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Clinical and Developmental Immunology
Volume 2012 (2012), Article ID 610504, 11 pages
http://dx.doi.org/10.1155/2012/610504
Review Article

Sex Differences Associated with Primary Biliary Cirrhosis

1Institute of Liver Studies, King’s College London School of Medicine, Denmark Hill Campus, London SE59PJ, UK
2Department of Medicine, University of Thessaly Medical School, Viopolis, 41110 Larissa, Greece
3Liver Unit, CIBEREHD, IDIBAPS, Hospital Clinic University of Barcelona, 08036 Barcelona, Spain
4Department of Microbiology and Parasitology, Faculty of Veterinary Medicine, University of Thessaly, 43100 Karditsa, Greece
5The Sheila Sherlock Liver Centre, and University Department of Surgery, Royal Free Hospital, London NW32QG, UK
6Department of Clinical Medicine, Alma Mater Studiorum, Università di Bologna, Policlinico Sant'Orsola-Malpighi, 40138 Bologna, Italy
7Center for Autoimmune Liver Diseases, Division of Internal Medicine, IRCCS Istituto Clinico Humanitas, 20089 Rozzano, Italy
8Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616, USA
9Department of Cellular Immunotherapy and Molecular Immunodiagnostics, Institute for Biomedical Research & Technology, 41222 Larissa, Greece

Received 27 January 2012; Accepted 27 February 2012

Academic Editor: T. Nakayama

Copyright © 2012 Daniel S. Smyk et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. M. M. Kaplan and M. E. Gershwin, “Primary biliary cirrhosis,” New England Journal of Medicine, vol. 353, no. 12, pp. 1261–1273, 2005. View at Publisher · View at Google Scholar · View at Scopus
  2. S. Hohenester, R. P. J. Oude-Elferink, and U. Beuers, “Primary biliary cirrhosis,” Seminars in Immunopathology, vol. 31, no. 3, pp. 283–307, 2009. View at Publisher · View at Google Scholar · View at Scopus
  3. J. Neuberger, “Primary biliary cirrhosis,” The Lancet, vol. 350, no. 9081, pp. 875–879, 1997. View at Publisher · View at Google Scholar · View at Scopus
  4. D.S. Smyk, E. I. Rigopoulou, A. Lleo et al., “Immunopathogenesis of primary biliary cirrhosis: an old wives' tale,” Immunity & Ageing, vol. 8, no. 1, p. 12, 2011.
  5. O. E. W. James, R. Bhopal, D. Howel, J. Gray, A. D. Burt, and J. V. Metcalf, “Primary biliary cirrhosis once rare, now common in the United Kingdom?” Hepatology, vol. 30, no. 2, pp. 390–394, 1999. View at Publisher · View at Google Scholar · View at Scopus
  6. S. Sood, P. J. Gow, J. M. Christie, and P. W. Angus, “Epidemiology of primary biliary cirrhosis in Victoria, Australia: high prevalence in migrant populations,” Gastroenterology, vol. 127, no. 2, pp. 470–475, 2004. View at Publisher · View at Google Scholar · View at Scopus
  7. W. R. Kim, K. D. Lindor, G. R. Locke et al., “Epidemiology and natural history of primary biliary cirrhosis in a U.S. community,” Gastroenterology, vol. 119, no. 6, pp. 1631–1636, 2000. View at Scopus
  8. M. G. Peters, A. M. Di Bisceglie, K. V. Kowdley et al., “Differences between Caucasian, African American, and Hispanic patients with primary biliary cirrhosis in the United States,” Hepatology, vol. 46, no. 3, pp. 769–775, 2007. View at Publisher · View at Google Scholar · View at Scopus
  9. R. G. Watson, P. W. Angus, M. Dewar, B. Goss, R. B. Sewell, and R. A. Smallwood, “Low prevalence of primary biliary cirrhosis in Victoria, Australia. Melbourne Liver Group,” Gut, vol. 36, no. 6, pp. 927–930, 1995.
  10. A. C. Anand, E. Elias, and J. M. Neuberger, “End-stage primary biliary cirrhosis in a first generation migrant south Asian population,” European Journal of Gastroenterology and Hepatology, vol. 8, no. 7, pp. 663–666, 1996. View at Scopus
  11. N. Guanabens, D. Cerda, A. Monegal et al., “Low bone mass and severity of cholestasis affect fracture risk in patients with primary biliary cirrhosis,” Gastroenterology, vol. 138, no. 7, pp. 2348–2356, 2010.
  12. A. Parés and N. Guañabens, “Osteoporosis in primary biliary cirrhosis: pathogenesis and treatment,” Clinics in Liver Disease, vol. 12, no. 2, pp. 407–424, 2008. View at Publisher · View at Google Scholar · View at Scopus
  13. C. Rigamonti, D. P. Bogdanos, M. G. Mytilinaiou, D. S. Smyk, E. I. Rigopoulou, and A. K. Burroughs, “Primary biliary cirrhosis associated with systemic sclerosis: diagnostic and clinical challenges,” International Journal of Rheumatology, vol. 2011, Article ID 976427, 12 pages, 2011.
  14. A. Pares, L. Caballeria, and J. Rodes, “Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic Acid,” Gastroenterology, vol. 130, no. 3, pp. 715–720, 2006.
