Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Genes and (auto)immunity in primary biliary cirrhosis

Genes & Immunity volume 6, pages 543–556 (2005)Cite this article

Abstract

Primary biliary cirrhosis (PBC) is a chronic autoimmune cholestatic liver disease most commonly encountered in postmenopausal women; it is characterized by high-titer serum autoantibodies to mitochondrial antigens, elevated serum IgM, progressive destruction of intrahepatic bile ducts, and ultimately liver cirrhosis and failure. The cytopathic mechanisms leading to the selective destruction of intrahepatic cholangiocytes are still largely unknown. The current theory on the pathogenesis of PBC indicated that environmental factors might trigger autoimmunity in genetically susceptible individuals. In fact, genetic predisposition is critical to disease onset and progression, yet peculiar among autoimmune diseases, as indicated by the lack of a strong association with major histocompatibility complex haplotypes. Further, the recently reported concordance rate among monozygotic twins strenghtens the importance of genetic factors, while also indicating that additional factors, possibly infectious agents or xenobiotics, intervene to trigger the disease. In this review, the available data regarding the genetic factors associated with PBC susceptibility and progression, as well as the available evidence regarding the immunomediated pathogenesis of PBC, will be critically illustrated and discussed.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

Article Open access 27 September 2021

Benedetta Terziroli Beretta-Piccoli, Giorgina Mieli-Vergani & Diego Vergani

References

  1. Talwalkar JA, Lindor KD . Primary biliary cirrhosis. Lancet 2003; 362: 53–61.

    CAS  PubMed  Google Scholar 

  2. Risch N . Searching for genes in complex diseases: lessons from systemic lupus erythematosus. J Clin Invest 2000; 105: 1503–1506.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Kim WR, Lindor KD, Locke III GR et al. Epidemiology and natural history of primary biliary cirrhosis in a US community. Gastroenterology 2000; 119: 1631–1636.

    CAS  PubMed  Google Scholar 

  4. Cardon LR, Bell JI . Association study designs for complex diseases. Nat Rev Genet 2001; 2: 91–99.

    Article  CAS  PubMed  Google Scholar 

  5. Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K . A comprehensive review of genetic association studies. Genet Med 2002; 4: 45–61.

    CAS  PubMed  Google Scholar 

  6. Sabatti C, Service S, Freimer N . False discovery rate in linkage and association genome screens for complex disorders. Genetics 2003; 164: 829–833.

    PubMed  PubMed Central  Google Scholar 

  7. Brind AM, Bray GP, Portmann BC, Williams R . Prevalence and pattern of familial disease in primary biliary cirrhosis. Gut 1995; 36: 615–617.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Hamlyn AN, Macklon AF, James O . Primary biliary cirrhosis: geographical clustering and symptomatic onset seasonality. Gut 1983; 24: 940–945.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Myszor M, James OF . The epidemiology of primary biliary cirrhosis in north-east England: an increasingly common disease? Q J Med 1990; 75: 377–385.

    CAS  PubMed  Google Scholar 

  10. Bach N, Schaffner F . Familial primary biliary cirrhosis. J Hepatol 1994; 20: 698–701.

    CAS  PubMed  Google Scholar 

  11. Danielsson A, Boqvist L, Uddenfeldt P . Epidemiology of primary biliary cirrhosis in a defined rural population in the northern part of Sweden. Hepatology 1990; 11: 458–464.

    CAS  PubMed  Google Scholar 

  12. Floreani A, Naccarato R, Chiaramonte M . Prevalence of familial disease in primary biliary cirrhosis in Italy. J Hepatol 1997; 26: 737–738.

    CAS  PubMed  Google Scholar 

  13. Tsuji K, Watanabe Y, Van De Water J et al. Familial primary biliary cirrhosis in Hiroshima. J Autoimmun 1999; 13: 171–178.

    CAS  PubMed  Google Scholar 

  14. Jones DE, Watt FE, Metcalf JV, Bassendine MF, James OF . Familial primary biliary cirrhosis reassessed: a geographically-based population study. J Hepatol 1999; 30: 402–407.

    CAS  PubMed  Google Scholar 

  15. Jones DE, Watt FE, Grove J et al. Tumour necrosis factor-alpha promoter polymorphisms in primary biliary cirrhosis (see comments). J Hepatol 1999; 30: 232–236.

    CAS  PubMed  Google Scholar 

  16. 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: 2143–2146.

    CAS  PubMed  Google Scholar 

  17. Feizi T, Naccarato R, Sherlock S, Doniach D . Mitochondrial and other tissue antibodies in relatives of patients with primary biliary cirrhosis. Clin Exp Immunol 1972; 10: 609–622.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Galbraith RM, Smith M, Mackenzie RM, Tee DE, Doniach D, Williams R . High prevalence of seroimmunologic abnormalities in relatives of patients with active chronic hepatitis or primary biliary cirrhosis. N Engl J Med 1974; 290: 63–69.

    CAS  PubMed  Google Scholar 

  19. Watt FE, James OF, Jones DE . Patterns of autoimmunity in primary biliary cirrhosis patients and their families: a population-based cohort study. QJM 2004; 97: 397–406.

    CAS  PubMed  Google Scholar 

  20. Bittencourt PL, Farias AQ, Abrantes-Lemos CP et al. Prevalence of immune disturbances and chronic liver disease in family members of patients with primary biliary cirrhosis. J Gastroenterol Hepatol 2004; 19: 873–878.

