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Medford A, Childs J, Little A, Chakraborty S, Baiocchi L, Alpini G, Glaser S. Emerging Therapeutic Strategies in The Fight Against Primary Biliary Cholangitis. J Clin Transl Hepatol 2023; 11:949-957. [PMID: 37408803 PMCID: PMC10318288 DOI: 10.14218/jcth.2022.00398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 11/29/2022] [Accepted: 01/04/2023] [Indexed: 07/03/2023] Open
Abstract
The liver has a vital role in many metabolic and regulatory processes in the body. Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is a chronic cholestatic autoimmune disease of the intrahepatic bile ducts associated with loss of tolerance to mitochondrial antigens. At this time there is no definitive cure for PBC; however, ursodeoxycholic acid (UDCA) has been shown to reduce injury when administered as the first line of treatment. Additional therapeutics can be given concurrently or as an alternative to UDCA to manage the symptoms and further curb disease progression. Currently, a liver transplant is the only potentially curative option when the patient has developed end-stage liver disease or intractable pruritus. This review aims to delineate the pathogenesis of primary biliary cholangitis and shed light on current therapeutic strategies in the treatment of PBC.
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Affiliation(s)
- Abigail Medford
- Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, TX, USA
| | - Jonathan Childs
- Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, TX, USA
| | - Ashleigh Little
- Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, TX, USA
| | - Sanjukta Chakraborty
- Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, TX, USA
| | | | - Gianfranco Alpini
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, TX, USA
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Proulx J, Ghaly M, Park IW, Borgmann K. HIV-1-Mediated Acceleration of Oncovirus-Related Non-AIDS-Defining Cancers. Biomedicines 2022; 10:biomedicines10040768. [PMID: 35453518 PMCID: PMC9024568 DOI: 10.3390/biomedicines10040768] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/22/2022] [Accepted: 03/22/2022] [Indexed: 11/25/2022] Open
Abstract
With the advent of combination antiretroviral therapy (cART), overall survival has been improved, and the incidence of acquired immunodeficiency syndrome (AIDS)-defining cancers has also been remarkably reduced. However, non-AIDS-defining cancers among human immunodeficiency virus-1 (HIV-1)-associated malignancies have increased significantly so that cancer is the leading cause of death in people living with HIV in certain highly developed countries, such as France. However, it is currently unknown how HIV-1 infection raises oncogenic virus-mediated cancer risks in the HIV-1 and oncogenic virus co-infected patients, and thus elucidation of the molecular mechanisms for how HIV-1 expedites the oncogenic viruses-triggered tumorigenesis in the co-infected hosts is imperative for developing therapeutics to cure or impede the carcinogenesis. Hence, this review is focused on HIV-1 and oncogenic virus co-infection-mediated molecular processes in the acceleration of non-AIDS-defining cancers.
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Hu C, Li Y, Liu Y, Lai Y, Ding L. A Sensitive HPLC-MS/MS Method for Determination of Obeticholic Acid in Human Plasma: Application to a Pharmacokinetic Study in Healthy Volunteers. J Chromatogr Sci 2021; 60:545-550. [PMID: 34313291 DOI: 10.1093/chromsci/bmab098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Indexed: 11/14/2022]
Abstract
A rapid and sensitive LC-MS/MS method was developed and fully validated for the determination of obeticholic acid in human plasma. Glimepiride was used as internal standard. For this method, liquid-liquid extraction was performed to extract analyte from the plasma samples. Chromatographic separation was performed on a C18 (2.1 × 50 mm, 2.7 μm, Agilent) column with isocratic elution using water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid at a flow rate of 0.4 mL/min. The mass detection was performed in negative mode. The precursor-product ion pairs for MRM were m/z 465.3 → 419.3 for obeticholic acid and m/z 489.3 → 224.8 for the IS. The method exhibited great linearity over the concentration range of 0.150-100 ng/mL for obeticholic acid. The sensitivity, linearity, accuracy, precision, recovery, matrix effect and stability of this method were all within the acceptable limits. The method was successfully validated and applied to the pharmacokinetic studies in healthy Chinese volunteers after a single oral dose administration of obeticholic acid tablets of 10 mg, and the pharmacokinetic characteristics of obeticholic acid in human were reported for the first time.