  15. D. P. Bogdanos, H. Baum, and D. Vergani, “Antimitochondrial and other autoantibodies,” Clinics in Liver Disease, vol. 7, no. 4, pp. 759–777, 2003. View at Publisher · View at Google Scholar · View at Scopus
  16. D. P. Bogdanos, P. Invernizzi, I. R. Mackay, and D. Vergani, “Autoimmune liver serology: current diagnostic and clinical challenges,” World Journal of Gastroenterology, vol. 14, no. 21, pp. 3374–3387, 2008. View at Publisher · View at Google Scholar · View at Scopus
  17. J. C. Courvalin and H. J. Worman, “Nuclear envelope protein autoantibodies in primary biliary cirrhosis,” Seminars in Liver Disease, vol. 17, no. 1, pp. 79–90, 1997. View at Scopus
  18. C. Szostecki, H. H. Guldner, and H. Will, “Autoantibodies against 'nuclear dots' in primary biliary cirrhosis,” Seminars in Liver Disease, vol. 17, no. 1, pp. 71–78, 1997. View at Scopus
  19. H. Liu, G. L. Norman, Z. Shums et al., “PBC Screen: an IgG/IgA dual isotype ELISA detecting multiple mitochondrial and nuclear autoantibodies specific for primary biliary cirrhosis,” Journal of Autoimmunity, vol. 35, no. 4, pp. 436–442, 2010. View at Publisher · View at Google Scholar · View at Scopus
  20. C. Dähnrich, A. Pares, L. Caballeria et al., “New ELISA for detecting primary biliary cirrhosis-specific antimitochondrial antibodies,” Clinical Chemistry, vol. 55, no. 5, pp. 978–985, 2009. View at Publisher · View at Google Scholar · View at Scopus
  21. D. P. Bogdanos and L. Komorowski, “Disease-specific autoantibodies in primary biliary cirrhosis,” Clinica Chimica Acta, vol. 412, no. 7-8, pp. 502–512, 2011. View at Publisher · View at Google Scholar · View at Scopus
  22. A. Granito, P. Muratori, C. Quarneti, G. Pappas, R. Cicola, and L. Muratori, “Antinuclear antibodies as ancillary markers in primary biliary cirrhosis,” Expert Review of Molecular Diagnostics, vol. 12, no. 1, pp. 65–74, 2012.
  23. P. Muratori, A. Granito, G. Pappas et al., “The serological profile of the autoimmune hepatitis/primary biliary cirrhosis overlap syndrome,” American Journal of Gastroenterology, vol. 104, no. 6, pp. 1420–1425, 2009. View at Publisher · View at Google Scholar · View at Scopus
  24. L. Muratori, A. Granito, P. Muratori, G. Pappas, and F. B. Bianchi, “Antimitochondrial antibodies and other antibodies in primary biliary cirrhosis: diagnostic and prognostic value,” Clinics in Liver Disease, vol. 12, no. 2, pp. 261–276, 2008. View at Publisher · View at Google Scholar · View at Scopus
  25. M. D. Van Norstrand, M. Malinchoc, K. D. Lindor et al., “Quantitative measurement of autoantibodies to recombinant mitochondrial antigens in patients with primary biliary cirrhosis: relationship of levels of autoantibodies to disease progression,” Hepatology, vol. 25, no. 1, pp. 6–11, 1997. View at Scopus
  26. E. I. Rigopoulou, D. P. Bogdanos, C. Liaskos 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, vol. 380, no. 1-2, pp. 118–121, 2007. View at Publisher · View at Google Scholar · View at Scopus
  27. E. I. Rigopoulou, E. T. Davies, D. P. Bogdanos et al., “Antimitochondrial antibodies of immunoglobulin G3 subclass are associated with a more severe disease course in primary biliary cirrhosis,” Liver International, vol. 27, no. 9, pp. 1226–1231, 2007. View at Publisher · View at Google Scholar · View at Scopus
  28. E. I. Rigopoulou, E. T. Davies, A. Pares et al., “Prevalence and clinical significance of isotype specific antinuclear antibodies in primary biliary cirrhosis,” Gut, vol. 54, no. 4, pp. 528–532, 2005. View at Publisher · View at Google Scholar · View at Scopus
  29. K. Miyachi, R. W. Hankins, H. Matsushima et al., “Profile and clinical significance of anti-nuclear envelope antibodies found in patients with primary biliary cirrhosis: a multicenter study,” Journal of Autoimmunity, vol. 20, no. 3, pp. 247–254, 2003. View at Publisher · View at Google Scholar · View at Scopus
  30. M. Nakamura, H. Kondo, T. Mori et al., “Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis,” Hepatology, vol. 45, no. 1, pp. 118–127, 2007. View at Publisher · View at Google Scholar · View at Scopus
  31. D. P. Bogdanos, C. Liaskos, A. Pares et al., “Anti-gp210 antibody mirrors disease severity in primary biliary cirrhosis,” Hepatology, vol. 45, no. 6, pp. 1583–1584, 2007. View at Publisher · View at Google Scholar · View at Scopus
  32. D. P. Bogdanos, C. Liaskos, E. I. Rigopoulou, and G. N. Dalekos, “Anti-mitochondrial antibodies in patients with systemic lupus erythematosus: revealing the unforeseen,” Clinica Chimica Acta, vol. 373, no. 1-2, pp. 183–185, 2006.
  33. D. P. Bogdanos, A. Pares, J. Rodes, and D. Vergani, “Primary biliary cirrhosis specific antinuclear antibodies in patients from Spain,” The American Journal of Gastroenterology, vol. 99, no. 4, pp. 763–765, 2004.
  34. D. P. Bogdanos, D. Vergani, P. Muratori, L. Muratori, and F. B. Bianchi, “Specificity of anti-sp100 antibody for primary biliary cirrhosis,” Scandinavian Journal of Gastroenterology, vol. 39, no. 4, pp. 405–407, 2004.
