Cutting-Edge issues in primary biliary cirrhosis

Clinical Reviews in Allergy and Immunology

Volumn 42, Issue 3, 2012, Pages 342-354

  Folci, Marco ^a   Meda, Francesca ^a,b   Gershwin, M Eric ^c   Selmi, Carlo ^a,b  

^a HUMANITAS CLINICAL AND RESEARCH CENTER   (Italy)

^b UNIVERSITY OF MILAN   (Italy)

^c UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Apoptosis; Autoimmune cholangitis; Autotaxin; Epigenetics; GWAS

Indexed keywords

AUTOTAXIN; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; EPITOPE; LYSOPHOSPHATIDIC ACID; LYSOPHOSPHATIDYLCHOLINE; STAT4 PROTEIN; TUMOR NECROSIS FACTOR ALPHA;

APOPTOSIS; AUTOIMMUNE LIVER DISEASE; BILE DUCT; CHOLANGITIS; DISEASE PREDISPOSITION; DISEASE SEVERITY; EPIGENETICS; GENETIC ASSOCIATION; HUMAN; IMMUNOSTIMULATION; PRIMARY BILIARY CIRRHOSIS; PROGNOSIS; PROTEIN EXPRESSION; PRURITUS; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM;

ANIMALS; APOPTOSIS; AUTOANTIGENS; EPIGENESIS, GENETIC; EPITOPES; GENOME-WIDE ASSOCIATION STUDY; HUMANS; LIVER CIRRHOSIS, BILIARY; PRURITUS;

EID: 84865271115     PISSN: 10800549     EISSN: 15590267     Source Type: Journal    
DOI: 10.1007/s12016-011-8253-3     Document Type: Review

References (181)