    CAS  PubMed  Google Scholar 

  21. MacGregor AJ, Snieder H, Rigby AS et al. Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum 2000; 43: 30–37.

    CAS  PubMed  Google Scholar 

  22. Greco L, Romino R, Coto I et al. The first large population based twin study of coeliac disease. Gut 2002; 50: 624–628.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Chohan MR . Primary biliary cirrhosis in twin sisters. Gut 1973; 14: 213–214.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Kaplan MM, Rabson AR, Lee YM, Williams DL, Montaperto PA . Discordant occurrence of primary biliary cirrhosis in monozygotic twins. N Engl J Med 1994; 331: 951.

    Google Scholar 

  25. Selmi C, Mayo MJ, Bach N et al. Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology 2004; 127: 485–492.

    PubMed  Google Scholar 

  26. Selmi C, Gershwin ME . Bacteria and human autoimmunity: the case of primary biliary cirrhosis. Curr Opin Rheumatol 2004; 16: 406–410.

    PubMed  Google Scholar 

  27. Kita H, He XS, Gershwin ME . Autoimmunity and environmental factors in the pathogenesis of primary biliary cirrhosis. Ann Med 2004; 36: 72–80.

    CAS  PubMed  Google Scholar 

  28. McCluskey J, Peh CA . The human leucocyte antigens and clinical medicine: an overview. Rev Immunogenet 1999; 1: 3–20.

    CAS  PubMed  Google Scholar 

  29. Ercilla G, Parés A, Arriaga F et al. Primary biliary cirrhosis associated with DLA-DRw3. Tissue Antigens 1979; 14: 449–452.

    CAS  PubMed  Google Scholar 

  30. Miyamori H, Kato Y, Kobayashi K, Hattori N . HLA antigens in Japanese patients with primary biliary cirrhosis and autoimmune hepatitis. Digestion 1983; 26: 213–217.

    CAS  PubMed  Google Scholar 

  31. Onishi S, Sakamaki T, Maeda T et al. DNA typing of HLA class II genes; DRB1*0803 increases the susceptibility of Japanese to primary biliary cirrhosis. J Hepatol 1994; 21: 1053–1060.

    CAS  PubMed  Google Scholar 

  32. Bassendine MF, Dewar PJ, James OF . HLA-DR antigens in primary biliary cirrhosis: lack of association. Gut 1985; 26: 625–628.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Briggs DC, Donaldson PT, Hayes P, Welsh KI, Williams R, Neuberger JM . A major histocompatibility complex class III allotype (C4B 2) associated with primary biliary cirrhosis (PBC). Tissue Antigens 1987; 29: 141–145.

    CAS  PubMed  Google Scholar 

  34. Manns MP, Bremm A, Schneider PM et al. HLA DRw8 and complement C4 deficiency as risk factors in primary biliary cirrhosis. Gastroenterology 1991; 101: 1367–1373.

    CAS  PubMed  Google Scholar 

  35. Morling N, Dalhoff K, Fugger L et al. DNA polymorphism of HLA class II genes in primary biliary cirrhosis. Immunogenetics 1992; 35: 112–116.

    CAS  PubMed  Google Scholar 

  36. Invernizzi P, Battezzati PM, Crosignani A et al. Peculiar HLA polymorphisms in Italian patients with primary biliary cirrhosis. J Hepatol 2003; 38: 401–406.

    CAS  PubMed  Google Scholar 

  37. Gores GJ, Moore SB, Fisher LD, Powell FC, Dickson ER . Primary biliary cirrhosis: associations with class II major histocompatibility complex antigens. Hepatology 1987; 7: 889–892.

    CAS  PubMed  Google Scholar 

  38. Begovich AB, Klitz W, Moonsamy PV, Van de Water J, Peltz G, Gershwin ME . Genes within the HLA class II region confer both predisposition and resistance to primary biliary cirrhosis. Tissue Antigens 1994; 43: 71–77.

    CAS  PubMed  Google Scholar 

  39. Wassmuth R, Depner F, Danielsson A et al. HLA class II markers and clinical heterogeneity in Swedish patients with primary biliary cirrhosis. Tissue Antigens 2002; 59: 381–387.

    CAS  PubMed  Google Scholar 

  40. Mullarkey ME, Stevens AM, McDonnell WM et al. Human leukocyte antigen class II alleles in Caucasian women with primary biliary cirrhosis. Tissue Antigens 2005; 65: 199–205.

    CAS  PubMed  Google Scholar 

  41. Donaldson P, Agarwal K, Craggs A, Craig W, James O, Jones D . HLA and interleukin 1 gene polymorphisms in primary biliary cirrhosis: associations with disease progression and disease susceptibility. Gut 2001; 48: 397–402.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhang L, Weetman AP, Bassendine M, Oliveira DB . Major histocompatibility complex class-II alleles in primary biliary cirrhosis. Scand J Immunol 1994; 39: 104–106.

    CAS  PubMed  Google Scholar 

  43. Bittencourt PL, Palacios SA, Farias AQ et al. Analysis of major histocompatibility complex and CTLA-4 alleles in Brazilian patients with primary biliary cirrhosis. J Gastroenterol Hepatol 2003; 18: 1061–1066.

    CAS  PubMed  Google Scholar 

  44. Mella JG, Roschmann E, Maier KP, Volk BA . Association of primary biliary cirrhosis with the allele HLA-DPB1*0301 in a German population. Hepatology 1995; 21: 398–402.

    CAS  PubMed  Google Scholar 

  45. Seki T, Kiyosawa K, Ota M et al. Association of primary biliary cirrhosis with human leukocyte antigen DPB1*0501 in Japanese patients. Hepatology 1993; 18: 73–78.

    CAS  PubMed  Google Scholar 

  46. Gregory WL, Daly AK, Dunn AN et al. Analysis of HLA-class-II-encoded antigen-processing genes TAP1 and TAP2 in primary biliary cirrhosis. Q J Med 1994; 87: 237–244.