  35. P. Invernizzi, M. Podda, P. M. Battezzati et al., “Autoantibodies against nuclear pore complexes are associated with more active and severe liver disease in primary biliary cirrhosis,” Journal of Hepatology, vol. 34, no. 3, pp. 366–372, 2001. View at Publisher · View at Google Scholar · View at Scopus
  36. D. P. Bogdanos and G. N. Dalekos, “Enzymes as target antigens of liver-specific autoimmunity: the case of cytochromes P450s,” Current Medicinal Chemistry, vol. 15, no. 22, pp. 2285–2292, 2008. View at Publisher · View at Google Scholar · View at Scopus
  37. J. Wesierska-Gadek, E. Penner, P. M. Battezzati et al., “Correlation of initial autoantibody profile and clinical outcome in primary biliary cirrhosis,” Hepatology, vol. 43, no. 5, pp. 1135–1144, 2006. View at Publisher · View at Google Scholar · View at Scopus
  38. S. Oertelt, R. Rieger, C. Selmi et al., “A sensitive bead assay for antimitochondrial antibodies: chipping away at AMA-negative primary biliary cirrhosis,” Hepatology, vol. 45, no. 3, pp. 659–665, 2007. View at Publisher · View at Google Scholar · View at Scopus
  39. G. M. Hirschfield, X. Liu, Y. Han et al., “Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis,” Nature Genetics, vol. 42, no. 8, pp. 655–657, 2010. View at Publisher · View at Google Scholar · View at Scopus
  40. D. Vergani and D. P. Bogdanos, “Positive markers in AMA-negative PBC,” American Journal of Gastroenterology, vol. 98, no. 2, pp. 241–243, 2003. View at Publisher · View at Google Scholar · View at Scopus
  41. J. V. Metcalf, H. C. Mitchison, J. M. Palmer, D. E. Jones, M. F. Bassendine, and O. F. W. James, “Natural history of early primary biliary cirrhosis,” The Lancet, vol. 348, no. 9039, pp. 1399–1402, 1996. View at Publisher · View at Google Scholar · View at Scopus
  42. H. C. Mitchison, M. F. Bassendine, A. Hendrick et al., “Positive antimitochondrial antibody but normal alkaline phosphatase: is this primary biliary cirrhosis?” Hepatology, vol. 6, no. 6, pp. 1279–1284, 1986.
  43. J. V. Metcalf, R. S. Bhopal, J. Gray, D. Howel, and O. F. W. James, “Incidence and prevalence of primary biliary cirrhosis in the city of Newcastle upon Tyne, England,” International Journal of Epidemiology, vol. 26, no. 4, pp. 830–836, 1997. View at Publisher · View at Google Scholar · View at Scopus
  44. K. E. Kisand, K. V. Kisand, A. L. Karvonen et al., “Antibodies to pyruvate dehydrogenase in primary biliary cirrhosis: correlation with histology,” Acta Pathologica, Microbiologica et Immunologica Scandinavica, vol. 106, no. 9, pp. 884–892, 1998. View at Scopus
  45. K. D. Lindor, M. E. Gershwin, R. Poupon, M. Kaplan, N. V. Bergasa, and E. J. Heathcote, “Primary biliary cirrhosis,” Hepatology, vol. 50, no. 1, pp. 291–308, 2009. View at Publisher · View at Google Scholar · View at Scopus
  46. M. E. Gershwin and I. R. Mackay, “Primary biliary cirrhosis: paradigm or paradox for autoimmunity,” Gastroenterology, vol. 100, no. 3, pp. 822–833, 1991. View at Scopus
  47. M. E. Gershwin and I. R. Mackay, “The causes of primary biliary cirrhosis: convenient and inconvenient truths,” Hepatology, vol. 47, no. 2, pp. 737–745, 2008. View at Publisher · View at Google Scholar · View at Scopus
  48. I. R. Mackay, S. Whittingham, S. Fida et al., “The peculiar autoimmunity of primary biliary cirrhosis,” Immunological Reviews, vol. 174, pp. 226–237, 2000. View at Publisher · View at Google Scholar · View at Scopus
  49. D. P. Bogdanos and D. Vergani, “Origin of cross-reactive autoimmunity in primary biliary cirrhosis,” Liver International, vol. 26, no. 6, pp. 633–635, 2006. View at Publisher · View at Google Scholar · View at Scopus
  50. D. P. Bogdanos and D. Vergani, “Bacteria and primary biliary cirrhosis,” Clinical Reviews in Allergy and Immunology, vol. 36, no. 1, pp. 30–39, 2009. View at Publisher · View at Google Scholar · View at Scopus
  51. D. P. Bogdanos, H. Baum, D. Vergani, and A. K. Burroughs, “The role of E. coli infection in the pathogenesis of primary biliary cirrhosis,” Disease Markers, vol. 29, no. 6, pp. 301–311, 2010. View at Publisher · View at Google Scholar · View at Scopus
  52. P. Muratori, A. Granito, G. Pappas et al., “Clinical and serological profile of primary biliary cirrhosis in men,” QJM, vol. 100, no. 8, pp. 534–535, 2007. View at Publisher · View at Google Scholar · View at Scopus
  53. R. J. Q. McNally, S. Ducker, and O. F. W. James, “Are transient environmental agents involved in the cause of primary biliary cirrhosis? Evidence from space-time clustering analysis,” Hepatology, vol. 50, no. 4, pp. 1169–1174, 2009. View at Publisher · View at Google Scholar · View at Scopus