1. Selmi C, Bowlus CL, Gershwin ME, Coppel RL (2011) Primary biliary cirrhosis. Lancet (in press)
2. Lan RY, Salunga TL, Tsuneyama K et al (2009) Hepatic IL-17 responses in human and murine primary biliary cirrhosis. J Autoimmun 32:43-51
3. Padgett KA, Lan RY, Leung PC et al (2009) Primary biliary cirrhosis is associated with altered hepatic microRNA expression. J Autoimmun 32:246-253
4. European Association for the Study of the Liver (2009) EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 51:237-267
5. Paus R, Schmelz M, Biro T, Steinhoff M (2006) Frontiers in pruritus research: scratching the brain for more effective itch therapy. J Clin Invest 116:1174-1186
6. Sun YG, Chen ZF (2007) A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature 448:700-703
7. Sun YG, Zhao ZQ, Meng XL, Yin J, Liu XY, Chen ZF (2009) Cellular basis of itch sensation. Science 325:1531-1534
8. Kremer AE, Martens JJ, KulikW (2010) Lysophosphatidic acidis a potential mediator of cholestatic pruritus. Gastroenterology 139:1008-1018, 1018 e1001
9. Beuers U (2006) Drug insight: mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nat Clin Pract Gastroenterol Hepatol 3:318-328
10. Kremer AE, Beuers U, Oude-Elferink RP, Pusl T (2008) Pathogenesis and treatment of pruritus in cholestasis. Drugs 68:2163-2182
11. Umezu-Goto M, Kishi Y, Taira A et al (2002) Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production. J Cell Biol 158:227-233
12. Tokumura A, Majima E, Kariya Y et al (2002) Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase. J Biol Chem 277:39436-39442
13. Stracke ML, Krutzsch HC, Unsworth EJ et al (1992) Identification, purification, and partial sequence analysis of autotaxin, a novel motility-stimulating protein. J Biol Chem 267:2524-2529
14. Liotta L, Schiffmann E (1988) Tumor autocrine motility factors. Important Adv Oncol 17-30
15. Mills GB, Moolenaar WH (2003) The emerging role of lysophosphatidic acid in cancer. Nat Rev Cancer 3:582-591
16. Tanaka M, Okudaira S, Kishi Y et al (2006) Autotaxin stabilizes blood vessels and is required for embryonic vasculature by producing lysophosphatidic acid. J Biol Chem 281:25822-25830
17. van Meeteren LA, Ruurs P, Stortelers C et al (2006) Autotaxin, a secreted lysophospholipase D, is essential for blood vessel formation during development. Mol Cell Biol 26:5015-5022
18. van Meeteren LA, Moolenaar WH (2007) Regulation and biological activities ofthe autotaxin-LPA axis. Prog Lipid Res 46:145-160
19. Inoue M, Rashid MH, Fujita R, Contos JJ, Chun J, Ueda H
20. Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling. Nat Med 10:712-718
21. Ueda H (2006) Molecular mechanisms of neuropathic pain-phenotypic switch and initiation mechanisms. Pharmacol Ther 109:57-77
22. Savaskan NE, Rocha L, Kotter MR et al (2007) Autotaxin (NPP-2) in the brain: cell type-specific expression and regulation during development and after neurotrauma. Cell Mol Life Sci 64:230-243
23. Zhao Y, Tong J, He D et al (2009) Role of lysophosphatidic acid receptor LPA2 in the development of allergic airway inflammation in a murine model of asthma. Respir Res 10:114
24. Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjork HE (1997) Specific C-receptors for itch in human skin. J Neurosci 17:8003-8008
25. Davidson S, Zhang X, Yoon CH, Khasabov SG, Simone DA, Giesler GJ Jr (2007) The itch-producing agents histamine and cowhage activate separate populations of primate spinothalamic tract neurons. J Neurosci 27:10007-10014
26. Stander S, Schmelz M (2006) Chronic itch and pain-similarities and differences. Eur J Pain 10:473-478
27. Jansen S, Andries M, Vekemans K, Vanbilloen H, Verbruggen A, Bollen M (2009) Rapid clearance of the circulating metastatic factor autotaxin by the scavenger receptors of liver sinusoidal endothelial cells. Cancer Lett 284:216-221
28. Ferry G, Tellier E, Try A et al (2003) Autotaxin is released from adipocytes, catalyzes lysophosphatidic acid synthesis, and activates preadipocyte proliferation. Up-regulated expression with adipocyte differentiation and obesity. J Biol Chem 278:18162-18169
29. Kanda H, Newton R, Klein R, Morita Y, Gunn MD, Rosen SD
30. Autotaxin, an ectoenzyme that produces lysophosphatidic acid, promotes the entry of lymphocytes into secondary lymphoid organs. Nat Immunol 9:415-423
