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Clinical Reviews in Allergy & Immunology
Published in: Clinical Reviews in Allergy & Immunology 3/2012

01-06-2012

Cutting-Edge Issues in Primary Biliary Cirrhosis

Authors: Marco Folci, Francesca Meda, M. Eric Gershwin, Carlo Selmi

Published in: Clinical Reviews in Allergy & Immunology | Issue 3/2012

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Abstract

Several crucial issues remain open in our understanding of primary biliary cirrhosis (PBC), an autoimmune liver disease targeting the small- and medium-sized intrahepatic bile ducts. These issues include the high tissue specificity of the autoimmune injury despite the nontraditional autoantigens found in all mitochondria recognized by PBC-associated autoantibodies, the causes of the commonly observed pruritus, and the disease etiology per se. In all these fields, there has been recent interest secondary to the use of large-scale efforts (such as genome-wide association studies) that were previously considered poorly feasible in a rare disease such as PBC as well as other intuitions. Accordingly, there are now fascinating theories to explain the onset and severity of pruritus due to elevated autotaxin levels, the peculiar apoptotic features of bile duct cells to explain the tissue specificity, and genomic and epigenetic associations contributing to disease susceptibility. We have arbitrarily chosen these four aspects as the most promising in the PBC recent literature and will provide herein a discussion of the recent data and their potential implications.
Literature
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 32:43–51PubMedCrossRef
3.
Padgett KA, Lan RY, Leung PC et al (2009) Primary biliary cirrhosis is associated with altered hepatic microRNA expression. J Autoimmun 32:246–253PubMedCrossRef
4.
European Association for the Study of the Liver (2009) EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 51:237–267CrossRef
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 116:1174–1186PubMedCrossRef
6.
Sun YG, Chen ZF (2007) A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature 448:700–703PubMedCrossRef
7.
Sun YG, Zhao ZQ, Meng XL, Yin J, Liu XY, Chen ZF (2009) Cellular basis of itch sensation. Science 325:1531–1534PubMedCrossRef
8.
Kremer AE, Martens JJ, Kulik W (2010) Lysophosphatidic acid is a potential mediator of cholestatic pruritus. Gastroenterology 139:1008–1018, 1018 e1001PubMedCrossRef
9.
Beuers U (2006) Drug insight: mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nat Clin Pract Gastroenterol Hepatol 3:318–328PubMedCrossRef
10.
Kremer AE, Beuers U, Oude-Elferink RP, Pusl T (2008) Pathogenesis and treatment of pruritus in cholestasis. Drugs 68:2163–2182PubMedCrossRef
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 158:227–233PubMedCrossRef
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 277:39436–39442PubMedCrossRef
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 267:2524–2529PubMed
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 3:582–591PubMedCrossRef
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 281:25822–25830PubMedCrossRef
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 26:5015–5022PubMedCrossRef
18.
van Meeteren LA, Moolenaar WH (2007) Regulation and biological activities of the autotaxin-LPA axis. Prog Lipid Res 46:145–160PubMedCrossRef
19.
Inoue M, Rashid MH, Fujita R, Contos JJ, Chun J, Ueda H (2004) Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling. Nat Med 10:712–718PubMedCrossRef
20.
Ueda H (2006) Molecular mechanisms of neuropathic pain-phenotypic switch and initiation mechanisms. Pharmacol Ther 109:57–77PubMedCrossRef
21.
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 64:230–243PubMedCrossRef
22.
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 10:114PubMedCrossRef
23.
Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjork HE (1997) Specific C-receptors for itch in human skin. J Neurosci 17:8003–8008PubMed
24.
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 27:10007–10014PubMedCrossRef
25.
Stander S, Schmelz M (2006) Chronic itch and pain—similarities and differences. Eur J Pain 10:473–478PubMedCrossRef
26.
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 284:216–221PubMedCrossRef
27.
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 278:18162–18169PubMedCrossRef
28.
Kanda H, Newton R, Klein R, Morita Y, Gunn MD, Rosen SD (2008) Autotaxin, an ectoenzyme that produces lysophosphatidic acid, promotes the entry of lymphocytes into secondary lymphoid organs. Nat Immunol 9:415–423PubMedCrossRef
29.
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 283:7776–7789PubMedCrossRef
30.
Cooper AB, Wu J, Lu D, Maluccio MA (2007) Is autotaxin (ENPP2) the link between hepatitis C and hepatocellular cancer? J Gastrointest Surg 11:1628–1634PubMedCrossRef
31.