    CAS  PubMed  Google Scholar 

  47. Donaldson PT . TNF gene polymorphisms in primary biliary cirrhosis: a critical appraisal. J Hepatol 1999; 31: 366–368.

    CAS  PubMed  Google Scholar 

  48. Wilson AG, di Giovine FS, Blakemore AI, Duff GW . Single base polymorphism in the human tumour necrosis factor alpha (TNF alpha) gene detectable by NcoI restriction of PCR product. Hum Mol Genet 1992; 1: 353.

    CAS  PubMed  Google Scholar 

  49. Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW . Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci USA 1997; 94: 3195–3199.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Kroeger KM, Carville KS, Abraham LJ . The −308 tumor necrosis factor-alpha promoter polymorphism effects transcription. Mol Immunol 1997; 34: 391–399.

    CAS  PubMed  Google Scholar 

  51. Wu WS, McClain KL . DNA polymorphisms and mutations of the tumor necrosis factor-alpha (TNF-alpha) promoter in Langerhans cell histiocytosis (LCH). J Interferon Cytokine Res 1997; 17: 631–635.

    CAS  PubMed  Google Scholar 

  52. Gordon MA, Oppenheim E, Camp NJ, di Giovine FS, Duff GW, Gleeson D . Primary biliary cirrhosis shows association with genetic polymorphism of tumour necrosis factor alpha promoter region (see comments). J Hepatol 1999; 31: 242–247.

    CAS  PubMed  Google Scholar 

  53. Tanaka A, Quaranta S, Mattalia A et al. The tumor necrosis factor-alpha promoter correlates with progression of primary biliary cirrhosis. J Hepatol 1999; 30: 826–829.

    CAS  PubMed  Google Scholar 

  54. Dickson ER, Grambsch PM, Fleming TR, Fisher LD, Langworthy A . Prognosis in primary biliary cirrhosis: model for decision making. Hepatology 1989; 10: 1–7.

    CAS  PubMed  Google Scholar 

  55. Bathgate AJ, Pravica V, Perrey C, Hayes PC, Hutchinson IV . Polymorphisms in tumour necrosis factor alpha, interleukin-10 and transforming growth factor beta1 genes and end-stage liver disease. Eur J Gastroenterol Hepatol 2000; 12: 1329–1333.

    CAS  PubMed  Google Scholar 

  56. Fan LY, Zhong RQ, Tu XQ et al. Genetic association of tumor necrosis factor (TNF)-alpha polymorphisms with primary biliary cirrhosis and autoimmune liver diseases in a Chinese population. Zhonghua Gan Zang Bing Za Zhi 2004; 12: 160–162.

    CAS  PubMed  Google Scholar 

  57. Jazrawi SF, Zaman A, Muhammad Z et al. Tumor necrosis factor-alpha promoter polymorphisms and the risk of rejection after liver transplantation: a case control analysis of 210 donor-recipient pairs. Liver Transplant 2003; 9: 377–382.

    Google Scholar 

  58. Agarwal K, Jones DE, Daly AK et al. CTLA-4 gene polymorphism confers susceptibility to primary biliary cirrhosis (in process citation). J Hepatol 2000; 32: 538–541.

    CAS  PubMed  Google Scholar 

  59. Fan LY, Tu XQ, Cheng QB et al. Cytotoxic T lymphocyte associated antigen-4 gene polymorphisms confer susceptibility to primary biliary cirrhosis and autoimmune hepatitis in Chinese population. World J Gastroenterol 2004; 10: 3056–3059.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Kershenobich D, Rojkind M, Quiroga A, Alcocer-Varela J . Effect of colchicine on lymphocyte and monocyte function and its relation to fibroblast proliferation in primary biliary cirrhosis. Hepatology 1990; 11: 205–209.

    CAS  PubMed  Google Scholar 

  61. Lakatos LP, Bajnok E, Hegedus D, Toth T, Lakatos P, Szalay F . Vitamin D receptor, oestrogen receptor-alpha gene and interleukin-1 receptor antagonist gene polymorphisms in Hungarian patients with primary biliary cirrhosis. Eur J Gastroenterol Hepatol 2002; 14: 733–740.

    CAS  PubMed  Google Scholar 

  62. Fan LY, Zhu Y, Zhong RQ et al. Genetic association between interleukins gene polymorphisms with primary biliary cirrhosis in Chinese population. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2004; 26: 505–509.

    PubMed  Google Scholar 

  63. Fan LY, Tu XQ, Zhu Y et al. Genetic association of cytokines polymorphisms with autoimmune hepatitis and primary biliary cirrhosis in the Chinese. World J Gastroenterol 2005; 11: 2768–2772.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Matsushita M, Tanaka A, Kikuchi K et al. Association of single nucleotide polymorphisms of the interleukin-10 promoter gene and susceptibility to primary biliary cirrhosis: immunogenetic differences in Italian and Japanese patients. Autoimmunity 2002; 35: 531–536.

    CAS  PubMed  Google Scholar 

  65. Vogel A, Strassburg CP, Manns MP . Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis. Hepatology 2002; 35: 126–131.

    CAS  PubMed  Google Scholar 

  66. Halmos B, Szalay F, Cserniczky T et al. Association of primary biliary cirrhosis with vitamin D receptor BsmI genotype polymorphism in a Hungarian population. Dig Dis Sci 2000; 45: 1091–1095.

    CAS  PubMed  Google Scholar 

  67. Fan LY, Zhong RQ, Tu XQ et al. Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune liver diseases on Chinese. Zhonghua Yi Xue Za Zhi 2003; 83: 1852–1855.

    CAS  PubMed  Google Scholar 

  68. Springer JE, Cole DE, Rubin LA et al. Vitamin D-receptor genotypes as independent genetic predictors of decreased bone mineral density in primary biliary cirrhosis. Gastroenterology 2000; 118: 145–151.

