eISSN: 1896-9151
ISSN: 1734-1922
Archives of Medical Science
Current issue Archive Manuscripts accepted About the journal Special issues Editorial board Abstracting and indexing Subscription Contact Instructions for authors
SCImago Journal & Country Rank
4/2018
vol. 14
 
Share:
Share:
more
 
 
abstract:
Commentary

Therapeutic and immunological interventions in primary biliary cholangitis: from mouse models to humans

Atsushi Tanaka, Patrick S.C. Leung, Howard A. Young, M. Eric Gershwin

Arch Med Sci 2018; 14, 4: 930–940
Online publish date: 2017/10/24
View full text
Get citation
ENW
EndNote
BIB
JabRef, Mendeley
RIS
Papers, Reference Manager, RefWorks, Zotero
AMA
APA
Chicago
Harvard
MLA
Vancouver
 
Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that predominantly affects women in their fifth and sixth decades. The diagnostic hallmarks of PBC are detection of anti-mitochondrial antibodies (AMAs) and chronic non-suppurative destructive cholangitis (CNSDC) of small- and medium-sized intrahepatic bile ducts in liver histological examination [1, 2]. A significant amount of data suggests that immunological activity against small biliary epithelial cells (BECs), found histologically as portal inflammation, leads to clinical disease. In PBC, as with other autoimmune diseases, both genetic and environmental factors contribute to the development of pathology [3–8]. The first-line therapy of PBC is ursodeoxycholic acid (UDCA), although obeticholic acid (OCA) has been approved recently for patients with an incomplete response to UDCA [9–11]. Unfortunately, unlike other autoimmune diseases, no successful clinical trials of biologics have been conducted, and the mechanisms of action of UDCA and OCA are not fully understood [12–16].
The clinical phenotype and the natural history of PBC vary between patients and can have other overlapping autoimmune diseases [12, 17–19]. For example, some patients may have mild elevation of liver enzyme levels and remain asymptomatic for life. By contrast, other patients can develop signs of liver failure and rapidly decompensate despite therapy, requiring liver transplantation. A presumption is that these differences are due to genetic and environmental factors, both contributing to the development of PBC to various degrees in each patient [4, 7, 20]. Although multiple genome-wide association studies (GWASs) have been reported differences in several genes [21–24], their clinical implications and relevance remain elusive [25]. In fact, in PBC, in autoimmune diseases, including PBC, the results of GWASs have been disappointing, and efforts have been made recently for both deep sequencing and study of epigenetic events [26–30]. To understand the importance of developing a useful mouse model, other aspects of PBC such as spectra of disease and gender dominance should be considered [18, 31].

Toward solving the etiological mystery

Most autoimmune diseases, including PBC, have a strong sex bias towards women [32, 33]. Male and female immune responses differ and are affected by sex hormones, X-linked genes, and sex-specific microbiota [34–38]. Despite extensive studies with...