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Affiliation(s)
- Can Hu
- College of Pharmacy and Chemistry, Dali University, Dali 671000, China
- Nanjing Clinical Tech Laboratories Inc., Nanjing 211000, China
| | - Ya Li
- Nanjing Clinical Tech Laboratories Inc., Nanjing 211000, China
| | - Yujie Liu
- Nanjing Chia Tai Tianqing Pharmaceutical Co., Ltd, Nanjing 210009, China
| | - Yong Lai
- College of Pharmacy and Chemistry, Dali University, Dali 671000, China
| | - Li Ding
- Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China
- Nanjing Clinical Tech Laboratories Inc., Nanjing 211000, China
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Abstract
PURPOSE OF REVIEW Primary biliary cholangitis (PBC) is characterized by autoimmune damage of intrahepatic bile ducts associated with a loss of tolerance to mitochondrial antigens. PBC etiopathogenesis is intriguing because of different perplexing features, namely: a) although mitochondria are present in all cell types and tissues, the damage is mainly restricted to biliary epithelial cells (BECs); b) despite being an autoimmune disorder, it does not respond to immunosuppressive drugs but rather to ursodeoxycholic acid, a bile salt that induces HCO3- rich choleresis; c) the overwhelming female preponderance of the disease remains unexplained. Here we present an etiopathogenic view of PBC which sheds light on these puzzling facts of the disease. RECENT FINDINGS PBC develops in patients with genetic predisposition to autoimmunity in whom epigenetic mechanisms silence the Cl-/HCO3- exchanger AE2 in both cholangiocytes and lymphoid cells. Defective AE2 function can produce BECs damage as a result of decreased biliary HCO3- secretion with disruption of the protective alkaline umbrella that normally prevents the penetration of toxic apolar bile salts into cholangiocytes. AE2 dysfunction also causes increased intracellular pH (pHi) in cholangiocytes, leading to the activation of soluble adenylyl cyclase, which sensitizes BECs to bile salt-induced apoptosis. Recently, mitophagy was found to be inhibited by cytosolic alkalization and stimulated by acidification. Accordingly, we propose that AE2 deficiency may disturb mitophagy in BECs, thus, promoting the accumulation of defective mitochondria, oxidative stress and presentation of mitochondrial antigens to the immune cells. As women possess a more acidic endolysosomal milieu than men, mitophagy might be more affected in women in an AE2-defective background. Apart from affecting BECs function, AE2 downregulation in lymphocytes may also contribute to alter immunoregulation facilitating autoreactive T-cell responses. SUMMARY PBC can be considered as a disorder of Cl-/HCO3- exchange in individuals with genetic predisposition to autoimmunity.