    CAS  PubMed  Google Scholar 

  69. Pares A, Guanabens N, Alvarez L et al. Collagen type Ialpha1 and vitamin D receptor gene polymorphisms and bone mass in primary biliary cirrhosis. Hepatology 2001; 33: 554–560.

    CAS  PubMed  Google Scholar 

  70. Vong S, Bell BP . Chronic liver disease mortality in the United States, 1990-1998. Hepatology 2004; 39: 476–483.

    PubMed  Google Scholar 

  71. 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: 779–791.

    CAS  PubMed  Google Scholar 

  72. Pauli-Magnus C, Lang T, Meier Y et al. Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy. Pharmacogenetics 2004; 14: 91–102.

    CAS  PubMed  Google Scholar 

  73. Selmi C, Invernizzi P, Keefe EB et al. Epidemiology and pathogenesis of primary biliary cirrhosis. J Clin Gastroenterol 2004; 38: 264–271.

    PubMed  Google Scholar 

  74. Kimura Y, Selmi C, Leung PS et al. Genetic polymorphisms influencing xenobiotic metabolism and transport in patients with primary biliary cirrhosis. Hepatology 2005; 41: 55–63.

    CAS  PubMed  Google Scholar 

  75. Higuchi M, Horiuchi T, Kojima T et al. Analysis of CD40 ligand gene mutations in patients with primary biliary cirrhosis. Scand J Clin Lab Invest 1998; 58: 429–432.

    CAS  PubMed  Google Scholar 

  76. Corpechot C, Poupon R . Promoter polymorphism of the CD14 endotoxin receptor gene and primary biliary cirrhosis. Hepatology 2002; 35: 242–243.

    PubMed  Google Scholar 

  77. Selmi C, Zuin M, Biondi ML et al. Genetic variants of endothelial nitric oxide synthase in patients with primary biliary cirrhosis: association with disease severity. J Gastroenterol Hepatol 2003; 18: 1150–1155.

    CAS  PubMed  Google Scholar 

  78. Kikuchi K, Tanaka A, Miyakawa H et al. Eta-1/osteopontin genetic polymorphism and primary biliary cirrhosis. Hepatol Res 2003; 26: 87–90.

    CAS  PubMed  Google Scholar 

  79. Selmi C, Invernizzi P, Tripputi P et al. T-cell receptor polymorphism in primary biliary cirrhosis. Ann Ital Med Int 2003; 18: 149–153.

    PubMed  Google Scholar 

  80. Lakatos PL, Bajnok E, Tornai I et al. Insulin-like growth factor I gene microsatellite repeat, collagen type Ialpha1 gene Sp1 polymorphism, and bone disease in primary biliary cirrhosis. Eur J Gastroenterol Hepatol 2004; 16: 753–759.

    CAS  PubMed  Google Scholar 

  81. Kikuchi K, Lian ZX, Kimura Y et al. Genetic polymorphisms of toll-like receptor 9 influence the immune response to CpG and contribute to hyper-IgM in primary biliary cirrhosis. J Autoimmun 2005; 24: 344–352.

    Google Scholar 

  82. Ranke MB, Saenger P . Turner's syndrome. Lancet 2001; 358: 309–314.

    CAS  PubMed  Google Scholar 

  83. Davis CJ, Davison RM, Payne NN, Rodeck CH, Conway GS . Female sex preponderance for idiopathic familial premature ovarian failure suggests an X chromosome defect: opinion. Hum Reprod 2000; 15: 2418–2422.

    CAS  PubMed  Google Scholar 

  84. Invernizzi P, Miozzo M, Battezzati PM et al. Frequency of monosomy X in women with primary biliary cirrhosis. Lancet 2004; 363: 533–535.

    PubMed  Google Scholar 

  85. Guttenbach M, Koschorz B, Bernthaler U, Grimm T, Schmid M . Sex chromosome loss and aging: in situ hybridization studies on human interphase nuclei. Am J Hum Genet 1995; 57: 1143–1150.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Kaplan MM, Bianchi DW . Primary biliary cirrhosis: for want of an X chromosome? Lancet 2004; 363: 505–506.

    PubMed  Google Scholar 

  87. Invernizzi P, Miozzo M, Selmi C et al. X chromosome monosomy: a common mechanism for autoimmune diseases. J Immunol 2005; 175: 575–578.

    CAS  PubMed  Google Scholar 

  88. Lambert N, Nelson JL . Microchimerism in autoimmune disease: more questions than answers? Autoimmun Rev 2003; 2: 133–139.

    CAS  PubMed  Google Scholar 

  89. Fanning PA, Jonsson JR, Clouston AD et al. Detection of male DNA in the liver of female patients with primary biliary cirrhosis. J Hepatol 2000; 33: 690–695.

    CAS  PubMed  Google Scholar 

  90. Tanaka A, Lindor K, Gish R et al. Fetal microchimerism alone does not contribute to the induction of primary biliary cirrhosis. Hepatology 1999; 30: 833–838.

    CAS  PubMed  Google Scholar 

  91. Invernizzi P, De Andreis C, Sirchia SM et al. Blood fetal microchimerism in primary biliary cirrhosis. Clin Exp Immunol 2000; 122: 418–422.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Oertelt S, Selmi C, Invernizzi P, Podda M, Gershwin ME . Genes and goals: an approach to microarray analysis in autoimmunity. Autoimmun Rev 2005, in press.

  93. Hinds DA, Stuve LL, Nilsen GB et al. Whole-genome patterns of common DNA variation in three human populations. Science 2005; 307: 1072–1079.