31. Giganti A, Rodriguez M, Fould B et al (2008) Murine and human autotaxin alpha, beta, and gamma isoforms: gene organization, tissue distribution, and biochemical characterization. J Biol Chem 283:7776-7789
32. Cooper AB, Wu J, Lu D, Maluccio MA (2007) Is autotaxin (ENPP2) the link between hepatitis C and hepatocellular cancer? J Gastrointest Surg 11:1628-1634
33. Watanabe N, Ikeda H, Nakamura K et al (2007) Both plasma lysophosphatidic acid and serum autotaxin levels are increased in chronic hepatitis C. J Clin Gastroenterol 41:616-623
34. Baumforth KR, Flavell JR, Reynolds GM et al (2005) Induction of autotaxin by the epstein-barr virus promotes the growth and survival of hodgkin lymphoma cells. Blood 106:2138-2146
35. Rubenstein M, Duvic M (2006) Cutaneous manifestations of Hodgkin's disease. Int J Dermatol 45:251-256
36. Gobbi PG, Attardo-Parrinello G, Lattanzio G, Rizzo SC, Ascari E (1983) Severe pruritus should be a B-symptom in Hodgkin's disease. Cancer 51:1934-1936
37. Balazs L, Okolicany J, Ferrebee M, Tolley B, Tigyi G (2001) Topical application of the phospholipid growth factor lysophos-phatidic acid promotes wound healing in vivo. Am J Physiol Regul tntegr Comp Physiol 280:R466-R472
38. Peyruchaud O (2009) Novel implications for lysophospholipids, lysophosphatidic acid and sphingosine 1-phosphate, as drug targets in cancer. Anticancer Agents Med Chem 9:381-391
39. Lander ES, Schork NJ (1994) Genetic dissection of complex traits. Science 265:2037-2048
40. Botstein D, Risch N (2003) Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease. Nat Genet 33(Suppl):228-237
41. Wang Y, O'Connell JR, McArdle PF et al (2009) From the cover: whole-genome association study identifies STK39 as a hypertension susceptibility gene. Proc Natl Acad Sci USA 106:226231
42. Hakonarson H, Grant SF, Bradfield JP et al (2007) A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene. Nature 448:591-594
43. Sladek R, Rocheleau G, Rung J et al (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445:881-885
44. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661678
45. Waring SC, Rosenberg RN (2008) Genome-wide association studies in Alzheimer disease. Arch Neurol 65:329-334
46. Tregouet DA, Konig IR, Erdmann J et al (2009) Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease. Nat Genet 41:283-285
47. Lander ES, Linton LM, Birren B et al (2001) Initial sequencing and analysis of the human genome. Nature 409:860-921
48. The International HapMap Project. Nature 426:789-796
49. Gabriel SB, Schaffner SF, Nguyen H et al (2002) The structure of haplotype blocks in the human genome. Science 296:22252229
50. Sebastiani P, Lazarus R, Weiss ST, Kunkel LM, Kohane IS, Ramoni MF (2003) Minimal haplotype tagging. Proc Natl Acad Sci USA 100:9900-9905
51. Perry GH, Ben-Dor A, Tsalenko A et al (2008) The fine-scale and complex architecture of human copy-number variation. Am J Hum Genet 82:685-695
52. Redon R, Ishikawa S, Fitch KR et al (2006) Global variation in copy number in the human genome. Nature 444:444-454
53. McCarroll SA (2008) Extending genome-wide association studies to copy-number variation. Hum Mol Genet 17:R135-R142
54. McCarroll SA, Kuruvilla FG, Korn JM et al (2008) Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat Genet 40:1166-1174
55. Korn JM, Kuruvilla FG, McCarroll SA et al (2008) Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs. Nat Genet 40:1253-1260
56. Aitman TJ, Dong R, Vyse TJ et al (2006) Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. Nature 439:851-855
57. Bae JS, Cheong HS, Kim JO et al (2008) Identification of SNP markers for common CNV regions and association analysis of risk of subarachnoid aneurysmal hemorrhage in Japanese population. Biochem Biophys Res Commun 373:593-596
58. Willer CJ, Speliotes EK, Loos RJ et al (2009) Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 41:25-34
59. Perry GH, Dominy NJ, Claw KG et al (2007) Diet and the evolution of human amylase gene copy number variation. Nat Genet 39:1256-1260
60. Barrett JC, Clayton DG, Concannon P et al (2009) Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 41:703-707