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 41:616–623PubMedCrossRef
32.
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 106:2138–2146PubMedCrossRef
33.
Rubenstein M, Duvic M (2006) Cutaneous manifestations of Hodgkin's disease. Int J Dermatol 45:251–256PubMedCrossRef
34.
Gobbi PG, Attardo-Parrinello G, Lattanzio G, Rizzo SC, Ascari E (1983) Severe pruritus should be a B-symptom in Hodgkin's disease. Cancer 51:1934–1936PubMedCrossRef
35.
Balazs L, Okolicany J, Ferrebee M, Tolley B, Tigyi G (2001) Topical application of the phospholipid growth factor lysophosphatidic acid promotes wound healing in vivo. Am J Physiol Regul Integr Comp Physiol 280:R466–R472PubMed
36.
Peyruchaud O (2009) Novel implications for lysophospholipids, lysophosphatidic acid and sphingosine 1-phosphate, as drug targets in cancer. Anticancer Agents Med Chem 9:381–391PubMed
37.
38.
Botstein D, Risch N (2003) Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease. Nat Genet 33(Suppl):228–237PubMedCrossRef
39.
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 106:226–231PubMedCrossRef
40.
Hakonarson H, Grant SF, Bradfield JP et al (2007) A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene. Nature 448:591–594PubMedCrossRef
41.
Sladek R, Rocheleau G, Rung J et al (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445:881–885PubMedCrossRef
42.
(2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661–678
43.
Waring SC, Rosenberg RN (2008) Genome-wide association studies in Alzheimer disease. Arch Neurol 65:329–334PubMedCrossRef
44.
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 41:283–285PubMedCrossRef
45.
Lander ES, Linton LM, Birren B et al (2001) Initial sequencing and analysis of the human genome. Nature 409:860–921PubMedCrossRef
46.
(2003) The International HapMap Project. Nature 426:789–796
47.
Gabriel SB, Schaffner SF, Nguyen H et al (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229PubMedCrossRef
48.
Sebastiani P, Lazarus R, Weiss ST, Kunkel LM, Kohane IS, Ramoni MF (2003) Minimal haplotype tagging. Proc Natl Acad Sci USA 100:9900–9905PubMedCrossRef
49.
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 82:685–695PubMedCrossRef
50.
Redon R, Ishikawa S, Fitch KR et al (2006) Global variation in copy number in the human genome. Nature 444:444–454PubMedCrossRef
51.
McCarroll SA (2008) Extending genome-wide association studies to copy-number variation. Hum Mol Genet 17:R135–R142PubMedCrossRef
52.
McCarroll SA, Kuruvilla FG, Korn JM et al (2008) Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat Genet 40:1166–1174PubMedCrossRef
53.
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 40:1253–1260PubMedCrossRef
54.
Aitman TJ, Dong R, Vyse TJ et al (2006) Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. Nature 439:851–855PubMedCrossRef
55.
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 373:593–596PubMedCrossRef
56.
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 41:25–34PubMedCrossRef
57.
Perry GH, Dominy NJ, Claw KG et al (2007) Diet and the evolution of human amylase gene copy number variation. Nat Genet 39:1256–1260PubMedCrossRef
58.
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 41:703–707PubMedCrossRef
59.
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 40:955–962PubMedCrossRef
60.
Mathew CG (2008) New links to the pathogenesis of Crohn disease provided by genome-wide association scans. Nat Rev Genet 9:9–14PubMedCrossRef
61.
Karlsen TH, Hov JR (2010) Genetics of cholestatic liver disease in 2010. Curr Opin Gastroenterol 26:251–258PubMedCrossRef
62.
Gaya DR, Russell RK, Nimmo ER, Satsangi J (2006) New genes in inflammatory bowel disease: lessons for complex diseases? Lancet 367:1271–1284PubMedCrossRef
63.
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 39:995–999PubMedCrossRef
64.
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 18:2711–2718PubMedCrossRef
65.
Karlsen TH, Franke A, Melum E et al (2010) Genome-wide association analysis in primary sclerosing cholangitis. Gastroenterology 138:1102–1111PubMedCrossRef
66.
Hirschfield GM, Liu X, Xu C et al (2009) Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N Engl J Med 360:2544–2555PubMedCrossRef
67.
Ge D, Fellay J, Thompson AJ et al (2009) Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 461:399–401PubMedCrossRef
68.
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 83:520–528PubMedCrossRef
69.
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 41:816–819PubMedCrossRef
70.
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 48:1906–1912PubMedCrossRef
71.