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Affiliation(s)
- Jesús Prieto
- Center for Applied Medical Research (Centro de Investigación Médica Aplicada, CIMA), University of Navarra, Pamplona
| | - Jesus M. Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute – Donostia University Hospital – University of the Basque Country (UPV/EHU), San Sebastian
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, ‘Instituto de Salud Carlos III’)
- IKERBASQUE, Basque Foundation for Science, Bilbao
| | - Juan F. Medina
- Unit of Medical Training, School of Medicine, University of Navarra, Pamplona, Spain
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Outcomes of Liver Transplant Candidates with Primary Biliary Cholangitis: The Data from the Scientific Registry of Transplant Recipients. Dig Dis Sci 2020; 65:416-422. [PMID: 31451982 DOI: 10.1007/s10620-019-05786-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 08/07/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is progressive and can cause end-stage liver disease necessitating a liver transplant (LT). PBC patients may be disadvantaged on LT waitlist due to MELD-based priority listing or other factors. AIM The aim was to assess waitlist duration, waitlist mortality, and post-LT outcomes of PBC patients. METHODS The Scientific Registry of Transplant Recipients data for 1994-2016 was utilized. Adult patients with PBC without hepatocellular carcinoma (HCC) were selected. Their clinico-demographic parameters and waitlist and post-transplant outcomes were compared to those of patients with hepatitis C (HCV) without HCC. RESULTS Out of 223,391 listings for LT in 1994-2016, 8133 (3.6%) was for PBC without HCC. Mean age was 55.5 years, 76.9% white, 86.2% female, mean MELD score 21, 6.6% retransplants. There were 52,017 patients with hepatitis C included for comparison. The mean waitlist mortality was 17.9% for PBC and 17.6% for HCV (p > 0.05). The average transplantation rate was 57.7% for PBC and 53.3% for HCV (p < 0.0001), while waitlist dropout (death or removal due to deterioration) rate was 25.0% for PBC and 25.4% for HCV (p > 0.05). There was no significant difference in median waiting duration till transplantation between PBC patients and HCV after 2002 (103 vs. 95 days, p > 0.05). Post-LT mortality and graft loss rates were significantly lower in PBC than in HCV patients (all p < 0.02). CONCLUSIONS Despite no evidence of impaired waitlist outcomes and favorable post-transplant survival in patients with PBC, there is still a high waitlist dropout rate suggesting the presence of an unmet need for effective treatment.
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Madir A, Božin T, Mikolašević I, Milić S, Štimac D, Mijić M, Filipec Kanižaj T, Biloglav Z, Lucijanić M, Lucijanić I, Grgurević I. Epidemiological and clinical features of primary biliary cholangitis in two Croatian regions: a retrospective study. Croat Med J 2019; 60:494-502. [PMID: 31894914 PMCID: PMC6952898 DOI: 10.3325/cmj.2019.60.494] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 11/07/2019] [Indexed: 01/03/2023] Open
Abstract
AIM To assess the measures of disease frequency and determine the clinical features of primary biliary cholangitis (PBC) in two Croatian regions. METHODS Databases of two tertiary hospitals, one located in the continental and one in the coastal region of Croatia, were retrospectively searched for PBC patients diagnosed from 2007 to 2018. Epidemiologic data analysis was restricted to patients from each hospital's catchment area. We analyzed factors related to response to therapy and event-free survival (EFS), defined as absence of ascites, variceal bleeding, encephalopathy, hepatocellular carcinoma, liver transplantation (LT), or death. In addition, we determined clinical and demographic data of transplanted PBC patients. RESULTS Out of 83 PBC patients, 86.7% were female, with a median age at diagnosis of 55 years. Average PBC incidence for the 11-year period was 0.79 and 0.89 per 100000 population, whereas the point prevalence on December 31, 2017 was 11.5 and 12.5 in the continental and coastal region, respectively. Of 76 patients with complete medical records, 21% had an advanced disease stage, 31.6% had an associated autoimmune condition, and all received ursodeoxycholic acid. EFS rate at 5 years was 95.8%. In an age and sex-adjusted multivariate Cox regression model, the only factor significantly associated with inferior EFS was no response to therapy (HR=18.4; P=0.018). Of all Croatian patients who underwent LT, 3.8% had PBC, with the survival rate at 5 years after LT of 93.4%. CONCLUSION This study gives pioneer insights into the epidemiological and clinical data on PBC in Croatia, thus complementing the PBC map of Southeast Europe.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Ivica Grgurević