View full text...
references:
Kaplan MM, Gershwin ME. Primary biliary cirrhosis. New Engl J Med 2005; 353: 1261-73.
Carey EJ, Ali AH, Lindor KD. Primary biliary cirrhosis. Lancet 2015; 386: 1565-75.
Hardtke-Wolenski M, Dywicki J, Fischer K, et al. The influence of genetic predisposition and autoimmune hepatitis inducing antigens in disease development. J Autoimmun 2017; 78: 39-45.
Hirschfield GM, Siminovitch KA. Genetics in PBC: what do the “risk genes” teach us? Clin Rev Allergy Immunol 2015; 48: 176-81.
Kerstein A, Schuler S, Cabral-Marques O, et al. Environmental factor and inflammation-driven alteration of the total peripheral T-cell compartment in granulomatosis with polyangiitis. J Autoimmun 2017; 78: 79-91.
Nielsen PR, Kragstrup TW, Deleuran BW, Benros ME. Infections as risk factor for autoimmune diseases – a  nationwide study. J Autoimmun 2016; 74: 176-81.
Zhang H, Carbone M, Lleo A, Invernizzi P. Geoepidemiology, genetic and environmental risk factors for PBC. Dig Dis 2015; 33 Suppl 2: 94-101.
Marzorati S, Lleo A, Carbone M, Gershwin ME, Invernizzi P. The epigenetics of PBC: the link between genetic susceptibility and environment. Clin Res Hepatol Gastroenterol 2016; 40: 650-9.
Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ; American Association for Study of Liver D. Primary biliary cirrhosis. Hepatology 2009; 50: 291-308.
Nevens F, Andreone P, Mazzella G, et al. A  placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med 2016; 375: 631-43.
Mousa HS, Carbone M, Malinverno F, Ronca V, Gershwin ME, Invernizzi P. Novel therapeutics for primary biliary cholangitis: toward a  disease-stage-based approach. Autoimmun Rev 2016; 15: 870-6.
Yang F, Wang Q, Wang Z, et al. The natural history and prognosis of primary biliary cirrhosis with clinical features of autoimmune hepatitis. Clin Rev Allergy Immunol 2016; 50: 114-23.
Ali AH, Lindor KD. Obeticholic acid for the treatment of primary biliary cholangitis. Expert Opin Pharmacother 2016; 17: 1809-15.
de Vries E, Beuers U. Management of cholestatic disease in 2017. Liver Int 2017; 37 Suppl 1: 123-9.
Zhu C, Fuchs CD, Halilbasic E, Trauner M. Bile acids in regulation of inflammation and immunity: friend or foe? Clin Exp Rheumatol 2016; 34: 25-31.
Tang R, Wei Y, Li Y, et al. Gut microbial profile is altered in primary biliary cholangitis and partially restored after UDCA therapy. Gut 2017 in press; doi: 10.1136/gutjnl-2016-313332.
Sun Y, Zhang W, Li B, Zou Z, Selmi C, Gershwin ME. The coexistence of Sjogren’s syndrome and primary biliary cirrhosis: a  comprehensive review. Clin Rev Allergy Immunol 2015; 48: 301-15.
Lleo A, Jepsen P, Morenghi E, et al. Evolving trends in female to male incidence and male mortality of primary biliary cholangitis. Sci Rep 2016; 6: 25906.
Terziroli Beretta-Piccoli B, Guillod C, Marsteller I, et al. Primary biliary cholangitis associated with skin disorders: a  case report and review of the literature. Arch Immunol Ther Exp (Warsz) 2017 in press.
Amano K, Leung P, 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: 5874-83.
Cordell HJ, Han Y, Mells GF, et al. International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways. Nat Commun 2015; 6: 8019.
Dong M, Li J, Tang R, et al. Multiple genetic variants associated with primary biliary cirrhosis in a  Han Chinese population. Clin Rev Allergy Immunol 2015; 48: 316-21.
Hirschfield GM, Liu X, Xu C, et al. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N Engl J Med 2009; 360: 2544-55.
Nakamura M, Nishida N, Kawashima M, et al. Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population. Am J Hum Genet 2012; 91: 721-8.
Webb GJ, Hirschfield GM. Using GWAS to identify genetic predisposition in hepatic autoimmunity. J Autoimmun 2016; 66: 25-39.