    CAS  PubMed  Google Scholar 

  94. Miyakawa H, Tanaka A, Kikuchi K et al. Detection of antimitochondrial autoantibodies in immunofluorescent AMA-negative patients with primary biliary cirrhosis using recombinant autoantigens. Hepatology 2001; 34: 243–248.

    CAS  PubMed  Google Scholar 

  95. Gershwin ME, Mackay IR, Sturgess A, Coppel RL . Identification and specificity of a cDNA encoding the 70 kd mitochondrial antigen recognized in primary biliary cirrhosis. J Immunol 1987; 138: 3525–3531.

    CAS  PubMed  Google Scholar 

  96. Gershwin ME, Ansari AA, Mackay IR et al. Primary biliary cirrhosis: an orchestrated immune response against epithelial cells. Immunol Rev 2000; 174: 210–225.

    CAS  PubMed  Google Scholar 

  97. Bruggraber SF, Leung PS, Amano K et al. Autoreactivity to lipoate and a conjugated form of lipoate in primary biliary cirrhosis. Gastroenterology 2003; 125: 1705–1713.

    CAS  PubMed  Google Scholar 

  98. Mao TK, Davis PA, Odin JA, Coppel RL, Gershwin ME . Sidechain biology and the immunogenicity of PDC-E2, the major autoantigen of primary biliary cirrhosis. Hepatology 2004; 40: 1241–1248.

    CAS  PubMed  Google Scholar 

  99. Quinn J, Diamond AG, Palmer JM, Bassendine MF, James OF, Yeaman SJ . Lipoylated and unlipoylated domains of human PDC-E2 as autoantigens in primary biliary cirrhosis: significance of lipoate attachment. Hepatology 1993; 18: 1384–1391.

    CAS  PubMed  Google Scholar 

  100. Van Norstrand MD, Malinchoc M, Lindor KD 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 1997; 25: 6–11.

    CAS  PubMed  Google Scholar 

  101. Vleggaar FP, van Buuren HR . No prognostic significance of antimitochondrial antibody profile testing in primary biliary cirrhosis. Hepatogastroenterology 2004; 51: 937–940.

    PubMed  Google Scholar 

  102. Invernizzi P, Crosignani A, Battezzati PM et al. Comparison of the clinical features and clinical course of antimitochondrial antibody-positive and -negative primary biliary cirrhosis. Hepatology 1997; 25: 1090–1095.

    CAS  PubMed  Google Scholar 

  103. Krams SM, Dorshkind K, Gershwin ME . Generation of biliary lesions after transfer of human lymphocytes into severe combined immunodeficient (SCID) mice. J Exp Med 1989; 170: 1919–1930.

    CAS  PubMed  Google Scholar 

  104. Metcalf JV, Mitchison HC, Palmer JM, Jones DE, Bassendine MF, James OF . Natural history of early primary biliary cirrhosis. Lancet 1996; 348: 1399–1402.

    CAS  PubMed  Google Scholar 

  105. Invernizzi P, Selmi C, Ranftler C, Podda M, Wesierska-Gadek J . Antinuclear antibodies in primary biliary cirrhosis. Semin Liver Dis 2005, in press.

  106. Janka C, Selmi C, Gershwin ME, Will H, Sternsdorf T . Small ubiquitin-related modifiers: A novel and independent class of autoantigens in primary biliary cirrhosis. Hepatology 2005; 41: 609–616.

    CAS  PubMed  Google Scholar 

  107. Invernizzi P, Podda M, Battezzati PM et al. Autoantibodies against nuclear pore complexes are associated with more active and severe liver disease in primary biliary cirrhosis. J Hepatol 2001; 34: 366–372.

    CAS  PubMed  Google Scholar 

  108. Invernizzi P, Wesierska-Gadek J, Battezzati PM et al. Prognostic value of autoantibodies against proteins of nuclear pore complexes (anti-NPCs) in early primary biliary cirrhosis (PBC). J Hepatol 2004; 40: 159–160 (abstract).

    Google Scholar 

  109. Hashimoto E, Lindor KD, Homburger HA et al. Immunohistochemical characterization of hepatic lymphocytes in primary biliary cirrhosis in comparison with primary sclerosing cholangitis and autoimmune chronic active hepatitis. Mayo Clin Proc 1993; 68: 1049–1055.

    CAS  PubMed  Google Scholar 

  110. Van de Water J, Ansari A, Prindiville T et al. Heterogeneity of autoreactive T cell clones specific for the E2 component of the pyruvate dehydrogenase complex in primary biliary cirrhosis. J Exp Med 1995; 181: 723–733.

    CAS  PubMed  Google Scholar 

  111. Shimoda S, Nakamura M, Ishibashi H, Hayashida K, Niho Y . HLA DRB4 0101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis: evidence of molecular mimicry in human autoimmune diseases. J Exp Med 1995; 181: 1835–1845.

    CAS  PubMed  Google Scholar 

  112. 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: 1831–1840.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Shimoda S, Nakamura M, Ishibashi H et al. Molecular mimicry of mitochondrial and nuclear autoantigens in primary biliary cirrhosis. Gastroenterology 2003; 124: 1915–1925.

    CAS  PubMed  Google Scholar 

  114. Moebius U, Manns M, Hess G, Kober G, Meyer zum Büschenfelde KH, Meuer SC . T cell receptor gene rearrangements of T lymphocytes infiltrating the liver in chronic active hepatitis B and primary biliary cirrhosis (PBC): oligoclonality of PBC-derived T cell clones. Eur J Immunol 1990; 20: 889–896.