- Ivica Grgurević, Department of Gastroenterology, Hepatology and Clinical Nutrition, Department of Medicine, University Hospital Dubrava, Avenija Gojka Šuška 6, Zagreb 10 000, Croatia,
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Immunological abnormalities in patients with primary biliary cholangitis. Clin Sci (Lond) 2019; 133:741-760. [DOI: 10.1042/cs20181123] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2018] [Revised: 02/28/2019] [Accepted: 03/05/2019] [Indexed: 12/13/2022]
Abstract
Abstract
Primary biliary cholangitis (PBC), an autoimmune liver disease occurring predominantly in women, is characterized by high titers of serum anti-mitochondrial antibodies (AMAs) and progressive intrahepatic cholestasis. The immune system plays a critical role in PBC pathogenesis and a variety of immune cell subsets have been shown to infiltrate the portal tract areas of patients with PBC. Amongst the participating immune cells, CD4 T cells are important cytokine-producing cells that foster an inflammatory microenvironment. Specifically, these cells orchestrate activation of other immune cells, including autoreactive effector CD8 T cells that cause biliary epithelial cell (BEC) injury and B cells that produce large quantities of AMAs. Meanwhile, other immune cells, including dendritic cells (DCs), natural killer (NK) cells, NKT cells, monocytes, and macrophages are also important in PBC pathogenesis. Activation of these cells initiates and perpetuates bile duct damage in PBC patients, leading to intrahepatic cholestasis, hepatic damage, liver fibrosis, and eventually cirrhosis or even liver failure. Taken together, the body of accumulated clinical and experimental evidence has enhanced our understanding of the immunopathogenesis of PBC and suggests that immunotherapy may be a promising treatment option. Herein, we summarize current knowledge regarding immunological abnormalities of PBC patients, with emphasis on underlying pathogenic mechanisms. The differential immune response which occurs over decades of disease activity suggests that different therapies may be needed at different stages of disease.
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Asuri S, McIntosh S, Taylor V, Rokeby A, Kelly J, Shumansky K, Field LL, Yoshida EM, Arbour L. Primary Biliary Cholangitis in British Columbia First Nations: Clinical features and discovery of novel genetic susceptibility loci. Liver Int 2018; 38:940-948. [PMID: 29297981 DOI: 10.1111/liv.13686] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 12/21/2017] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disease characterized by destruction of intrahepatic bile ducts, portal inflammation and cirrhosis. Although rare in most populations, it is prevalent and often familial in British Columbia First Nations. We hypothesized that major genetic factors increased the risk in First Nations. METHODS In all, 44 individuals with Primary Biliary Cholangitis and 61 unaffected relatives from 32 First Nations families participated. Family history and co-morbidities were documented. Medical records were reviewed and available biopsies were re-reviewed by our team pathologist. Genotyping was performed on DNA from 36 affected persons and 27 unaffected relatives using the Affymetrix Human Mapping 500K Array Set. MERLIN software was used to carry out multipoint parametric and nonparametric linkage analysis. Candidate genes were identified and entered into InnateDB and KEGG software to identify potential pathways affecting pathogenesis. RESULTS In all, 34% of families were multiplex. Fifty per cent of cases and 33% of unaffected relatives reported other autoimmune disease. Three genomic regions (9q21, 17p13 and 19p13) produced LOD scores of 2.3 or greater suggestive of linkage, but no single linkage peak reached statistical significance. Candidate genes identified in the three regions suggested involvement of IL17, NFκB, IL6, JAK-STAT, IFNγ and TGFβ immune signalling pathways. Specifically, four genes-ACT1, PIN1, DNMT1 and NTN1-emerged as having roles in these pathways that may influence Primary Biliary Cholangitis pathogenesis. CONCLUSIONS Our whole genome linkage study results reflect the multifactorial nature of Primary Biliary Cholangitis, support previous studies suggesting signalling pathway involvement and identify new candidate genes for consideration.