Remmers EF, Plenge RM, Lee AT et al (2007) STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 357:977–986PubMedCrossRef
72.
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 10:188–191PubMedCrossRef
73.
Hunt KA, Zhernakova A, Turner G et al (2008) Newly identified genetic risk variants for celiac disease related to the immune response. Nat Genet 40:395–402PubMedCrossRef
74.
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 18:347–361PubMedCrossRef
75.
Selmi C, Gershwin ME (2009) The role of environmental factors in primary biliary cirrhosis. Trends Immunol 30:415–420PubMedCrossRef
76.
Airoldi I, Di Carlo E, Cocco C et al (2005) Lack of Il12rb2 signaling predisposes to spontaneous autoimmunity and malignancy. Blood 106:3846–3853PubMedCrossRef
77.
Pulickal AS, Hambleton S, Callaghan MJ et al (2008) Biliary cirrhosis in a child with inherited interleukin-12 deficiency. J Trop Pediatr 54:269–271PubMedCrossRef
78.
Liu X, Invernizzi P, Lu Y et al (2010) Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis. Nat Genet 42:658–660PubMedCrossRef
79.
Bouzigon E, Corda E, Aschard H et al (2008) Effect of 17q21 variants and smoking exposure in early-onset asthma. N Engl J Med 359:1985–1994PubMedCrossRef
80.
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 18:3419–3430PubMedCrossRef
81.
Wang JH, Avitahl N, Cariappa A et al (1998) Aiolos regulates B cell activation and maturation to effector state. Immunity 9:543–553PubMedCrossRef
82.
Sun J, Matthias G, Mihatsch MJ, Georgopoulos K, Matthias P (2003) Lack of the transcriptional coactivator OBF-1 prevents the development of systemic lupus erythematosus-like phenotypes in Aiolos mutant mice. J Immunol 170:1699–1706PubMed
83.
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 10:399–408PubMedCrossRef
84.
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 42:655–657PubMedCrossRef
85.
Raychaudhuri S, Remmers EF, Lee AT et al (2008) Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Nat Genet 40:1216–1223PubMedCrossRef
86.
Coenen MJ, Trynka G, Heskamp S et al (2009) Common and different genetic background for rheumatoid arthritis and coeliac disease. Hum Mol Genet 18:4195–4203PubMedCrossRef
87.
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 32:254–260PubMedCrossRef
88.
Kochi Y, Suzuki A, Yamada R, Yamamoto K (2009) Genetics of rheumatoid arthritis: underlying evidence of ethnic differences. J Autoimmun 32:158–162PubMedCrossRef
89.
Kushida T, Ueda Y, Umeda M et al (2009) Allogeneic intra-bone marrow transplantation prevents rheumatoid arthritis in SKG/Jcl mice. J Autoimmun 32:216–222PubMedCrossRef
90.
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 32:64–69PubMedCrossRef
91.
Selmi C, Mayo MJ, Bach N et al (2004) Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology 127:485–492PubMedCrossRef
92.
93.
94.
Yoshida M, Matsuyama A, Komatsu Y, Nishino N (2003) From discovery to the coming generation of histone deacetylase inhibitors. Curr Med Chem 10:2351–2358PubMedCrossRef
95.
Yang XJ (2004) The diverse superfamily of lysine acetyltransferases and their roles in leukemia and other diseases. Nucleic Acids Res 32:959–976PubMedCrossRef
96.
Gregory PD, Wagner K, Horz W (2001) Histone acetylation and chromatin remodeling. Exp Cell Res 265:195–202PubMedCrossRef
97.
98.
99.
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 370:737–749PubMedCrossRef
100.
Michan S, Sinclair D (2007) Sirtuins in mammals: insights into their biological function. Biochem J 404:1–13PubMedCrossRef
101.
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 983:84–100PubMedCrossRef
102.
103.
104.
Hewagama A, Richardson B (2009) The genetics and epigenetics of autoimmune diseases. J Autoimmun 33:3–11PubMedCrossRef
105.
106.
Baylin SB, Herman JG (2000) DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 16:168–174PubMedCrossRef
107.
108.
109.
Wysocka J, Allis CD, Coonrod S (2006) Histone arginine methylation and its dynamic regulation. Front Biosci 11:344–355PubMedCrossRef
110.
Osley MA, Fleming AB, Kao CF (2006) Histone ubiquitylation and the regulation of transcription. Results Probl Cell Differ 41:47–75PubMedCrossRef
111.