    CAS  PubMed  Google Scholar 

  115. Tsai SL, Lai MY, Chen DS . Analysis of rearranged T cell receptor (TCR) Vβ transcripts in livers of primary biliary cirrhosis: preferential Vβ usage suggests antigen-driven selection. Clin Exp Immunol 1996; 103: 99–104.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Ichiki Y, Shimoda S, Hara H et al. Analysis of T-cell receptor beta of the T-cell clones reactive to the human PDC-E2 163-176 peptide in the context of HLA-DR53 in patients with primary biliary cirrhosis. Hepatology 1997; 26: 728–733.

    CAS  PubMed  Google Scholar 

  117. Meuer SC, Moebius U, Manns MM et al. Clonal analysis of human T lymphocytes infiltrating the liver in chronic active hepatitis B and primary biliary cirrhosis. Eur J Immunol 1988; 18: 1447–1452.

    CAS  PubMed  Google Scholar 

  118. Kita H, Lian ZX, Van de Water J 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. J Exp Med 2002; 195: 113–123.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Matsumura S, Van De Water J, Kita H et al. Contribution to antimitochondrial antibody production: cleavage of pyruvate dehydrogenase complex-E2 by apoptosis-related proteases. Hepatology 2002; 35: 14–22.

    CAS  PubMed  Google Scholar 

  120. Bachmann MF, Kopf M . On the role of the innate immunity in autoimmune disease. J Exp Med 2001; 193: F47–F50.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Ballot E, Bandin O, Chazouilleres O, Johanet C, Poupon R . Immune response to lipopolysaccharide in primary biliary cirrhosis and autoimmune diseases. J Autoimmun 2004; 22: 153–158.

    CAS  PubMed  Google Scholar 

  122. 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: 409–416.

    CAS  PubMed  Google Scholar 

  123. Ide T, Sata M, Nakano H, Suzuki H, Tanikawa K . Increased serum IgM class anti-lipid A antibody and therapeutic effect of ursodeoxycholic acid in primary biliary cirrhosis. Hepatogastroenterology 1997; 44: 1569–1573.

    CAS  PubMed  Google Scholar 

  124. Masanaga T, Watanabe Y, Van de Water J et al. Induction and persistence of immune-mediated cholangiohepatitis in neonatally thymectomized mice. Clin Immunol Immunopathol 1998; 89: 141–149.

    CAS  PubMed  Google Scholar 

  125. Takii Y, Nakamura M, Ito M et al. Enhanced expression of type I interferon and toll-like receptor-3 in primary biliary cirrhosis. Lab Invest 2005; 85: 908–920.

    CAS  PubMed  Google Scholar 

  126. Kita H, Naidenko OV, Kronenberg M et al. Quantitation and phenotypic analysis of natural killer T cells in primary biliary cirrhosis using a human CD1d tetramer. Gastroenterology 2002; 123: 1031–1043.

    CAS  PubMed  Google Scholar 

  127. Hammond KJ, Kronenberg M . Natural killer T cells: natural or unnatural regulators of autoimmunity? Curr Opin Immunol 2003; 15: 683–689.

    CAS  PubMed  Google Scholar 

  128. Harada K, Isse K, Tsuneyama K, Ohta H, Nakanuma Y . Accumulating CD57+ CD3+ natural killer T cells are related to intrahepatic bile duct lesions in primary biliary cirrhosis. Liver Int 2003; 23: 94–100.

    PubMed  Google Scholar 

  129. 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: 304–312.

    CAS  PubMed  Google Scholar 

  130. Kikuchi K, Lian ZX, Kimura Y et al. Genetic polymorphisms of toll-like receptor 9 influence the immune response to CpG and contribute to hyper-IgM in primary biliary cirrhosis. J Autoimmun 2005; in press.

  131. Harada K, Van de Water J, Leung PS et al. In situ nucleic acid hybridization of cytokines in primary biliary cirrhosis: predominance of the Th1 subset. Hepatology 1997; 25: 791–796.

    CAS  PubMed  Google Scholar 

  132. Löhr HF, Schlaak JF, Gerken G, Fleischer B, Dienes HP, Meyer zum Büschenfelde KH . Phenotypical analysis and cytokine release of liver-infiltrating and peripheral blood T lymphocytes from patients with chronic hepatitis of different etiology. Liver 1994; 14: 161–166.

    PubMed  Google Scholar 

  133. Martinez OM, Villanueva JC, Gershwin ME, Krams SM . Cytokine patterns and cytotoxic mediators in primary biliary cirrhosis. Hepatology 1995; 21: 113–119.

    CAS  PubMed  Google Scholar 

  134. Shindo M, Mullin GE, Braun-Elwert L, Bergasa NV, Jones EA, James SP . Cytokine mRNA expression in the liver of patients with primary biliary cirrhosis (PBC) and chronic hepatitis B (CHB). Clin Exp Immunol 1996; 105: 254–259.

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Nagano T, Yamamoto K, Matsumoto S et al. Cytokine profile in the liver of primary biliary cirrhosis. J Clin Immunol 1999; 19: 422–427.

    CAS  PubMed  Google Scholar 

  136. Eksteen B, Grant AJ, 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: 1511–1517.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Jones DE, Palmer JM, Yeaman SJ, Kirby JA, Bassendine MF . Breakdown of tolerance to pyruvate dehydrogenase complex in experimental autoimmune cholangitis: a mouse model of primary biliary cirrhosis. Hepatology 1999; 30: 65–70.

    CAS  PubMed  Google Scholar 

  138. Sasaki M, Allina J, Odin JA et al. Autoimmune cholangitis in the SJL/J mouse is antigen non-specific. Dev Immunol 2002; 9: 103–111.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Christen U, von Herrath MG . Induction, acceleration or prevention of autoimmunity by molecular mimicry. Mol Immunol 2004; 40: 1113–1120.