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Affiliation(s)
- Sirisha Asuri
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - Sarah McIntosh
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - Valerie Taylor
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | - Andrew Rokeby
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | - James Kelly
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Karey Shumansky
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - Lanora Leigh Field
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - Eric M Yoshida
- Division of Gastroenterology, University of British Columbia, Vancouver, BC, Canada
| | - Laura Arbour
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.,Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
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Chen G, Mao W, Wu SQ, Wang Y, Ji GY, Zhang MM, Liu QQ, He JQ. Rs7574865 polymorphism of STAT4 and risk of anti-tuberculosis drug-induced hepatotoxicity in Chinese Han. Genes Genomics 2017. [DOI: 10.1007/s13258-017-0592-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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10
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Shin S, Moh IH, Woo YS, Jung SW, Kim JB, Park JW, Suk KT, Kim HS, Hong M, Park SH, Lee MS. Evidence from a familial case suggests maternal inheritance of primary biliary cholangitis. World J Gastroenterol 2017; 23:7191-7197. [PMID: 29093628 PMCID: PMC5656467 DOI: 10.3748/wjg.v23.i39.7191] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 08/23/2017] [Accepted: 09/05/2017] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cholangitis (PBC) is an idiopathic autoimmune liver disease characterized by chronic cholestasis and destruction of the intrahepatic bile ducts. Similar to other autoimmune diseases, the pathogenesis of PBC is considered to be a complex etiologic phenomenon involving the interaction of genetic and environmental factors. Although a number of common variants associated with PBC have been reported from genome-wide association studies, a precise genetic mechanism underlying PBC has yet to be identified. Here, we describe a family with four sisters who were diagnosed with PBC. After the diagnosis of the index patient who was in an advanced stage of PBC, one sister presented with acute hepatitis, and two sisters were subsequently diagnosed with PBC. Notably, one half-sister with a different mother exhibited no evidence of PBC following clinical investigation. Our report suggests the possibility of a maternal inheritance of PBC susceptibility. Moreover, judging from the high-penetrance of the disease observed in this family, we inferred that a pathogenic genetic variant might be the cause of PBC development. We describe a family that exhibited diverse clinical presentations of PBC that included asymptomatic stages with mildly increased liver enzyme levels and symptomatic stages with acute hepatitis or advanced liver fibrosis. Additional studies are needed to investigate the role of genetic factors in the pathogenesis of this rare autoimmune disease.
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Affiliation(s)
- Saeam Shin
- Department of Laboratory Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07441, South Korea
| | - In Ho Moh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07441, South Korea
| | - Young Sik Woo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07441, South Korea
| | - Sung Won Jung
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07441, South Korea
| | - Jin Bae Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07441, South Korea
| | - Ji Won Park
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07441, South Korea
| | - Ki Tae Suk
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07441, South Korea
| | - Hyoung Su Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07441, South Korea
| | - Mineui Hong
- Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07441, South Korea
| | - Sang Hoon Park
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07441, South Korea
| | - Myung Seok Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07441, South Korea
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Ali AH, Carey EJ, Lindor KD. The management of autoimmunity in patients with cholestatic liver diseases. Expert Rev Gastroenterol Hepatol 2016; 10:73-91. [PMID: 26523975 DOI: 10.1586/17474124.2016.1095088] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cholestatic liver diseases are rare diseases that often lead to cirrhosis and its consequent complications. In addition to liver-related morbidity, patients with cholestatic liver diseases often suffer from autoimmune diseases that affect several organs and tissues. The robust and efficient data collection and collaboration between hepatologists and rheumatologists have led to significant advancements in understanding the relationship between the cholestatic liver diseases and associated autoimmune diseases. In this paper, we discuss the cholestatic liver diseases (primary biliary cirrhosis, primary sclerosing cholangitis and immunoglobulin G4 associated cholangitis) and associated autoimmune diseases.