61. Barrett JC, Hansoul S, Nicolae DL et al (2008) Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 40:955-962
62. Mathew CG (2008) New links to the pathogenesis of Crohn disease provided by genome-wide association scans. Nat Rev Genet 9:9-14
63. Karlsen TH, Hov JR (2010) Genetics of cholestatic liver disease in 2010. Curr Opin Gastroenterol 26:251-258
64. Gaya DR, Russell RK, Nimmo ER, Satsangi J (2006) New genes in inflammatory bowel disease: lessons for complex diseases? Lancet 367:1271-1284
65. Buch S, Schafmayer C, Volzke H et al (2007) A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease. Nat Genet 39:995-999
66. Sanna S, Busonero F, Maschio A et al (2009) Common variants in the SLCO1B3 locus are associated with bilirubin levels and unconjugated hyperbilirubinemia. Hum Mol Genet 18:2711-2718
67. Karlsen TH, Franke A, Melum E et al (2010) Genome-wide association analysis in primary sclerosing cholangitis. Gastroenterology 138:1102-1111
68. Hirschfield GM, Liu X, Xu C et al (2009) Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N Engl J Med 360:2544-2555
69. Ge D, Fellay J, Thompson AJ et al (2009) Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 461:399-401
70. Yuan X, Waterworth D, Perry JR et al (2008) Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. Am J Hum Genet 83:520-528
71. Daly AK, Donaldson PT, Bhatnagar P et al (2009) HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet 41:816-819
72. Invernizzi P, Selmi C, Poli F et al (2008) Human leukocyte antigen polymorphisms in Italian primary biliary cirrhosis: a multicenter study of 664 patients and 1992 healthy controls. Hepatology 48:1906-1912
73. Remmers EF, Plenge RM, Lee AT et al (2007) STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 357:977-986
74. Fung EY, Smyth DJ, Howson JM et al (2009) Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus. Genes Immun 10:188-191
75. Hunt KA, Zhernakova A, Turner G et al (2008) Newly identified genetic risk variants for celiac disease related to the immune response. Nat Genet 40:395-402
76. Filipe-Santos O, Bustamante J, Chapgier A et al (2006) Inborn errors of IL-12/23- and IFN-gamma-mediated immunity: molecular, cellular, and clinical features. Semin Immunol 18:347-361
77. Selmi C, Gershwin ME (2009) The role of environmental factors in primary biliary cirrhosis. Trends Immunol 30:415-420
78. Airoldi I, Di Carlo E, Cocco C et al (2005) Lack of Il12rb2 signaling predisposes to spontaneous autoimmunity and malignancy. Blood 106:3846-3853
79. Pulickal AS, Hambleton S, Callaghan MJ et al (2008) Biliary cirrhosis in a child with inherited interleukin-12 deficiency. J Trop Pediatr 54:269-271
80. Liu X, Invernizzi P, Lu Y et al (2010) Genome-wide metaanalyses identify three loci associated with primary biliary cirrhosis. Nat Genet 42:658-660
81. Bouzigon E, Corda E, Aschard H et al (2008) Effect of 17q21 variants and smoking exposure in early-onset asthma. N Engl J Med 359:1985-1994
82. Romero F, Martinez AC, Camonis J, Rebollo A (1999) Aiolos transcription factor controls cell death in T cells by regulating Bcl-2 expression and its cellular localization. EMBO J 18:34193430
83. Wang JH, Avitahl N, Cariappa A et al (1998) Aiolos regulates B cell activation and maturation to effector state. Immunity 9:543-553
84. Sun J, Matthias G, Mihatsch MJ, Georgopoulos K, Matthias P
85. Lack of the transcriptional coactivator OBF-1 prevents the development of systemic lupus erythematosus-like phenotypes in Aiolos mutant mice. J Immunol 170:1699-1706
86. Garrett-Sinha LA, Su GH, Rao S et al (1999) PU.1 and Spi-B are required for normal B cell receptor-mediated signal transduction. Immunity 10:399-408
87. Hirschfield GM, Liu X, Han Y et al (2010) Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis. Nat Genet 42:655-657
88. Raychaudhuri S, Remmers EF, Lee AT et al (2008) Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Nat Genet 40:1216-1223
89. Coenen MJ, Trynka G, Heskamp S et al (2009) Common and different genetic background for rheumatoid arthritis and coeliac disease. Hum Mol Genet 18:4195-4203
90. Cutolo M, Montagna P, Brizzolara R et al (2009) Sex hormones modulate the effects of Leflunomide on cytokine production by cultures of differentiated monocyte/macrophages and synovial macrophages from rheumatoid arthritis patients. J Autoimmun 32:254-260