Lleo A, Zhang W, Zhao M, et al. DNA methylation profiling of the X chromosome reveals an aberrant demethylation on CXCR3 promoter in primary biliary cirrhosis. Clin Epigenetics 2015; 7: 61.
Long H, Yin H, Wang L, Gershwin ME, Lu Q. The critical role of epigenetics in systemic lupus erythematosus and autoimmunity. J Autoimmun 2016; 74: 118-38.
Xie YQ, Ma HD, Lian ZX. Epigenetics and primary biliary cirrhosis: a  comprehensive review and implications for autoimmunity. Clin Rev Allergy Immunol 2016; 50: 390-403.
Pollock RA, Abji F, Gladman DD. Epigenetics of psoriatic disease: a  systematic review and critical appraisal. J Autoimmun 2017; 78: 29-38.
Shu Y, Hu Q, Long H, Chang C, Lu Q, Xiao R. Epigenetic variability of CD4+CD25+ Tregs contributes to the pathogenesis of autoimmune diseases. Clin Rev Allergy Immunol 2016; 52: 260-72.
He XS, Gershwin ME, Ansari AA. Checkpoint-based immunotherapy for autoimmune diseases – opportunities and challenges. J Autoimmun 2017; 79: 1-3.
Sun Y, Haapanen K, Li B, Zhang W, Van de Water J, Gershwin ME. Women and primary biliary cirrhosis. Clin Rev Allergy Immunol 2015; 48: 285-300.
Wang Q, Yang F, Miao Q, Krawitt EL, Gershwin ME, Ma X. The clinical phenotypes of autoimmune hepatitis: a  comprehensive review. J Autoimmun 2016; 66: 98-107.
Rubtsova K, Marrack P, Rubtsov AV. TLR7, IFNgamma, and T-bet: their roles in the development of ABCs in female-biased autoimmunity. Cell Immunol 2015; 294: 80-3.
Fish EN. The X-files in immunity: sex-based differences predispose immune responses. Nat Rev Immunol 2008; 8: 737-44.
Markle JG, Frank DN, Mortin-Toth S, et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 2013; 339: 1084-8.
Rosser EC, Mauri C. A  clinical update on the significance of the gut microbiota in systemic autoimmunity. J Autoimmun 2016; 74: 85-93.
Shamriz O, Mizrahi H, Werbner M, Shoenfeld Y, Avni O, Koren O. Microbiota at the crossroads of autoimmunity. Autoimmun Rev 2016; 15: 859-69.
Arsenijevic A, Milovanovic M, Milovanovic J, et al. Deletion of galectin-3 enhances xenobiotic induced murine primary biliary cholangitis by facilitating apoptosis of BECs and release of autoantigens. Sci Rep 2016; 6: 23348.
Choi J, Selmi C, Leung PS, Kenny TP, Roskams T, Gershwin ME. Chemokine and chemokine receptors in autoimmunity: the case of primary biliary cholangitis. Expert Rev Clin Immunol 2016; 12: 661-72.
Hisamoto S, Shimoda S, Harada K, et al. Hydrophobic bile acids suppress expression of AE2 in biliary epithelial cells and induce bile duct inflammation in primary biliary cholangitis. J Autoimmun 2016; 75: 150-60.
Lleo A, Bian Z, Zhang H, et al. Quantitation of the Rank-Rankl axis in primary biliary cholangitis. PLoS One 2016; 11: e0159612.
Ma HD, Ma WT, Liu QZ, et al. Chemokine receptor CXCR3 deficiency exacerbates murine autoimmune cholangitis by promoting pathogenic CD8+ T cell activation. J Autoimmun 2017; 78: 19-28.
Syu BJ, Loh CE, Hsueh YH, Gershwin ME, Chuang YH. Dual roles of IFN-gamma and IL-4 in the natural history of murine autoimmune cholangitis: IL-30 and implications for precision medicine. Sci Rep 2016; 6: 34884.
Hsueh YH, Chang YN, Loh CE, Gershwin ME, Chuang YH. AAV-IL-22 modifies liver chemokine activity and ameliorates portal inflammation in murine autoimmune cholangitis. J Autoimmun 2016; 66: 89-97.
Tomiyama T, Yang GX, Zhao M, et al. The modulation of co-stimulatory molecules by circulating exosomes in primary biliary cirrhosis. Cell Mol Immunol 2017; 14: 276-84.
Shuai Z, Wang J, Badamagunta M, et al. The fingerprint of antimitochondrial antibodies and the etiology of primary biliary colangitis. Hepatology 2017; 65: 1670-82.
Yang F, Yang Y, Wang Q, et al. The risk predictive values of UK-PBC and GLOBE scoring system in Chinese patients with primary biliary cholangitis: the additional effect of anti-gp210. Aliment Pharmacol Ther 2017; 45: 733-43.
