bogdanos DP, Baum H, Gunsar F, et al. Extensive homology between the major immunodominant mitochondrial antigen in primary biliary cirrhosis and Helicobacter pylori does not lead to immunological cross-reactivity. Scand J Gastroenterol. 2004;39:981–7.PubMedCrossRefGoogle Scholar
  50. 50.
    Lan RY, Cheng C, Lian ZX, et al. Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis. Hepatology. 2006;43:729–37.PubMedCrossRefGoogle Scholar
  51. 51.
    Longhi MS, Ma Y, Bogdanos DP, et al. Impairment of CD4(+)CD25(+) regulatory T-cells in autoimmune liver disease. J Hepatol. 2004;41:31–7.PubMedCrossRefGoogle Scholar
  52. 52.
    Selmi C, Mayo MJ, Bach N, et al. Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology. 2004;127:485–92.PubMedCrossRefGoogle Scholar
  53. 53.
    Invernizzi P, Selmi C, Poli F, et al. Human leukocyte antigen polymorphisms in Italian primary biliary cirrhosis: a multicenter study of 664 patients and 1992 healthy controls. Hepatology. 2008;48:1906–12.PubMedCrossRefGoogle Scholar
  54. 54.
    Mells GF, Floyd JA, Morley KI, et al. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nat Genet. 2011;43:329–32.PubMedCrossRefGoogle Scholar
  55. 55.
    Tanaka A, Ohira H, Kikuchi K, et al. Genetic association of Fc receptor-like 3 polymorphisms with susceptibility to primary biliary cirrhosis: ethnic comparative study in Japanese and Italian patients. Tissue Antigens. 2011;77:239–43.PubMedCrossRefGoogle Scholar
  56. 56.
    • Hirschfield GM, Liu X, Han Y, et al. Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis. Nat Genet. 2010;42:655–7. One of the very first GWAS that identified non-HLA immunoregulatory genes as risk factors for the development of PBC.PubMedCrossRefGoogle Scholar
  57. 57.
    Tanaka A, Invernizzi P, Ohira H, et al. Replicated association of 17q12-21 with susceptibility of primary biliary cirrhosis in a Japanese cohort. Tissue Antigens. 2011;78:65–8.PubMedCrossRefGoogle Scholar
  58. 58.
    • Liu X, Invernizzi P, Lu Y, et al. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis. Nat Genet. 2010;42:658–60. This metanalysis of GWAS identified three new loci conferring risk to PBC.PubMedCrossRefGoogle Scholar
  59. 59.
    • Corpechot C, Chretien Y, Chazouilleres O, et al. Demographic, lifestyle, medical and familial factors associated with primary biliary cirrhosis. J Hepatol. 2010;53:162–9. This epidemiological study conducted in a large cohort of French PBC patients confirmed the previously reported findings indicating that most significant infectious risk factor in PBC was a history of recurrent urinary tract infections (rUTI).PubMedCrossRefGoogle Scholar
  60. 60.
    Gershwin ME, Selmi C, Worman HJ, et al. Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients. Hepatology. 2005;42:1194–202.PubMedCrossRefGoogle Scholar
  61. 61.
    Parikh-Patel A, Gold EB, Worman H, et al. Risk factors for primary biliary cirrhosis in a cohort of patients from the united states. Hepatology. 2001;33:16–21.PubMedCrossRefGoogle Scholar
  62. 62.
    Prince MI, Ducker SJ, James OF. Case–control studies of risk factors for primary biliary cirrhosis in two United Kingdom populations. Gut. 2010;59:508–12.PubMedCrossRefGoogle Scholar
  63. 63.
    Burroughs AK, Rosenstein IJ, Epstein O, et al. Bacteriuria and primary biliary cirrhosis. Gut. 1984;25:133–7.PubMedCrossRefGoogle Scholar
  64. 64.
    Burroughs AK, Butler P, Sternberg MJ, et al. Molecular mimicry in liver disease. Nature. 1992;358:377–8.PubMedCrossRefGoogle Scholar
  65. 65.
    Bogdanos DP, Baum H, Grasso A, et al. Microbial mimics are major targets of crossreactivity with human pyruvate dehydrogenase in primary biliary cirrhosis. J Hepatol. 2004;40:31–9.PubMedCrossRefGoogle Scholar
  66. 66.
    Palermo JJ. Recurrent urinary tract infection in mice results in immune-mediated cholangiopathy similar to human primary biliary cirrhosis. Gastroenterology. 2008;134:A837.CrossRefGoogle Scholar
  67. 67.
    Selmi C, Balkwill DL, Invernizzi P, et al. Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium. Hepatology. 2003;38:1250–7.PubMedCrossRefGoogle Scholar
  68. 68.
    Olafsson S, Gudjonsson H, Selmi C, et al. Antimitochondrial antibodies and reactivity to N. aromaticivorans proteins in Icelandic patients with primary biliary cirrhosis and their relatives. Am J Gastroenterol. 2004;99:2143–6.PubMedCrossRefGoogle Scholar
  69. 69.