91. Kochi Y, Suzuki A, Yamada R, Yamamoto K (2009) Genetics of rheumatoid arthritis: underlying evidence of ethnic differences. J Autoimmun 32:158-162
92. Kushida T, Ueda Y, Umeda M et al (2009) Allogeneic intra-bone marrow transplantation prevents rheumatoid arthritis in SKG/Jcl mice. J Autoimmun 32:216-222
93. Rojas-Villarraga A, Diaz FJ, Calvo-Paramo E et al (2009) Familial disease, the HLA-DRB1 shared epitope and anti-CCP antibodies influence time at appearance of substantial joint damage in rheumatoid arthritis. J Autoimmun 32:64-69
94. Selmi C, Mayo MJ, Bach N et al (2004) Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology 127:485-492
95. Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403:41-45
96. Turner BM (2000) Histone acetylation and an epigenetic code. Bioessays 22:836-845
97. Yoshida M, Matsuyama A, Komatsu Y, Nishino N (2003) From discovery to the coming generation of histone deacetylase inhibitors. Curr Med Chem 10:2351-2358
98. Yang XJ (2004) The diverse superfamily of lysine acetyltrans-ferases and their roles in leukemia and other diseases. Nucleic Acids Res 32:959-976
99. Gregory PD, Wagner K, Horz W (2001) Histone acetylation and chromatin remodeling. Exp Cell Res 265:195-202
100. Kalkhoven E (2004) CBP and p300: HATs for different occasions. Biochem Pharmacol 68:1145-1155
101. Roth SY, Denu JM, Allis CD (2001) Histone acetyltransferases. Annu Rev Biochem 70:81-120
102. de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB (2003) Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 370:737-749
103. Michan S, Sinclair D (2007) Sirtuins in mammals: insights into their biological function. Biochem J 404:1-13
104. Thiagalingam S, Cheng KH, Lee HJ, Mineva N, Thiagalingam A, Ponte JF (2003) Histone deacetylases: unique players in shaping the epigenetic histone code. Ann NY Acad Sci 983:84-100
105. Gardiner-Garden M, Frommer M (1987) CpG islands in vertebrate genomes. J Mol Biol 196:261-282
106. Illingworth RS, Bird AP (2009) CpG islands-'a rough guide'. FEBS Lett 583:1713-1720
107. Hewagama A, Richardson B (2009) The genetics and epigenetics of autoimmune diseases. J Autoimmun 33:3-11
108. Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16:6-21
109. Baylin SB, Herman JG (2000) DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 16:168-174
110. Bannister AJ, Kouzarides T (2005) Reversing histone methylation. Nature 436:1103-1106
111. Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693-705
112. Wysocka J, Allis CD, Coonrod S (2006) Histone arginine methylation and its dynamic regulation. Front Biosci 11:344-355
113. Osley MA, Fleming AB, Kao CF (2006) Histone ubiquitylation and the regulation of transcription. Results Probl Cell Differ 41:47-75
114. Migeon BR (2007) Why females are mosaics, X-chromosome inactivation, and sex differences in disease. Gend Med 4:97-105
115. Sun BK, Tsao H (2008) X-chromosome inactivation and skin disease. J Invest Dermatol 128:2753-2759
116. Erwin JA, Lee JT (2008) New twists in X-chromosome inactivation. Curr Opin Cell Biol 20:349-355
117. Chow J, Heard E (2009) X inactivation and the complexities of silencing a sex chromosome. Curr Opin Cell Biol 21:359-366
118. Dementyeva EV, Shevchenko AI, Zakian SM (2009) X-chromosome upregulation and inactivation: two sides of the dosage compensation mechanism in mammals. Bioessays 31:21-28
119. Ezhkova E, Pasolli HA, Parker JS et al (2009) Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells. Cell 136:1122-1135
120. Dupont C, Armant DR, Brenner CA (2009) Epigenetics: definition, mechanisms and clinical perspective. Semin Reprod Med 27:351-357
121. Egger G, Liang G, Aparicio A, Jones PA (2004) Epigenetics in human disease and prospects for epigenetic therapy. Nature 429:457-463
122. Zhou Y, Lu Q (2008) DNA methylation in T cells from idiopathic lupus and drug-induced lupus patients. Autoimmun Rev 7:376-383
123. Yung RL, Richardson BC (1994) Drug-induced lupus. Rheum Dis Clin North Am 20:61-86
124. Maciejewska-Rodrigues H, Karouzakis E, Strietholt S.*et al
125. Epigenetics and rheumatoid arthritis: the role of SENP1 in the regulation of MMP-1 expression. J Autoimmun 35:15-22