  54. D. Alvaro, P. Invernizzi, P. Onori et al., “Estrogen receptors in cholangiocytes and the progression of primary biliary cirrhosis,” Journal of Hepatology, vol. 41, no. 6, pp. 905–912, 2004. View at Publisher · View at Google Scholar · View at Scopus
  55. K. Amano, P. S. C. Leung, R. Rieger et al., “Chemical xenobiotics and mitochondrial autoantigens in primary biliary cirrhosis: identification of antibodies against a common environmental, cosmetic, and food additive, 2-octynoic acid,” Journal of Immunology, vol. 174, no. 9, pp. 5874–5883, 2005. View at Scopus
  56. K. Amano, P. S. C. Leung, Q. Xu et al., “Xenobiotic-induced loss of tolerance in rabbits to the mitochondrial autoantigen of primary biliary cirrhosis is reversible,” Journal of Immunology, vol. 172, no. 10, pp. 6444–6452, 2004. View at Scopus
  57. D. Bogdanos, T. Pusl, C. Rust, D. Vergani, and U. Beuers, “Primary biliary cirrhosis following lactobacillus vaccination for recurrent vaginitis,” Journal of Hepatology, vol. 49, no. 3, pp. 466–473, 2008. View at Publisher · View at Google Scholar · View at Scopus
  58. D. P. Bogdanos, H. Baum, M. Okamoto et al., “Primary biliary cirrhosis is characterized by IgG3 antibodies cross-reactive with the major mitochondrial autoepitope and its lactobacillus mimic,” Hepatology, vol. 42, no. 2, pp. 458–465, 2005. View at Publisher · View at Google Scholar · View at Scopus
  59. D. P. Bogdanos, H. Baum, U. C. Sharma et al., “Antibodies against homologous microbial caseinolytic proteases P characterise primary biliary cirrhosis,” Journal of Hepatology, vol. 36, no. 1, pp. 14–21, 2002. View at Publisher · View at Google Scholar · View at Scopus
  60. P. Invernizzi, M. Miozzo, P. M. Battezzati et al., “Frequency of monosomy X in women with primary biliary cirrhosis,” The Lancet, vol. 363, no. 9408, pp. 533–535, 2004. View at Publisher · View at Google Scholar · View at Scopus
  61. D. E. Jones, “Pathogenesis of primary biliary cirrhosis,” Gut, vol. 56, no. 11, pp. 1615–1624, 2007.
  62. D. E. J. Jones and P. T. Donaldson, “Genetic factors in the pathogenesis of primary biliary cirrhosis,” Clinics in Liver Disease, vol. 7, no. 4, pp. 841–864, 2003. View at Publisher · View at Google Scholar · View at Scopus
  63. C. Selmi and M. E. Gershwin, “The role of environmental factors in primary biliary cirrhosis,” Trends in Immunology, vol. 30, no. 8, pp. 415–420, 2009. View at Publisher · View at Google Scholar · View at Scopus
  64. C. Selmi, P. Invernizzi, M. Zuin, M. Podda, and M. E. Gershwin, “Genetics and geoepidemiology of primary biliary cirrhosis: following the footprints to disease etiology,” Seminars in Liver Disease, vol. 25, no. 3, pp. 265–280, 2005. View at Publisher · View at Google Scholar · View at Scopus
  65. C. Selmi, P. Invernizzi, M. Zuin, M. Podda, M. F. Seldin, and M. E. Gershwin, “Genes and (auto)immunity in primary biliary cirrhosis,” Genes and Immunity, vol. 6, no. 7, pp. 543–556, 2005. View at Publisher · View at Google Scholar · View at Scopus
  66. X. Liu, P. Invernizzi, Y. Lu et al., “Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis,” Nature Genetics, vol. 42, no. 8, pp. 658–660, 2010. View at Publisher · View at Google Scholar · View at Scopus
  67. G. M. Hirschfield, X. Liu, C. Xu et al., “Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants,” New England Journal of Medicine, vol. 360, no. 24, pp. 2544–2555, 2009. View at Publisher · View at Google Scholar · View at Scopus
  68. D. Smyk, M. G. Mytilinaiou, E. I. Rigopoulou, and D. P. Bogdanos, “PBC triggers in water reservoirs, coal mining areas and waste disposal sites: from Newcastle to New York,” Disease Markers, vol. 29, no. 6, pp. 337–344, 2010. View at Publisher · View at Google Scholar · View at Scopus
  69. D. Smyk, E. I. Rigopoulou, H. Baum, A. K. Burroughs, D. Vergani, and D. P. Bogdanos, “Autoimmunity and environment: am i at risk?” Clinical Reviews in Allergy and Immunology, vol. 42, no. 2, pp. 199–212, 2012. View at Publisher · View at Google Scholar · View at Scopus
  70. P. Invernizzi, C. Selmi, and M. E. Gershwin, “Update on primary biliary cirrhosis,” Digestive and Liver Disease, vol. 42, no. 6, pp. 401–408, 2010. View at Publisher · View at Google Scholar · View at Scopus
  71. P. Invernizzi and M. E. Gershwin, “The genetic basis of primary biliary cirrhosis: premises, not promises,” Gastroenterology, vol. 135, no. 4, pp. 1044–1047, 2008. View at Publisher · View at Google Scholar · View at Scopus
  72. L. Persani, M. Bonomi, A. Lleo et al., et al., “Increased loss of the Y chromosome in peripheral blood cells in male patients with autoimmune thyroiditis,” Journal of Autoimmunity, vol. 38, no. 2-3, pp. 193–196, 2012.