    Mattner J, Savage PB, Leung P, et al. Liver autoimmunity triggered by microbial activation of natural killer T cells. Cell Host Microbe. 2008;3:304–15.PubMedCrossRefGoogle Scholar
  70. 70.
    •• Mohammed JP, Fusakio ME, Rainbow DB, et al. Identification of Cd101 as a susceptibility gene for Novosphingobium aromaticivorans-induced liver autoimmunity. J Immunol. 2011;187:337–49. This study identified the genetic variants that are important for susceptibility or resistance to N. amoraticivorans-induced biliary epithelial cell destruction.PubMedCrossRefGoogle Scholar
  71. 71.
    Koutsoumpas A, Mytilinaiou M, Polymeros D, et al. Anti-Helicobacter pylori antibody responses specific for VacA do not trigger primary biliary cirrhosis-specific antimitochondrial antibodies. Eur J Gastroenterol Hepatol. 2009;21:1220.PubMedCrossRefGoogle Scholar
  72. 72.
    Durazzo M, Rosina F, Premoli A, et al. Lack of association between seroprevalence of Helicobacter pylori infection and primary biliary cirrhosis. World J Gastroenterol. 2004;10:3179–81.PubMedGoogle Scholar
  73. 73.
    • Shapira Y, Agmon-Levin N, Renaudineau Y, et al. Serum markers of infections in patients with primary biliary cirrhosis: evidence of infection burden. Exp Mol Pathol. 2012. This study revealed for the first time the possible link between T.gondii and PBC.Google Scholar
  74. 74.
    Ustun S, Aksoy U, Dagci H, et al. Incidence of toxoplasmosis in patients with cirrhosis. World J Gastroenterol. 2004;10:452–4.PubMedGoogle Scholar
  75. 75.
    Morshed SA, Nishioka M, Saito I, et al. Increased expression of Epstein-Barr virus in primary biliary cirrhosis patients. Gastroenterol Jpn. 1992;27:751–8.PubMedGoogle Scholar
  76. 76.
    Barzilai O, Sherer Y, Ram M, et al. Epstein-Barr virus and cytomegalovirus in autoimmune diseases: are they truly notorious? A preliminary report. Ann N Y Acad Sci. 2007;1108:567–77.PubMedCrossRefGoogle Scholar
  77. 77.
    Xie K, Snyder M. Two short autoepitopes on the nuclear dot antigen are similar to epitopes encoded by the Epstein-Barr virus. Proc Natl Acad Sci U S A. 1995;92:1639–43.PubMedCrossRefGoogle Scholar
  78. 78.
    Mason A, Xu L, Shen Z, et al. Patients with primary biliary cirrhosis make anti-viral and anti-mitochondrial antibodies to mouse mammary tumor virus. Gastroenterology. 2004;127:1863–4. author reply 4–5.PubMedCrossRefGoogle Scholar
  79. 79.
    Mason AL, Xu L, Guo L, et al. Retroviruses in autoimmune liver disease: genetic or environmental agents? Arch Immunol Ther Exp (Warsz). 1999;47:289–97.Google Scholar
  80. 80.
    Mason AL, Xu L, Guo L, et al. Detection of retroviral antibodies in primary biliary cirrhosis and other idiopathic biliary disorders. Lancet. 1998;351:1620–4.PubMedCrossRefGoogle Scholar
  81. 81.
    Xu L, Sakalian M, Shen Z, et al. Cloning the human betaretrovirus proviral genome from patients with primary biliary cirrhosis. Hepatology. 2004;39:151–6.PubMedCrossRefGoogle Scholar
  82. 82.
    Xu L, Shen Z, Guo L, et al. Does a betaretrovirus infection trigger primary biliary cirrhosis? Proc Natl Acad Sci U S A. 2003;100:8454–9.PubMedCrossRefGoogle Scholar
  83. 83.
    Wasilenko ST, Mason GE, Mason AL. Primary biliary cirrhosis, bacteria and molecular mimicry: what's the molecule and where's the mimic? Liver Int. 2009;29:779–82.PubMedCrossRefGoogle Scholar
  84. 84.
    Selmi C. The evidence does not support a viral etiology for primary biliary cirrhosis. J Hepatol. 2011;54:1315–6.PubMedCrossRefGoogle Scholar
  85. 85.
    Selmi C, Ross SR, Ansari AA, et al. Lack of immunological or molecular evidence for a role of mouse mammary tumor retrovirus in primary biliary cirrhosis. Gastroenterology. 2004;127:493–501.PubMedCrossRefGoogle Scholar
  86. 86.
    • Zhang G, Chen M, Graham D, et al. Mouse mammary tumor virus in anti-mitochondrial antibody producing mouse models. J Hepatol. 2011;55:876–84. The first study to provide evidence of MMTV in a mouse experimental model of PBC.PubMedCrossRefGoogle Scholar
  87. 87.