Migeon BR (2007) Why females are mosaics, X-chromosome inactivation, and sex differences in disease. Gend Med 4:97–105PubMedCrossRef
112.
Sun BK, Tsao H (2008) X-chromosome inactivation and skin disease. J Invest Dermatol 128:2753–2759PubMedCrossRef
113.
114.
Chow J, Heard E (2009) X inactivation and the complexities of silencing a sex chromosome. Curr Opin Cell Biol 21:359–366PubMedCrossRef
115.
Dementyeva EV, Shevchenko AI, Zakian SM (2009) X-chromosome upregulation and inactivation: two sides of the dosage compensation mechanism in mammals. Bioessays 31:21–28PubMedCrossRef
116.
Ezhkova E, Pasolli HA, Parker JS et al (2009) Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells. Cell 136:1122–1135PubMedCrossRef
117.
Dupont C, Armant DR, Brenner CA (2009) Epigenetics: definition, mechanisms and clinical perspective. Semin Reprod Med 27:351–357PubMedCrossRef
118.
Egger G, Liang G, Aparicio A, Jones PA (2004) Epigenetics in human disease and prospects for epigenetic therapy. Nature 429:457–463PubMedCrossRef
119.
Zhou Y, Lu Q (2008) DNA methylation in T cells from idiopathic lupus and drug-induced lupus patients. Autoimmun Rev 7:376–383PubMedCrossRef
120.
Yung RL, Richardson BC (1994) Drug-induced lupus. Rheum Dis Clin North Am 20:61–86PubMed
121.
Maciejewska-Rodrigues H, Karouzakis E, Strietholt S et al (2010) Epigenetics and rheumatoid arthritis: the role of SENP1 in the regulation of MMP-1 expression. J Autoimmun 35:15–22PubMedCrossRef
122.
Karouzakis E, Gay RE, Michel BA, Gay S, Neidhart M (2009) DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum 60:3613–3622PubMedCrossRef
123.
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 43:2634–2647PubMedCrossRef
124.
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 58:2686–2693PubMedCrossRef
125.
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 54:779–787PubMedCrossRef
126.
Liu X, Invernizzi P, Lu Y et al (2010) Genome-wide meta-analyses identifies three loci associated with primary biliary cirrhosis. Nat Genet 42(8):658–660PubMedCrossRef
127.
Invernizzi P, Selmi C, Mackay IR, Podda M, Gershwin ME (2005) From bases to basis: linking genetics to causation in primary biliary cirrhosis. Clin Gastroenterol Hepatol 3:401–410PubMedCrossRef
128.
Selmi C, Invernizzi P, Miozzo M, Podda M, Gershwin ME (2004) Primary biliary cirrhosis: does X mark the spot? Autoimmun Rev 3:493–499PubMedCrossRef
129.
Fraga MF, Ballestar E, Paz MF et al (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 102:10604–10609PubMedCrossRef
130.
131.
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)
132.
Invernizzi P, Miozzo M, Battezzati PM et al (2004) Frequency of monosomy X in women with primary biliary cirrhosis. Lancet 363:533–535PubMedCrossRef
133.
134.
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 45:659–665PubMedCrossRef
135.
Lleo A, Invernizzi P, Mackay IR, Prince H, Zhong RQ, Gershwin ME (2008) Etiopathogenesis of primary biliary cirrhosis. World J Gastroenterol 14:3328–3337PubMedCrossRef
136.
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. Hepatology 23:436–444PubMedCrossRef
137.
Leung PS, Chuang DT, Wynn RM et al (1995) Autoantibodies to BCOADC-E2 in patients with primary biliary cirrhosis recognize a conformational epitope. Hepatology 22:505–513PubMed
138.
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 138:3525–3531PubMed
139.
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 28:83–91PubMedCrossRef
140.
Agmon-Levin N, Shapira Y, Selmi C et al (2010) A comprehensive evaluation of serum autoantibodies in primary biliary cirrhosis. J Autoimmun 34:55–58PubMedCrossRef
141.
Bruggraber SF, Leung PS, Amano K et al (2003) Autoreactivity to lipoate and a conjugated form of lipoate in primary biliary cirrhosis. Gastroenterology 125:1705–1713PubMedCrossRef
142.
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 27:7–16PubMedCrossRef
143.
Gershwin ME, Mackay IR (2008) The causes of primary biliary cirrhosis: convenient and inconvenient truths. Hepatology 47:737–745PubMedCrossRef
144.
Alpini G, Lenzi R, Sarkozi L, Tavoloni N (1988) Biliary physiology in rats with bile ductular cell hyperplasia.Evidence for a secretory function of proliferated bile ductules. J Clin Invest 81:569–578PubMedCrossRef
145.