  73. D. S. Smyk, E. I. Rigopoulou, L. Muratori, A. K. Burroughs, and D. P. Bogdanos, “Smoking as a risk factor for autoimmune liver disease: what we can learn from primary biliary cirrhosis,” Annals of Hepatology, vol. 11, no. 1, pp. 7–14, 2012.
  74. G. M. Hirschfield and P. Invernizzi, “Progress in the genetics of primary biliary cirrhosis,” Seminars in Liver Disease, vol. 31, no. 2, pp. 147–156, 2011. View at Publisher · View at Google Scholar · View at Scopus
  75. R. Y. Lan, C. Cheng, Z. X. Lian et al., “Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis,” Hepatology, vol. 43, no. 4, pp. 729–737, 2006. View at Publisher · View at Google Scholar · View at Scopus
  76. M. S. Longhi, Y. Ma, D. P. Bogdanos, P. Cheeseman, G. Mieli-Vergani, and D. Vergani, “Impairment of CD4+CD25+ regulatory T-cells in autoimmune liver disease,” Journal of Hepatology, vol. 41, no. 1, pp. 31–37, 2004. View at Publisher · View at Google Scholar · View at Scopus
  77. M. S. Longhi, Y. Ma, R. R. Mitry et al., “Effect of CD4+CD25+ regulatory T-cells on CD8 T-cell function in patients with autoimmune hepatitis,” Journal of Autoimmunity, vol. 25, no. 1, pp. 63–71, 2005. View at Publisher · View at Google Scholar · View at Scopus
  78. R. Poupon, C. Ping, Y. Chretien et al., et al., “Genetic factors of susceptibility and of severity in primary biliary cirrhosis,” Journal of Hepatology, vol. 49, no. 6, pp. 1038–1045, 2008.
  79. R. Poupon and R. E. Poupon, “Retrovirus infection as a trigger for primary biliary cirrhosis?” The Lancet, vol. 363, no. 9405, pp. 260–261, 2004. View at Publisher · View at Google Scholar · View at Scopus
  80. D. P. Bogdanos, H. Baum, A. Grasso et al., “Microbial mimics are major targets of crossreactivity with human pyruvate dehydrogenase in primary biliary cirrhosis,” Journal of Hepatology, vol. 40, no. 1, pp. 31–39, 2004. View at Publisher · View at Google Scholar · View at Scopus
  81. D. P. Bogdanos, M. Lenzi, M. Okamoto et al., “Multiple viral/self immunological cross-reactivity in liver kidney microsomal antibody positive hepatitis C virus-infected patients is associated with the possession of HLA B51,” International Journal of Immunopathology and Pharmacology, vol. 17, no. 1, pp. 83–92, 2004. View at Scopus
  82. N. Kerkar, K. Choudhuri, Y. Ma et al., “Cytochrome P4502D6193-212: a new immunodominant epitope and target of virus/self cross-reactivity in liver kidney microsomal autoantibody type 1-positive liver disease,” Journal of Immunology, vol. 170, no. 3, pp. 1481–1489, 2003. View at Scopus
  83. D. P. Bogdanos, G. Mieli-Vergani, and D. Vergani, “Virus, liver and autoimmunity,” Digestive and Liver Disease, vol. 32, no. 5, pp. 440–446, 2000. View at Scopus
  84. D. Polymeros, D. P. Bogdanos, R. Day, D. Arioli, D. Vergani, and A. Forbes, “Does cross-reactivity between mycobacterium avium paratuberculosis and human intestinal antigens characterize crohn's disease?” Gastroenterology, vol. 131, no. 1, pp. 85–96, 2006. View at Publisher · View at Google Scholar · View at Scopus
  85. L. Wen, Y. Ma, D. P. Bogdanos et al., “Pédiatrie autoimmune liver diseases: the molecular basis of humoral and cellular immunity,” Current Molecular Medicine, vol. 1, no. 3, pp. 379–389, 2001. View at Scopus
  86. D. P. Bogdanos, H. Baum, F. Gunsar et al., “Extensive homology between the major immunodominant mitochondrial antigen in primary biliary cirrhosis and Helicobacter pylori does not lead to immunological cross-reactivity,” Scandinavian Journal of Gastroenterology, vol. 39, no. 10, pp. 981–987, 2004. View at Publisher · View at Google Scholar · View at Scopus
  87. L. Muratori, D. P. Bogdanos, P. Muratori et al., “Susceptibility to thyroid disorders in hepatitis C,” Clinical Gastroenterology and Hepatology, vol. 3, no. 6, pp. 595–603, 2005. View at Publisher · View at Google Scholar · View at Scopus
  88. S. Shimoda, M. Nakamura, H. Shigematsu et al., “Mimicry peptides of human PDC-E2 163-176 peptide, the immunodominant T- cell epitope of primary biliary cirrhosis,” Hepatology, vol. 31, no. 6, pp. 1212–1216, 2000. View at Scopus
  89. S. Shimoda, J. Van De Water, A. Ansari et al., “Identification and precursor frequency analysis of a common T cell epitope motif in mitochondrial autoantigens in primary biliary cirrhosis,” Journal of Clinical Investigation, vol. 102, no. 10, pp. 1831–1840, 1998. View at Scopus
