Play all audios:
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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your
institution Subscribe to this journal Receive 6 digital issues and online access to articles $119.00 per year only $19.83 per issue Learn more Buy this article * Purchase on SpringerLink *
Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional
subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS DISSECTING CAUSAL RELATIONSHIPS BETWEEN PRIMARY BILIARY CHOLANGITIS AND EXTRAHEPATIC
AUTOIMMUNE DISEASES BASED ON MENDELIAN RANDOMIZATION Article Open access 21 May 2024 RISK OF HEPATOCELLULAR CARCINOMA AND CIRRHOSIS DECOMPENSATION IN A LARGE RETROSPECTIVE COHORT OF
CIRRHOTIC PATIENTS WITH AUTOIMMUNE HEPATITIS Article Open access 16 April 2025 _MARC1_ P.A165T VARIANT IS ASSOCIATED WITH DECREASED MARKERS OF LIVER INJURY AND ENHANCED ANTIOXIDANT CAPACITY
IN AUTOIMMUNE HEPATITIS Article Open access 23 December 2021 REFERENCES * Talwalkar JA, Lindor KD . Primary biliary cirrhosis. _Lancet_ 2003; 362: 53–61. CAS PubMed Google Scholar * 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 * 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 * Cardon LR,
Bell JI . Association study designs for complex diseases. _Nat Rev Genet_ 2001; 2: 91–99. Article CAS PubMed Google Scholar * 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 * 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 * 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 * 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 * 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 * Bach N, Schaffner F . Familial primary biliary cirrhosis. _J
Hepatol_ 1994; 20: 698–701. CAS PubMed Google Scholar * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * Chohan MR . Primary biliary cirrhosis in twin sisters.
_Gut_ 1973; 14: 213–214. CAS PubMed PubMed Central Google Scholar * 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 * 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 * Selmi C, Gershwin ME . Bacteria and human autoimmunity: the case of primary biliary cirrhosis. _Curr Opin
Rheumatol_ 2004; 16: 406–410. PubMed Google Scholar * 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 * McCluskey J, Peh CA . The human leucocyte antigens and clinical medicine: an overview. _Rev Immunogenet_ 1999; 1: 3–20. CAS PubMed Google Scholar
* 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 * 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 * 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 * 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 *
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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 *
Donaldson PT . TNF gene polymorphisms in primary biliary cirrhosis: a critical appraisal. _J Hepatol_ 1999; 31: 366–368. CAS PubMed Google Scholar * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 *
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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * Vong S, Bell BP . Chronic liver disease mortality in the United States, 1990-1998. _Hepatology_ 2004; 39: 476–483. PubMed Google Scholar * 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 *
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 * 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 * 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 * 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 * Corpechot C, Poupon R . Promoter polymorphism of the CD14 endotoxin receptor gene and primary biliary
cirrhosis. _Hepatology_ 2002; 35: 242–243. PubMed Google Scholar * 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 * 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 * 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 * 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 * 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 * Ranke MB, Saenger P . Turner's syndrome. _Lancet_ 2001; 358: 309–314. CAS PubMed Google Scholar * 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 * 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 * 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 * Kaplan MM, Bianchi DW . Primary biliary cirrhosis: for want of an X chromosome? _Lancet_ 2004; 363: 505–506. PubMed Google Scholar * 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 * Lambert N, Nelson JL . Microchimerism in autoimmune disease:
more questions than answers? _Autoimmun Rev_ 2003; 2: 133–139. CAS PubMed Google Scholar * 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 * 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 * 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 * 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. * 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 * 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 * 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 * 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 * 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 *
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 * 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 * 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 * 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 * 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 * 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 * 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 * Invernizzi P, Selmi C, Ranftler C, Podda M,
Wesierska-Gadek J . Antinuclear antibodies in primary biliary cirrhosis. _Semin Liver Dis_ 2005, in press. * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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
* 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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. * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * Christen U, von Herrath MG . Induction, acceleration or prevention of autoimmunity by molecular mimicry. _Mol Immunol_ 2004; 40:
1113–1120. CAS PubMed Google Scholar * 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 * 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 * 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 * 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 *
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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 *
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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * 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 * Donaldson PT . Genetics of liver
disease: immunogenetics and disease pathogenesis. _Gut_ 2004; 53: 599–608. CAS PubMed PubMed Central Google Scholar * 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 * 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 * 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 * 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 * 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 * 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 * 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 * Division of Internal Medicine, San Paolo School of Medicine, University of Milan, Milan, Italy C Selmi, P
Invernizzi, M Zuin & M Podda * Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, 95616, CA, USA C Selmi, M F Seldin & M E Gershwin
* Biochemistry and Rowe Program in Human Genetics, University of California at Davis, School of Medicine, Davis, CA, USA M F Seldin Authors * C Selmi View author publications You can also
search for this author inPubMed Google Scholar * P Invernizzi View author publications You can also search for this author inPubMed Google Scholar * M Zuin View author publications You can
also search for this author inPubMed Google Scholar * M Podda View author publications You can also search for this author inPubMed Google Scholar * M F Seldin View author publications You
can also search for this author inPubMed Google Scholar * M E Gershwin View author publications You can also search for this author inPubMed 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: 17 June 2005 * Accepted: 17 June 2005 * Published: 21 July
2005 * Issue Date: 01 October 2005 * DOI: https://doi.org/10.1038/sj.gene.6364248 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable
link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * autoimmune
cholangitis * complex disease * association study * environmental factors * pathogenesis