126. Karouzakis E, Gay RE, Michel BA, Gay S, Neidhart M (2009) DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum 60:3613-3622
127. Neidhart M, Rethage J, Kuchen S et al (2000) Retrotransposable L1 elements expressed in rheumatoid arthritis synovial tissue: association with genomic DNA hypomethylation and influence on gene expression. Arthritis Rheum 43:2634-2647
128. Nile CJ, Read RC, Akil M, Duff GW, Wilson AG (2008) Methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and rheumatoid arthritis. Arthritis Rheum 58:2686-2693
129. Takami N, Osawa K, Miura Y et al (2006) Hypermethylated promoter region of DR3, the death receptor 3 gene, in rheumatoid arthritis synovial cells. Arthritis Rheum 54:779-787
130. Liu X, Invernizzi P, Lu Y et al (2010) Genome-wide metaanalyses identifies three loci associated with primary biliary cirrhosis. Nat Genet 42(8):658-660
131. Invernizzi P, Selmi C, Mackay IR, Podda M, Gershwin ME
132. From bases to basis: linking genetics to causation in primary biliary cirrhosis. Clin Gastroenterol Hepatol 3:401-410
133. Selmi C, Invernizzi P, Miozzo M, Podda M, Gershwin ME
134. Primary biliary cirrhosis: does X mark the spot? Autoimmun Rev 3:493-499
135. Fraga MF, Ballestar E, Paz MF et al (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 102:10604-10609
136. Jarvinen P, Aho K (1994) Twin studies in rheumatic diseases. Semin Arthritis Rheum 24:19-28
137. Mitchell MM, Lleo A, Zammataro L et al (2011) Epigenetic investigation of variably X chromosome inactivated genes in monozygotic female twins discordant for primary biliary cirrhosis. Epigenetics 6(1
138. Invernizzi P, Miozzo M, Battezzati PM et al (2004) Frequency of monosomy X in women with primary biliary cirrhosis. Lancet 363:533-535
139. Kaplan MM, Gershwin ME (2005) Primary biliary cirrhosis. N Engl J Med 353:1261-1273
140. Oertelt S, Rieger R, Selmi C et al (2007) A sensitive bead assay for antimitochondrial antibodies: chipping away at AMA-negative primary biliary cirrhosis. Hepatology 45:659-665
141. Lleo A, Invernizzi P, Mackay IR, Prince H, Zhong RQ, Gershwin ME (2008) Etiopathogenesis of primary biliary cirrhosis. World J Gastroenterol 14:3328-3337
142. Moteki S, Leung PS, Dickson ER et al (1996) Epitope mapping and reactivity of autoantibodies to the E2 component of 2-oxoglutarate dehydrogenase complex in primary biliary cirrhosis using recombinant 2-oxoglutarate dehydrogenase complex. Hep-atology 23:436-444
143. Leung PS, Chuang DT, Wynn RM et al (1995) Autoantibodies to BCOADC-E2 in patients with primary biliary cirrhosis recognize a conformational epitope. Hepatology 22:505-513
144. Gershwin ME, Mackay IR, Sturgess A, Coppel RL (1987) Identification and specificity of a cDNA encoding the 70 kd mitochondrial antigen recognized in primary biliary cirrhosis. J Immunol 138:3525-3531
145. Ichiki Y, Selmi C, Shimoda S, Ishibashi H, Gordon SC, Gershwin ME (2005) Mitochondrial antigens as targets of cellular and humoral auto-immunity in primary biliary cirrhosis. Clin Rev Allergy Immunol 28:83-91
146. Agmon-Levin N, Shapira Y, Selmi C et al (2010) A comprehensive evaluation of serum autoantibodies in primary biliary cirrhosis. J Autoimmun 34:55-58
147. Bruggraber SF, Leung PS, Amano K et al (2003) Autoreactivity to lipoate and a conjugated form of lipoate in primary biliary cirrhosis. Gastroenterology 125:1705-1713
148. Rieger R, Leung PS, Jeddeloh MR et al (2006) Identification of 2-nonynoic acid, a cosmetic component, as a potential trigger of primary biliary cirrhosis. J Autoimmun 27:7-16
149. Gershwin ME, Mackay IR (2008) The causes of primary biliary cirrhosis: convenient and inconvenient truths. Hepatology 47:737-745
150. Alpini G, Lenzi R, Sarkozi L, Tavoloni N (1988) Biliary physiology in rats with bile ductular cell hyperplasia.Evidence
151. for a secretory function of proliferated bile ductules. J Clin Invest 81:569-578
152. Alvaro D, Cho WK, Mennone A, Boyer JL (1993) Effect of secretion on intracellular pH regulation in isolated rat bile duct epithelial cells. J Clin Invest 92:1314-1325
153. Harada K, Isse K, Nakanuma Y (2006) Interferon gamma accelerates NF-kappaB activation of biliary epithelial cells induced by Toll-like receptor and ligand interaction. J Clin Pathol 59:184-190