Gershwin ME, Selmi C, Worman HJ, et al. Risk factors and comorbidities in primary biliary cirrhosis: a  controlled interview-based study of 1032 patients. Hepatology 2005; 42: 1194-202.
Smyk DS, Rigopoulou EI, Lleo A, et al. Immunopathogenesis of primary biliary cirrhosis: an old wives’ tale. Immun Ageing 2011; 8: 12.
Invernizzi P, Miozzo M, Battezzati PM, et al. Frequency of monosomy X in women with primary biliary cirrhosis. Lancet 2004; 363: 533-5.
Selmi C, Invernizzi P, Miozzo M, Podda M, Gershwin ME. Primary biliary cirrhosis: does X mark the spot? Autoimmun Rev 2004; 3: 493-9.
Anaya JM, Ramirez-Santana C, Alzate MA, Molano-Gonzalez N, Rojas-Villarraga A. The autoimmune ecology. Front Immunol 2016; 7: 139.
Irie J, Wu Y, Wicker LS, et al. NOD.c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis. J Exp Med 2006; 203: 1209-19.
Koarada S, Wu Y, Fertig N, et al. Genetic control of autoimmunity: protection from diabetes, but spontaneous autoimmune biliary disease in a  nonobese diabetic congenic strain. J Immunol 2004; 173: 2315-23.
Oertelt S, Lian ZX, Cheng CM, et al. Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor II dominant-negative mice. J Immunol 2006; 177: 1655-60.
Moritoki Y, Lian ZX, Lindor K, et al. B-cell depletion with anti-CD20 ameliorates autoimmune cholangitis but exacerbates colitis in transforming growth factor-beta receptor II dominant negative mice. Hepatology 2009; 50: 1893-903.
Wakabayashi K, Lian ZX, Moritoki Y, et al. IL-2 receptor alpha(-/-) mice and the development of primary biliary cirrhosis. Hepatology 2006; 44: 1240-9.
Aoki CA, Roifman CM, Lian ZX, et al. IL-2 receptor alpha deficiency and features of primary biliary cirrhosis. J Autoimmun 2006; 27: 50-3.
Salas JT, Banales JM, Sarvide S, et al. Ae2a,b-deficient mice develop antimitochondrial antibodies and other features resembling primary biliary cirrhosis. Gastroenterology 2008; 134: 1482-93.
Wakabayashi K, Lian ZX, Leung PS, et al. Loss of tolerance in C57BL/6 mice to the autoantigen E2 subunit of pyruvate dehydrogenase by a  xenobiotic with ensuing biliary ductular disease. Hepatology 2008; 48: 531-40.
Kawata K, Tsuda M, Yang GX, et al. Identification of potential cytokine pathways for therapeutic intervention in murine primary biliary cirrhosis. PloS One 2013; 8: e74225.
Dhirapong A, Yang GX, Nadler S, et al. Therapeutic effect of cytotoxic T lymphocyte antigen 4/immunoglobulin on a  murine model of primary biliary cirrhosis. Hepatology 2013; 57: 708-15.
Yang CY, Ma X, Tsuneyama K, et al. IL-12/Th1 and IL-23/Th17 biliary microenvironment in primary biliary cirrhosis: implications for therapy. Hepatology 2014; 59: 1944-53.
Wang J, Yang GX, Tsuneyama K, Gershwin ME, Ridgway WM, Leung PS. Animal models of primary biliary cirrhosis. Semin Liver Dis 2014; 34: 285-96.
Zhang MA, Rego D, Moshkova M, et al. Peroxisome proliferator-activated receptor (PPAR)alpha and -gamma regulate IFNgamma and IL-17A production by human T cells in a  sex-specific way. Proc Natl Acad Sci USA 2012; 109: 9505-10.
Pelfrey CM, Cotleur AC, Lee JC, Rudick RA. Sex differences in cytokine responses to myelin peptides in multiple sclerosis. J Neuroimmunol 2002; 130: 211-23.
Hodge DL, Berthet C, Coppola V, et al. IFN-gamma AU-rich element removal promotes chronic IFN-gamma expression and autoimmunity in mice. J Autoimmun 2014; 53: 33-45.
Bae HR, Leung PS, Tsuneyama K, et al. Chronic expression of interferon-gamma leads to murine autoimmune cholangitis with a  female predominance. Hepatology 2016; 64: 1189-201.
Hirschfield GM, Gershwin ME, Strauss R, et al. Ustekinumab for patients with primary biliary cholangitis who have an inadequate response to ursodeoxycholic acid: a  proof-of-concept study. Hepatology 2016; 64: 189-99.