    CAS  PubMed  Google Scholar 

  140. Jones DE, Palmer JM, Bennett K et al. Investigation of a mechanism for accelerated breakdown of immune tolerance to the primary biliary cirrhosis-associated autoantigen, pyruvate dehydrogenase complex. Lab Invest 2002; 82: 211–219.

    CAS  PubMed  Google Scholar 

  141. 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: 1212–1216.

    CAS  PubMed  Google Scholar 

  142. Van de Water J, Ishibashi H, Coppel RL, Gershwin ME . Molecular mimicry and primary biliary cirrhosis: premises not promises. Hepatology 2001; 33: 771–775.

    CAS  PubMed  Google Scholar 

  143. Selmi C, Balkwill DL, Invernizzi P et al. Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium. Hepatology 2003; 38: 1250–1257.

    CAS  PubMed  Google Scholar 

  144. Padgett KA, Selmi C, Kenny TP et al. Phylogenetic and immunological definition of four lipoylated proteins from Novosphingobium aromaticivorans, implications for primary biliary cirrhosis. J Autoimmun 2005; 24: 209–219.

    CAS  PubMed  Google Scholar 

  145. Fujii K, Kikuchi S, Satomi M, Ushio-Sata N, Morita N . Degradation of 17beta-estradiol by a gram-negative bacterium isolated from activated sludge in a sewage treatment plant in Tokyo, Japan. Appl Environ Microbiol 2002; 68: 2057–2060.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Shi F, Ljunggren HG, Sarvetnick N . Innate immunity and autoimmunity: from self-protection to self-destruction. Trends Immunol 2001; 22: 97–101.

    CAS  PubMed  Google Scholar 

  147. Long SA, Quan C, Van de Water J et al. Immunoreactivity of organic mimeotopes of the E2 component of pyruvate dehydrogenase: connecting xenobiotics with primary biliary cirrhosis. J Immunol 2001; 167: 2956–2963.

    CAS  PubMed  Google Scholar 

  148. Xu L, Shen Z, Guo L et al. Does a betaretrovirus infection trigger primary biliary cirrhosis? Proc Natl Acad Sci USA 2003; 100: 8454–8459.

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 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.

    CAS  PubMed  Google Scholar 

  150. Jones DE, Palmer JM, Burt AD, Walker C, Robe AJ, Kirby JA . Bacterial motif DNA as an adjuvant for the breakdown of immune self-tolerance to pyruvate dehydrogenase complex. Hepatology 2002; 36: 679–686.

    CAS  PubMed  Google Scholar 

  151. Hastings KL, Thomas C, Hubbard AK, Gandolfi AJ . Screening for antibodies associated with halothane hepatitis. Br J Anaesth 1991; 67: 722–728.

    CAS  PubMed  Google Scholar 

  152. Leung PS, Quan C, Park O et al. Immunization with a xenobiotic 6-bromohexanoate bovine serum albumin conjugate induces antimitochondrial antibodies. J Immunol 2003; 170: 5326–5332.

    CAS  PubMed  Google Scholar 

  153. Amano K, Leung PS, Xu Q et al. Xenobiotic-induced loss of tolerance in rabbits to the mitochondrial autoantigen of primary biliary cirrhosis is reversible. J Immunol 2004; 172: 6444–6452.

    CAS  PubMed  Google Scholar 

  154. Palmer JM, Robe AJ, Burt AD, Kirby JA, Jones DE . Covalent modification as a mechanism for the breakdown of immune tolerance to pyruvate dehydrogenase complex in the mouse. Hepatology 2004; 39: 1583–1592.

    CAS  PubMed  Google Scholar 

  155. Amano K, Leung PS, Rieger R 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. J Immunol 2005; 174: 5874–5883.

    CAS  PubMed  Google Scholar 

  156. Katayanagi K, Kono N, Nakanuma Y . Isolation, culture and characterization of biliary epithelial cells from different anatomical levels of the intrahepatic and extrahepatic biliary tree from a mouse. Liver 1998; 18: 90–98.

    CAS  PubMed  Google Scholar 

  157. Ueno Y, Alpini G, Yahagi K et al. Evaluation of differential gene expression by microarray analysis in small and large cholangiocytes isolated from normal mice. Liver Int 2003; 23: 449–459.

    CAS  PubMed  Google Scholar 

  158. Ayres RC, Neuberger JM, Shaw J, Joplin R, Adams DH . Intercellular adhesion molecule-1 and MHC antigens on human intrahepatic bile duct cells: effect of pro-inflammatory cytokines. Gut 1993; 34: 1245–1249.

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Dienes HP, Lohse AW, Gerken G et al. Bile duct epithelia as target cells in primary biliary cirrhosis and primary sclerosing cholangitis. Virchows Arch 1997; 431: 119–124.

    CAS  PubMed  Google Scholar 

  160. Yasoshima M, Nakanuma Y, Tsuneyama K, Van de Water J, Gershwin ME . Immunohistochemical analysis of adhesion molecules in the micro-environment of portal tracts in relation to aberrant expression of PDC-E2 and HLA-DR on the bile ducts in primary biliary cirrhosis. J Pathol 1995; 175: 319–325.

    CAS  PubMed  Google Scholar 

  161. Hansson GK, Jonasson L, Holm J, Claesson-Welsh L . Class II MHC antigen expression in the atherosclerotic plaque: smooth muscle cells express HLA-DR, HLA-DQ and the invariant gamma chain. Clin Exp Immunol 1986; 64: 261–268.

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Tsuneyama K, Harada K, Yasoshima M, Kaji K, Gershwin ME, Nakanuma Y . Expression of co-stimulatory factor B7-2 on the intrahepatic bile ducts in primary biliary cirrhosis and primary sclerosing cholangitis: an immunohistochemical study. J Pathol 1998; 186: 126–130.