154. Saidman SL, Duquesnoy RJ, Zeevi A, Fung JJ, Starzl TE, Demetris AJ (1991) Recognition of major histocompatibility complex antigens on cultured human biliary epithelial cells by alloreactive lymphocytes. Hepatology 13:239-246
155. Fava G, Glaser S, Francis H, Alpini G (2005) The immuno-physiology of biliary epithelium. Semin Liver Dis 25:251-264
156. Savill J, Dransfield I, Gregory C, Haslett C (2002) A blast from the past: clearance of apoptotic cells regulates immune responses. Nat Rev Immunol 2:965-975
157. Ravichandran KS, Lorenz U (2007) Engulfment of apoptotic cells: signals for a good meal. Nat Rev Immunol 7:964-974
158. Torok NJ (2007) Apoptotic cell death takes its toll. Hepatology 46:1323-1325
159. Perniok A, Wedekind F, Herrmann M, Specker C, Schneider M (1998) High levels of circulating early apoptic peripheral blood mononuclear cells in systemic lupus erythematosus. Lupus 7:113-118
160. Salunga TL, Cui ZG, Shimoda S et al (2007) Oxidative stress-induced apoptosis of bile duct cells in primary biliary cirrhosis. J Autoimmun 29:78-86
161. Allina J, Hu B, Sullivan DM et al (2006) T cell targeting and phagocytosis of apoptotic biliary epithelial cells in primary biliary cirrhosis. J Autoimmun 27:232-241
162. Lleo A, Invernizzi P, Selmi C et al (2007) Autophagy: highlighting a novel player in the autoimmunity scenario. J Autoimmun 29:61-68
163. Schiller M, Bekeredjian-Ding I, Heyder P, Blank N, Ho AD, Lorenz HM (2008) Autoantigens are translocated into small apoptotic bodies during early stages of apoptosis. Cell Death Differ 15:183-191
164. Mandron M, Martin H, Bonjean B, Lule J, Tartour E, Davrinche C (2008) Dendritic cell-induced apoptosis of human cytomegalovirus-infected fibroblasts promotes crosspresentation of pp 65 to CD8+ T cells. J Gen Virol 89:78-86
165. Nagata S, Hanayama R, Kawane K (2010) Autoimmunity and the clearance of dead cells. Cell 140:619-630
166. Odin JA, Huebert RC, Casciola-Rosen L, LaRusso NF, Rosen A
167. Bcl-2-dependent oxidation of pyruvate dehydrogenase-E2, a primary biliary cirrhosis autoantigen, during apoptosis. J Clin Invest 108:223-232
168. Combes B, Emerson SS, Flye NL et al (2005) Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis. Hepatology 42:1184-1193
169. Van de Water J, Gerson LB, Ferrell LD (1996) Immunohisto-chemical evidence of disease recurrence after liver transplantation for primary biliary cirrhosis. Hepatology 24:1079-1084
170. Chamulitrat W, Burhenne J, Rehlen T, Pathil A, Stremmel W (2009) Bile salt-phospholipid conjugate ursodeoxycholyl lysophosphatidy-lethanolamide as a hepatoprotective agent. Hepatology 50:143-154
171. Amaral JD, Viana RJ, Ramalho RM, Steer CJ, Rodrigues CM
172. Bile acids: regulation of apoptosis by ursodeoxycholic acid. J Lipid Res 50:1721-1734
173. Fadok VA, Bratton DL, Rose DM, Pearson A, Ezekewitz RA, Henson PM (2000) A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 405:85-90
174. Henson PM (2005) Dampening inflammation. Nat Immunol 6:1179-1181
175. Huynh ML, Fadok VA, Henson PM (2002) Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation. J Clin Invest 109:41-50
176. Casciola-Rosen LA, Anhalt G, Rosen A (1994) Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes. J Exp Med 179:1317-1330
177. Amano K, Leung PS, Rieger R et al (2005) Chemical xeno-biotics and mitochondrial autoantigens in primary biliary cirrhosis: identification of antibodies against a common environmental, cosmetic, and food additive, 2-octynoic acid. J Immunol 174:5874-5883
178. Lleo A, Selmi C, Invernizzi P et al (2009) Apotopes and the biliary specificity of primary biliary cirrhosis. Hepatology 49:871-879
179. Long SA, Quan C, Van de Water J (2001) Immunoreactivity of organic mimeotopes of the E2 component of pyruvate dehydrogenase: connecting xenobiotics with primary biliary cirrhosis. J Immunol 167:2956-2963
180. Lleo A, Bowlus CL, Yang GX et al (2010) Biliary apotopes and anti-mitochondrial antibodies activate innate immune responses in primary biliary cirrhosis. Hepatology 52:987-998
181. Takeda K, Kojima Y, Ikejima K et al (2008) Death receptor 5 mediated-apoptosis contributes to cholestatic liver disease. Proc Natl Acad Sci USA 105:10895-10900