  90. D. P. Bogdanos, H. Smith, Y. Ma, H. Baum, G. Mieli-Vergani, and D. Vergani, “A study of molecular mimicry and immunological cross-reactivity between hepatitis B surface antigen and myelin mimics,” Clinical and Developmental Immunology, vol. 12, no. 3, pp. 217–224, 2005. View at Publisher · View at Google Scholar · View at Scopus
  91. D. P. Bogdanos, H. Baum, P. Butler et al., “Association between the primary biliary cirrhosis specific anti-sp100 antibodies and recurrent urinary tract infection,” Digestive and Liver Disease, vol. 35, no. 11, pp. 801–805, 2003. View at Publisher · View at Google Scholar · View at Scopus
  92. H. Baum, D. P. Bogdanos, and D. Vergani, “Antibodies to Clp protease in primary biliary cirrhosis: possible role of a mimicking T-cell epitope,” Journal of Hepatology, vol. 34, no. 5, pp. 785–787, 2001. View at Publisher · View at Google Scholar · View at Scopus
  93. D. Vergani, M. S. Longhi, D. P. Bogdanos, Y. Ma, and G. Mieli-Vergani, “Autoimmune hepatitis,” Seminars in Immunopathology, vol. 31, no. 3, pp. 421–435, 2009. View at Publisher · View at Google Scholar · View at Scopus
  94. S. Abu-Mouch, C. Selmi, G. D. Benson et al., “Geographic clusters of primary biliary cirrhosis,” Clinical and Developmental Immunology, vol. 10, no. 2–4, pp. 127–131, 2003. View at Publisher · View at Google Scholar · View at Scopus
  95. C. Selmi, M. J. Mayo, N. Bach et al., “Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment,” Gastroenterology, vol. 127, no. 2, pp. 485–492, 2004. View at Publisher · View at Google Scholar · View at Scopus
  96. D. Smyk, E. Cholongitas, S. Kriese, E. I. Rigopoulou, and D. P. Bogdanos, “Primary biliary cirrhosis: family stories,” Autoimmune Diseases, vol. 2011, Article ID 189585, 11 pages, 2011.
  97. D. P. Bogdanos, D. S. Smyk, E. I. Rigopoulou et al., “Twin studies in autoimmune disease: genetics, gender and environment,” Journal of Autoimmunity, vol. 38, no. 2-3, pp. 156–169, 2012.
  98. P. Invernizzi, “Human leukocyte antigen in primary biliary cirrhosis: an old story now reviving,” Hepatology, vol. 54, no. 2, pp. 714–723, 2011. View at Publisher · View at Google Scholar · View at Scopus
  99. P. Invernizzi, C. Selmi, F. Poli et al., “Human leukocyte antigen polymorphisms in Italian primary biliary cirrhosis: a multicenter study of 664 patients and 1992 healthy controls,” Hepatology, vol. 48, no. 6, pp. 1906–1912, 2008. View at Publisher · View at Google Scholar · View at Scopus
  100. G. F. Mells, J. A. Floyd, K. I. Morley et al., “Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis,” Nature genetics, vol. 43, no. 4, pp. 329–332, 2011. View at Publisher · View at Google Scholar · View at Scopus
  101. A. Tanaka, P. Invernizzi, H. Ohira et al., “Replicated association of 17q12-21 with susceptibility of primary biliary cirrhosis in a Japanese cohort,” Tissue Antigens, vol. 78, no. 1, pp. 65–68, 2011. View at Publisher · View at Google Scholar · View at Scopus
  102. A. Tanaka, H. Ohira, K. Kikuchi 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, vol. 77, no. 3, pp. 239–243, 2011. View at Publisher · View at Google Scholar · View at Scopus
  103. S. Shimoda, M. Nakamura, H. Ishibashi, K. Hayashida, and Y. Niho, “HLA DRB4 0101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis: evidence of molecular mimicry in human autoimmune diseases,” Journal of Experimental Medicine, vol. 181, no. 5, pp. 1835–1845, 1995. View at Scopus
  104. S. Shimoda, K. Harada, H. Niiro et al., “Interaction between Toll-like receptors and natural killer cells in the destruction of bile ducts in primary biliary cirrhosis,” Hepatology, vol. 53, no. 4, pp. 1270–1281, 2011. View at Publisher · View at Google Scholar · View at Scopus
  105. K. Harada, S. Shimoda, H. Ikeda et al., “Significance of periductal Langerhans cells and biliary epithelial cell-derived macrophage inflammatory protein-3α in the pathogenesis of primary biliary cirrhosis,” Liver International, vol. 31, no. 2, pp. 245–253, 2011. View at Publisher · View at Google Scholar · View at Scopus
  106. K. Harada, S. Shimoda, Y. Sato, K. Isse, H. Ikeda, and Y. Nakanuma, “Periductal interleukin-17 production in association with biliary innate immunity contributes to the pathogenesis of cholangiopathy in primary biliary cirrhosis,” Clinical and Experimental Immunology, vol. 157, no. 2, pp. 261–270, 2009. View at Publisher · View at Google Scholar · View at Scopus
  107. K. Harada and Y. Nakanuma, “Cholangiopathy with respect to biliary innate immunity,” International Journal of Hepatology, vol. 2012, Article ID 793569, 10 pages, 2012.