    Johal H, Scott GM, Jones R, et al. Mouse mammary tumour virus-like virus (MMTV-LV) is present within the liver in a wide range of hepatic disorders and unrelated to nuclear p53 expression or hepatocarcinogenesis. J Hepatol. 2009;50:548–54.PubMedCrossRefGoogle Scholar
  88. 88.
    Mason AL, Lindor KD, Bacon BR, et al. Clinical trial: randomized controlled trial of zidovudine and lamivudine for patients with primary biliary cirrhosis stabilized on ursodiol. Aliment Pharmacol Ther. 2008.Google Scholar
  89. 89.
    Vergani D, Bogdanos DP, Baum H. Unusual suspects in primary biliary cirrhosis. Hepatology. 2004;39:38–41.PubMedCrossRefGoogle Scholar
  90. 90.
    Bogdanos DP, Vergani D. Bacteria and primary biliary cirrhosis. Clin Rev Allergy Immunol. 2009;36:30–9.PubMedCrossRefGoogle Scholar
  91. 91.
    Brahm J, Chesta J. Bacteriuria in patients with primary biliary cirrhosis. Rev Med Chil. 1993;121:499–502.PubMedGoogle Scholar
  92. 92.
    Floreani A, Bassendine MF, Mitchison H, et al. No specific association between primary biliary cirrhosis and bacteriuria? J Hepatol. 1989;8:201–7.PubMedCrossRefGoogle Scholar
  93. 93.
    Liang Y, Yang Z, Zhong R. Smoking, family history and urinary tract infection are associated with primary biliary cirrhosis: a meta-analysis. Hepatol Res. 2011;41:572–8.PubMedCrossRefGoogle Scholar
  94. 94.
    Bogdanos DP, Baum H, Butler P, et al. Association between the primary biliary cirrhosis specific anti-sp100 antibodies and recurrent urinary tract infection. Dig Liver Dis. 2003;35:801–5.PubMedCrossRefGoogle Scholar
  95. 95.
    Butler P, Hamilton-Miller J, Baum H, et al. Detection of M2 antibodies in patients with recurrent urinary tract infection using an ELISA and purified PBC specific antigens. Evidence for a molecular mimicry mechanism in the pathogenesis of primary biliary cirrhosis? Biochem Mol Biol Int. 1995;35:473–85.PubMedGoogle Scholar
  96. 96.
    Bogdanos DP, Baum H, Sharma UC, et al. Antibodies against homologous microbial caseinolytic proteases P characterise primary biliary cirrhosis. J Hepatol. 2002;36:14–21.PubMedCrossRefGoogle Scholar
  97. 97.
    Bogdanos DP, Baum H, Okamoto M, et al. Primary biliary cirrhosis is characterized by IgG3 antibodies cross-reactive with the major mitochondrial autoepitope and its Lactobacillus mimic. Hepatology. 2005;42:458–65.PubMedCrossRefGoogle Scholar
  98. 98.
    Bogdanos D, Pusl T, Rust C, et al. Primary biliary cirrhosis following Lactobacillus vaccination for recurrent vaginitis. J Hepatol. 2008;49:466–73.PubMedCrossRefGoogle Scholar
  99. 99.
    O'Donohue J, McFarlane B, Bomford A, et al. Antibodies to atypical mycobacteria in primary biliary cirrhosis. J Hepatol. 1994;21:887–9.PubMedCrossRefGoogle Scholar
  100. 100.
    Vilagut L, Vila J, Vinas O, et al. Cross-reactivity of anti-Mycobacterium gordonae antibodies with the major mitochondrial autoantigens in primary biliary cirrhosis. J Hepatol. 1994;21:673–7.PubMedCrossRefGoogle Scholar
  101. 101.
    Vilagut L, Pares A, Vinas O, et al. Antibodies to mycobacterial 65-kD heat shock protein cross-react with the main mitochondrial antigens in patients with primary biliary cirrhosis. Eur J Clin Invest. 1997;27:667–72.PubMedCrossRefGoogle Scholar
  102. 102.
    Bogdanos DP, Pares A, Baum H, et al. Disease-specific cross-reactivity between mimicking peptides of heat shock protein of Mycobacterium gordonae and dominant epitope of E2 subunit of pyruvate dehydrogenase is common in Spanish but not British patients with primary biliary cirrhosis. J Autoimmun. 2004;22:353–62.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Daniel S. Smyk
    • 1
  • Eirini I. Rigopoulou
    • 2
  • Dimitrios P. Bogdanos
    • 1
    • 2
    • 3
    • 4
    Email author
  1. 1.Institute of Liver Studies, Division of Transplantation Immunology and Mucosal BiologyKing’s College London School of Medicine at King’s College HospitalLondonUnited Kingdom
  2. 2.Department of Medicine, University Hospital of LarissaUniversity of Thessaly Medical SchoolLarissaGreece
  3. 3.Cellular Immunotherapy and Molecular ImmunodiagnosticsInstitute of Research and Technology ThessalyLarissaGreece
  4. 4.Institute of Liver StudiesKing’s College London Medical School at King’s College London HospitalLondonUK

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