    CAS  PubMed  Google Scholar 

  163. Leon MP, Bassendine MF, Wilson JL, Ali S, Thick M, Kirby JA . Immunogenicity of biliary epithelium: investigation of antigen presentation to CD4+ T cells. Hepatology 1996; 24: 561–567.

    CAS  PubMed  Google Scholar 

  164. Harada K, Ozaki S, Gershwin ME, Nakanuma Y . Enhanced apoptosis relates to bile duct loss in primary biliary cirrhosis. Hepatology 1997; 26: 1399–1405.

    CAS  PubMed  Google Scholar 

  165. Afford SC, Ahmed-Choudhury J, Randhawa S et al. CD40 activation-induced, Fas-dependent apoptosis and NF-kappaB/AP-1 signaling in human intrahepatic biliary epithelial cells. FASEB J 2001; 15: 2345–2354.

    CAS  PubMed  Google Scholar 

  166. Odin JA, Huebert RC, Casciola-Rosen L, LaRusso NF, Rosen A . Bcl-2-dependent oxidation of pyruvate dehydrogenase-E2, a primary biliary cirrhosis autoantigen, during apoptosis. J Clin Invest 2001; 108: 223–232.

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Charlotte F, L'Hermine A, Martin N et al. Immunohistochemical detection of bcl-2 protein in normal and pathological human liver. Am J Pathol 1994; 144: 460–465.

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Nakopoulou L, Stefanaki K, Vourlakou C, Manolaki N, Gakiopoulou H, Michalopoulos G . Bcl-2 protein expression in acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma. Pathol Res Pract 1999; 195: 19–24.

    CAS  PubMed  Google Scholar 

  169. Tanaka A, Nalbandian G, Leung PS et al. Mucosal immunity and primary biliary cirrhosis: presence of antimitochondrial antibodies in urine. Hepatology 2000; 32: 910–915.

    CAS  PubMed  Google Scholar 

  170. Reynoso-Paz S, Leung PS, Van De Water J et al. Evidence for a locally driven mucosal response and the presence of mitochondrial antigens in saliva in primary biliary cirrhosis. Hepatology 2000; 31: 24–29.

    CAS  PubMed  Google Scholar 

  171. Fukushima N, Nalbandian G, Van De Water J et al. Characterization of recombinant monoclonal IgA anti-PDC-E2 autoantibodies derived from patients with PBC. Hepatology 2002; 36: 1383–1392.

    CAS  PubMed  Google Scholar 

  172. Matsumura S, Van De Water J, Leung P et al. Caspase induction by IgA antimitochondrial antibody: IgA-mediated biliary injury in primary biliary cirrhosis. Hepatology 2004; 39: 1415–1422.

    CAS  PubMed  Google Scholar 

  173. Migliaccio C, Nishio A, Van de Water J et al. Monoclonal antibodies to mitochondrial E2 components define autoepitopes in primary biliary cirrhosis. J Immunol 1998; 161: 5157–5163.

    CAS  PubMed  Google Scholar 

  174. Donaldson PT . Genetics of liver disease: immunogenetics and disease pathogenesis. Gut 2004; 53: 599–608.

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Johnston DE, Kaplan MM, Miller KB, Connors CM, Milford EL . Histocompatibility antigens in primary biliary cirrhosis. Am J Gastroenterol 1987; 82: 1127–1129.

    CAS  PubMed  Google Scholar 

  176. Prochazka EJ, Terasaki PI, Park MS, Goldstein LI, Busuttil RW . Association of primary sclerosing cholangitis with HLA-DRw52a. N Engl J Med 1990; 322: 1842–1844.

    CAS  PubMed  Google Scholar 

  177. Underhill J, Donaldson P, Bray G, Doherty D, Portmann B, Williams R . Susceptibility to primary biliary cirrhosis is associated with the HLA-DR8-DQB1*0402 haplotype. Hepatology 1992; 16: 1404–1408.

    CAS  PubMed  Google Scholar 

  178. Underhill JA, Donaldson PT, Doherty DG, Manabe K, Williams R . HLA DPB polymorphism in primary sclerosing cholangitis and primary biliary cirrhosis. Hepatology 1995; 21: 959–962.

    CAS  PubMed  Google Scholar 

  179. Agarwal K, Czaja AJ, Jones DE, Donaldson PT . Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis. Hepatology 2000; 31: 49–53.

    CAS  PubMed  Google Scholar 

  180. Graham AM, Dollinger MM, Howie SE, Harrison DJ . Identification of novel alleles at a polymorphic microsatellite repeat region in the human NRAMP1 gene promoter: analysis of allele frequencies in primary biliary cirrhosis. J Med Genet 2000; 37: 150–152.

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Zappala F, Grove J, Watt FE et al. No evidence for involvement of the interleukin-10 −592 promoter polymorphism in genetic susceptibility to primary biliary cirrhosis. J Hepatol 1998; 28: 820–823.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Internal Medicine, San Paolo School of Medicine, University of Milan, Milan, Italy

    C Selmi, P Invernizzi, M Zuin & M Podda

  2. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, 95616, CA, USA

    C Selmi, M F Seldin & M E Gershwin

  3. Biochemistry and Rowe Program in Human Genetics, University of California at Davis, School of Medicine, Davis, CA, USA

    M F Seldin

Authors
  1. C Selmi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P Invernizzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Zuin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Podda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M F Seldin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M E Gershwin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M E Gershwin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Selmi, C., Invernizzi, P., Zuin, M. et al. Genes and (auto)immunity in primary biliary cirrhosis. Genes Immun 6, 543–556 (2005). https://doi.org/10.1038/sj.gene.6364248

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6364248

Keywords

This article is cited by

Search

Advanced search

Quick links