  108. H. Kita, Z. X. Lian, J. Van De Water et al., “Identification of HLA-A2-restricted CD8+ cytotoxic T cell responses in primary biliary cirrhosis: T cell activation is augmented by immune complexes cross-presented by dendritic cells,” Journal of Experimental Medicine, vol. 195, no. 1, pp. 113–123, 2002. View at Publisher · View at Google Scholar · View at Scopus
  109. H. Kita, S. Matsumura, X. S. He et al., “Quantitative and functional analysis of PDC-E2-specific autoreactive cytotoxic T lymphocytes in primary biliary cirrhosis,” Journal of Clinical Investigation, vol. 109, no. 9, pp. 1231–1240, 2002. View at Publisher · View at Google Scholar · View at Scopus
  110. A. Lleo, C. L. Bowlus, G. X. Yang et al., “Biliary apotopes and anti-mitochondrial antibodies activate innate immune responses in primary biliary cirrhosis,” Hepatology, vol. 52, no. 3, pp. 987–998, 2010. View at Publisher · View at Google Scholar · View at Scopus
  111. A. Lleo, C. Selmi, P. Invernizzi et al., “Apotopes and the biliary specificity of primary biliary cirrhosis,” Hepatology, vol. 49, no. 3, pp. 871–879, 2009. View at Publisher · View at Google Scholar · View at Scopus
  112. G. Rong, R. Zhong, A. Lleo et al., “Epithelial cell specificity and apotope recognition by serum autoantibodies in primary biliary cirrhosis,” Hepatology, vol. 54, no. 1, pp. 196–203, 2011. View at Publisher · View at Google Scholar · View at Scopus
  113. J. Van de Water, D. Fregeau, P. Davis et al., “Autoantibodies of primary biliary cirrhosis recognize dihydrolipoamide acetyltransferase and inhibit enzyme function,” Journal of Immunology, vol. 141, no. 7, pp. 2321–2324, 1988. View at Scopus
  114. G. Nalbandian, J. Van De Water, R. Gish et al., “Is there a serological difference between men and women with primary biliary cirrhosis?” American Journal of Gastroenterology, vol. 94, no. 9, pp. 2482–2486, 1999. View at Publisher · View at Google Scholar · View at Scopus
  115. C. Selmi, F. Meda, A. Kasangian et al., “Experimental evidence on the immunopathogenesis of primary biliary cirrhosis,” Cellular and Molecular Immunology, vol. 7, no. 1, pp. 1–10, 2010. View at Publisher · View at Google Scholar · View at Scopus
  116. R. Bown, M. L. Clark, and D. Doniach, “Primary biliary cirrhosis in brothers,” Postgraduate Medical Journal, vol. 51, no. 592, pp. 110–115, 1975. View at Scopus
  117. A. Tanaka, A. T. Borchers, H. Ishibashi, A. A. Ansari, C. L. Keen, and M. E. Gershwin, “Genetic and familial considerations of primary biliary cirrhosis,” American Journal of Gastroenterology, vol. 96, no. 1, pp. 8–15, 2001. View at Publisher · View at Google Scholar · View at Scopus
  118. K. N. Lazaridis, B. D. Juran, G. M. Boe et al., “Increased prevalence of antimitochondrial antibodies in first-degree relatives of patients with primary biliary cirrhosis,” Hepatology, vol. 46, no. 3, pp. 785–792, 2007. View at Publisher · View at Google Scholar · View at Scopus
  119. C. Corpechot, Y. Chretien, O. Chazouilleres, and R. Poupon, “Demographic, lifestyle, medical and familial factors associated with primary biliary cirrhosis,” Journal of Hepatology, vol. 53, no. 1, pp. 162–169, 2010.
  120. M. E. Gershwin, C. Selmi, H. J. Worman et al., “Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients,” Hepatology, vol. 42, no. 5, pp. 1194–1202, 2005. View at Publisher · View at Google Scholar · View at Scopus
  121. A. Parikh-Patel, E. B. Gold, H. Worman, K. E. Krivy, and M. E. Gershwin, “Risk factors for primary biliary cirrhosis in a cohort of patients from the United States,” Hepatology, vol. 33, no. 1, pp. 16–21, 2001. View at Publisher · View at Google Scholar · View at Scopus
  122. M. I. Prince, S. J. Ducker, and O. F. W. James, “Case-control studies of risk factors for primary biliary cirrhosis in two United Kingdom populations,” Gut, vol. 59, no. 4, pp. 508–512, 2010. View at Publisher · View at Google Scholar · View at Scopus
  123. D. S. Smyk, D. P. Bogdanos, S. Kriese, C. Billinis, A. K. Burroughs, and E. I. Rigopoulou, “Urinary tract infection as a risk factor for autoimmune liver disease: from bench to bedside,” Clinical Research in Hepatology and Gastroentrology, vol. 36, no. 2, pp. 110–121, 2012.
  124. F. K. Varyani, J. West, and T. R. Card, “An increased risk of urinary tract infection precedes development of primary biliary cirrhosis,” BMC Gastroenterology, vol. 11, article 95, 2011.
  125. M. J. Goo, M. R. Ki, H. R. Lee et al., “Primary biliary cirrhosis, similar to that in human beings, in a male C57BL/6 mouse infected with Helicobacter pylori,” European Journal of Gastroenterology & Hepatology, vol. 20, no. 10, pp. 1045–1048, 2008.
  126. A. Koutsoumpas, M. Mytilinaiou, D. Polymeros, G. N. Dalekos, and D. P. Bogdanos, “Anti-Helicobacter pylori antibody responses specific for VacA do not trigger primary biliary cirrhosis-specific antimitochondrial antibodies,” European Journal of Gastroenterology & Hepatology, vol. 21, no. 10, p. 1220, 2009.
  127. L. R. Rubel, L. Rabin, L. B. Seeff, H. Licht, and B. A. Cuccherini, “Does primary biliary cirrhosis in men differ from primary biliary cirrhosis in women?” Hepatology, vol. 4, no. 4, pp. 671–677, 1984.