Beuers U, Hohenester S, de Buy Wenniger LJ, Kremer AE, Jansen PL, Elferink RP. The biliary HCO(3)(-) umbrella: a  unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies. Hepatology 2010; 52: 1489-96.
Beuers U, Gershwin ME, Gish RG, et al. Changing nomenclature for PBC: from ‘cirrhosis’ to ‘cholangitis’. Hepatology 2015; 62: 1620-2.
Trauner M, Fuchs CD, Halilbasic E, Paumgartner G. New therapeutic concepts in bile acid transport and signaling for management of cholestasis. Hepatology 2017; 65: 1393-404.
Myers RP, Swain MG, Lee SS, Shaheen AA, Burak KW. B-cell depletion with rituximab in patients with primary biliary cirrhosis refractory to ursodeoxycholic acid. Am J Gastroenterol 2013; 108: 933-41.
Tsuda M, Moritoki Y, Lian ZX, et al. Biochemical and immunologic effects of rituximab in patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Hepatology 2012; 55: 512-21.
Suresh T, Lee LX, Joshi J, Barta SK. New antibody approaches to lymphoma therapy. J Hematol Oncol 2014; 7: 58.
Shimoda S, Harada K, Niiro H, et al. CX3CL1 (fractalkine): a  signpost for biliary inflammation in primary biliary cirrhosis. Hepatology 2010; 51: 567-75.
Nanki T, Imai T, Kawai S. Fractalkine/CX3CL1 in rheumatoid arthritis. Mod Rheumatol 2017; 27: 392-7.
Pellicciari R, Fiorucci S, Camaioni E, et al. 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a  potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem 2002; 45: 3569-72.
Trivedi PJ, Hirschfield GM, Gershwin ME. Obeticholic acid for the treatment of primary biliary cirrhosis. Expert Rev Clin Pharmacol 2016; 9: 13-26.
Samur S, Klebanoff M, Banken R, et al. Long-term clinical impact and cost-effectiveness of obeticholic acid for the treatment of primary biliary cholangitis. Hepatology 2017; 65: 920-8.
Honda A, Ikegami T, Nakamuta M, et al. Anticholestatic effects of bezafibrate in patients with primary biliary cirrhosis treated with ursodeoxycholic acid. Hepatology 2013; 57: 1931-41.
Iwasaki S, Tsuda K, Ueta H, et al. Bezafibrate may have a  beneficial effect in pre-cirrhotic primary biliary cirrhosis. Hepatol Res 1999; 16: 12-8.
Tanaka A, Hirohara J, Nakanuma Y, Tsubouchi H, Takikawa H. Biochemical responses to bezafibrate improve long-term outcome in asymptomatic patients with primary biliary cirrhosis refractory to UDCA. J Gastroenterol 2015; 50: 675-82.
Hosonuma K, Sato K, Yamazaki Y, et al. A  prospective randomized controlled study of long-term combination therapy using ursodeoxycholic acid and bezafibrate in patients with primary biliary cirrhosis and dyslipidemia. Am J Gastroenterol 2015; 110: 423-31.
Cheung AC, Lapointe-Shaw L, Kowgier M, et al. Combined ursodeoxycholic acid (UDCA) and fenofibrate in primary biliary cholangitis patients with incomplete UDCA response may improve outcomes. Aliment Pharmacol Ther 2016; 43: 283-93.
Dohmen K, Mizuta T, Nakamuta M, Shimohashi N, Ishibashi H, Yamamoto K. Fenofibrate for patients with asymptomatic primary biliary cirrhosis. World J Gastroenterol 2004; 10: 894-8.
Hegade VS, Khanna A, Walker LJ, Wong LL, Dyson JK, Jones DE. Long-term fenofibrate treatment in primary biliary cholangitis improves biochemistry but not the UK-PBC risk score. Dig Dis Sci 2016; 61: 3037-44.
Hofmann AF. Inappropriate ileal conservation of bile acids in cholestatic liver disease: homeostasis gone awry. Gut 2003; 52: 1239-41.
Hegade VS, Kendrick SF, Dobbins RL, et al. Effect of ileal bile acid transporter inhibitor GSK2330672 on pruritus in primary biliary cholangitis: a  double-blind, randomised, placebo-controlled, crossover, phase 2a study. Lancet 2017; 389: 1114-3.
FEATURED PRODUCTS
Quick links
© 2018 Termedia Sp. z o.o. All rights reserved.
Developed by Bentus.
PayU - płatności internetowe