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 92:1314–1325PubMedCrossRef
146.
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 59:184–190PubMedCrossRef
147.
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 13:239–246PubMedCrossRef
148.
Fava G, Glaser S, Francis H, Alpini G (2005) The immunophysiology of biliary epithelium. Semin Liver Dis 25:251–264PubMedCrossRef
149.
Savill J, Dransfield I, Gregory C, Haslett C (2002) A blast from the past: clearance of apoptotic cells regulates immune responses. Nat Rev Immunol 2:965–975PubMedCrossRef
150.
Ravichandran KS, Lorenz U (2007) Engulfment of apoptotic cells: signals for a good meal. Nat Rev Immunol 7:964–974PubMedCrossRef
151.
152.
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 7:113–118PubMedCrossRef
153.
Salunga TL, Cui ZG, Shimoda S et al (2007) Oxidative stress-induced apoptosis of bile duct cells in primary biliary cirrhosis. J Autoimmun 29:78–86PubMedCrossRef
154.
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 27:232–241PubMedCrossRef
155.
Lleo A, Invernizzi P, Selmi C et al (2007) Autophagy: highlighting a novel player in the autoimmunity scenario. J Autoimmun 29:61–68PubMedCrossRef
156.
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 15:183–191PubMedCrossRef
157.
Mandron M, Martin H, Bonjean B, Lule J, Tartour E, Davrinche C (2008) Dendritic cell-induced apoptosis of human cytomegalovirus-infected fibroblasts promotes cross-presentation of pp 65 to CD8+ T cells. J Gen Virol 89:78–86PubMedCrossRef
158.
Nagata S, Hanayama R, Kawane K (2010) Autoimmunity and the clearance of dead cells. Cell 140:619–630PubMedCrossRef
159.
Odin JA, Huebert RC, Casciola-Rosen L, LaRusso NF, Rosen A (2001) Bcl-2-dependent oxidation of pyruvate dehydrogenase-E2, a primary biliary cirrhosis autoantigen, during apoptosis. J Clin Invest 108:223–232PubMed
160.
Combes B, Emerson SS, Flye NL et al (2005) Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis. Hepatology 42:1184–1193PubMedCrossRef
161.
Van de Water J, Gerson LB, Ferrell LD (1996) Immunohistochemical evidence of disease recurrence after liver transplantation for primary biliary cirrhosis. Hepatology 24:1079–1084PubMedCrossRef
162.
Chamulitrat W, Burhenne J, Rehlen T, Pathil A, Stremmel W (2009) Bile salt-phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide as a hepatoprotective agent. Hepatology 50:143–154PubMedCrossRef
163.
Amaral JD, Viana RJ, Ramalho RM, Steer CJ, Rodrigues CM (2009) Bile acids: regulation of apoptosis by ursodeoxycholic acid. J Lipid Res 50:1721–1734PubMedCrossRef
164.
Fadok VA, Bratton DL, Rose DM, Pearson A, Ezekewitz RA, Henson PM (2000) A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 405:85–90PubMedCrossRef
165.
166.
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 109:41–50PubMed
167.
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 179:1317–1330PubMedCrossRef
168.
Amano K, Leung PS, Rieger R et al (2005) 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 174:5874–5883PubMed
169.
Lleo A, Selmi C, Invernizzi P et al (2009) Apotopes and the biliary specificity of primary biliary cirrhosis. Hepatology 49:871–879PubMedCrossRef
170.
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 167:2956–2963PubMed
171.
Lleo A, Bowlus CL, Yang GX et al (2010) Biliary apotopes and anti-mitochondrial antibodies activate innate immune responses in primary biliary cirrhosis. Hepatology 52:987–998PubMedCrossRef
172.
Takeda K, Kojima Y, Ikejima K et al (2008) Death receptor 5 mediated-apoptosis contributes to cholestatic liver disease. Proc Natl Acad Sci USA 105:10895–10900PubMedCrossRef
Metadata
Title
Cutting-Edge Issues in Primary Biliary Cirrhosis
Authors
Marco Folci
Francesca Meda
M. Eric Gershwin
Carlo Selmi
Publication date
01-06-2012
Publisher
Humana Press Inc
Published in
Clinical Reviews in Allergy & Immunology / Issue 3/2012
Print ISSN: 1080-0549
Electronic ISSN: 1559-0267
DOI
https://doi.org/10.1007/s12016-011-8253-3

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