  128. M. R. Lucey, J. M. Neuberger, and R. Williams, “Primary biliary cirrhosis in men,” Gut, vol. 27, no. 11, pp. 1373–1376, 1986. View at Scopus
  129. N. Krasner, P. J. Johnson, B. Portmann, G. Watkinson, R. N. Macsween, and R. Williams, “Hepatocellular carcinoma in primary biliary cirrhosis: report of four cases,” Gut, vol. 20, no. 3, pp. 255–258, 1979.
  130. W. M. Melia, P.J. Johnson, J. Neuberger, S. Zaman, B. C. Portmann, and R. Williams, “Hepatocellular carcinoma in primary biliary cirrhosis: detection by alpha-fetoprotein estimation,” Gastroenterology, vol. 87, no. 3, pp. 660–663, 1984.
  131. C. Selmi, “The X in sex: how autoimmune diseases revolve around sex chromosomes,” Best Practice & Research Clinical Rheumatology, vol. 22, no. 5, pp. 913–922, 2008.
  132. I. Bianchi, A. Lleo, M. E. Gershwin, and P. Invernizzi, “The X chromosome and immune associated genes,” Journal of Autoimmunity, vol. 38, no. 2-3, pp. 187–192, 2012.
  133. P. Invernizzi, M. Miozzo, C. Selmi et al., “X chromosome monosomy: a common mechanism for autoimmune diseases,” Journal of Immunology, vol. 175, no. 1, pp. 575–578, 2005. View at Scopus
  134. A. Lleo, P. M. Battezzati, C. Selmi, M. E. Gershwin, and M. Podda, “Is autoimmunity a matter of sex?” Autoimmunity Reviews, vol. 7, no. 8, pp. 626–630, 2008. View at Publisher · View at Google Scholar · View at Scopus
  135. Z. Ozbalkan, S. Bagislar, S. Kiraz et al., “Skewed X chromosome inactivation in blood cells of women with scleroderma,” Arthritis & Rheumatism, vol. 52, no. 5, pp. 1564–1570, 2005.
  136. E. Uz, L. S. Loubiere, V. K. Gadi et al., “Skewed X-chromosome inactivation in scleroderma,” Clinical Reviews in Allergy and Immunology, vol. 34, no. 3, pp. 352–355, 2008. View at Publisher · View at Google Scholar · View at Scopus
  137. T. H. Brix, G. P. Knudsen, M. Kristiansen, K. O. Kyvik, K. H. Orstavik, and L. Hegedus, “High frequency of skewed X-chromosome inactivation in females with autoimmune thyroid disease: a possible explanation for the female predisposition to thyroid autoimmunity,” The Journal of Clinical Endocrinology & Metabolism, vol. 90, no. 11, pp. 5949–5953, 2005.
  138. T. Ozcelik, “X chromosome inactivation and female predisposition to autoimmunity,” Clinical Reviews in Allergy and Immunology, vol. 34, no. 3, pp. 348–351, 2008. View at Publisher · View at Google Scholar · View at Scopus
  139. M. Miozzo, C. Selmi, B. Gentilin et al., “Preferential X chromosome loss but random inactivation characterize primary biliary cirrhosis,” Hepatology, vol. 46, no. 2, pp. 456–462, 2007. View at Publisher · View at Google Scholar · View at Scopus
  140. M. M. Mitchell, A. Lleo, L. Zammataro et al., “Epigenetic investigation of variably X chromosome inactivated genes in monozygotic female twins discordant for primary biliary cirrhosis,” Epigenetics, vol. 6, no. 1, pp. 95–102, 2011. View at Publisher · View at Google Scholar · View at Scopus
  141. Y. Weinstein, S. Ran, and S. Segal, “Sex-associated differences in the regulation of immune responses controlled by the MHC of the mouse,” Journal of Immunology, vol. 132, no. 2, pp. 656–661, 1984. View at Scopus
  142. A. Amadori, R. Zamarchi, G. De Silvestro et al., “Genetic control of the CD4/CD8 T-cell ratio in humans,” Nature Medicine, vol. 1, no. 12, pp. 1279–1283, 1995. View at Scopus
  143. A. Bouman, M. Jan Heineman, and M. M. Faas, “Sex hormones and the immune response in humans,” Human Reproduction Update, vol. 11, no. 4, pp. 411–423, 2005. View at Publisher · View at Google Scholar · View at Scopus
  144. A. V. Rubtsov, K. Rubtsova, J. W. Kappler, and P. Marrack, “Genetic and hormonal factors in female-biased autoimmunity,” Autoimmunity Reviews, vol. 9, no. 7, pp. 494–498, 2010. View at Publisher · View at Google Scholar · View at Scopus
  145. N. Kanda and K. Tamaki, “Estrogen enhances immunoglobulin production by human PBMCs,” Journal of Allergy and Clinical Immunology, vol. 103, no. 2, pp. 282–288, 1999. View at Scopus
  146. N. Kanda, T. Tsuchida, and K. Tamaki, “Estrogen enhancement of anti-double-stranded DNA antibody and immunoglobulin G production in peripheral blood mononuclear cells from patients with systemic lupus erythematosus,” Arthritis & Rheumatism, vol. 42, no. 2, pp. 328–337, 1999.
  147. N. Kanda, T. Tsuchida, and K. Tamaki, “Testosterone inhibits immunoglobulin production by human peripheral blood mononuclear cells,” Clinical and Experimental Immunology, vol. 106, no. 2, pp. 410–415, 1996. View at Scopus