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Affiliation(s)
- Ahmad H Ali
- a 1 Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA
| | - Elizabeth J Carey
- a 1 Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA
| | - Keith D Lindor
- a 1 Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA.,b 2 Arizona State University, College of Health Solutions, Phoenix, AZ, USA
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12
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Ali AH, Carey EJ, Lindor KD. Targets and investigative treatments for primary biliary cholangitis. Expert Opin Orphan Drugs 2016. [DOI: 10.1080/21678707.2016.1227240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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13
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Qin B, Wei T, Wang L, Ma N, Tang Q, Liang Y, Yang Z, Zhou L, Zhong R. Decreased expression of TIPE2 contributes to the hyperreactivity of monocyte to Toll-like receptor ligands in primary biliary cirrhosis. J Gastroenterol Hepatol 2016; 31:1177-83. [PMID: 26644386 DOI: 10.1111/jgh.13251] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Revised: 11/03/2015] [Accepted: 11/29/2015] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIM Previous studies have shown differential TIPE2 expression in several autoimmune diseases. However, the expression levels of TIPE2 in primary biliary cirrhosis (PBC) remained unclear. The purposes of this study were to evaluate TIPE2 expression levels in patients with PBC and further investigate its role in PBC pathogenesis. METHODS A total of 40 PBC patients and 44 healthy controls were included in the present study. Quantitative reverse-transcription polymerase chain reaction and western blotting were used to determine the differences in mRNA and protein expression levels of TIPE2. The correlations of TIPE2 expression levels and clinical characteristics, inflammatory cytokines, and ursodeoxycholic acid treatment were also assessed. Besides, the influence of TIPE2 on the reactivity of monocyte to Toll-like receptor ligands was further analyzed. RESULTS The expression levels of TIPE2 were significantly decreased in PBC patients compared with normal controls (P < 0.01). The expression levels of TIPE2 were negatively correlated with alanine aminotransferase (r = -0.40, P = 0.01), alkaline phosphatase (r = -0.36, P = 0.02), gamma glutamyl transpeptidase (r = -0.53, P < 0.01), tumor necrosis factor (TNF)-α (r = -0.332, P = 0.03), interleukin (IL)-1β (r = -0.386, P = 0.01), and IL-8 (r = -0.366, P = 0.02) levels in sera from PBC patients. TIPE2 expression level could be significantly increased after ursodeoxycholic acid treatment (P < 0.01). The production of TNF-α, IL-1β, and IL-8 by monocytes from PBC patients after stimulation with lipopolysaccharide and lipoteichoic acid was significantly increased when TIPE2 was knocked down. Furthermore, TIPE2 knockdown could promote activation of nuclear factor-κB pathways through increasing phosphorylation and degradation of IκB in peripheral blood monocytes from PBC patients. CONCLUSION The present study reported that insufficient expression of TIPE2 might be involved in the hyperreactivity of monocyte to Toll-like receptor ligands in PBC.
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Affiliation(s)
- Baodong Qin
- Department of Laboratory Medicine, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Tingting Wei
- Department of Laboratory Medicine, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Lili Wang
- Department of Laboratory Medicine, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Ning Ma
- Department of Laboratory Medicine, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Qingqin Tang
- Department of Laboratory Medicine, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Yan Liang
- Department of Laboratory Medicine, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Zaixing Yang
- Department of Laboratory Medicine, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Lin Zhou
- Department of Laboratory Medicine, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Renqian Zhong
- Department of Laboratory Medicine, Changzheng Hospital, Second Military Medical University, Shanghai, China
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14
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Li P, Lu G, Cui Y, Wu Z, Chen S, Li J, Wen X, Zhang H, Mu S, Zhang F, Li Y. Association of IL12A Expression Quantitative Trait Loci (eQTL) With Primary Biliary Cirrhosis in a Chinese Han Population. Medicine (Baltimore) 2016; 95:e3665. [PMID: 27175695 PMCID: PMC4902537 DOI: 10.1097/md.0000000000003665] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Genome-wide association studies in European individuals have revealed that IL12A is strongly associated with primary biliary cirrhosis (PBC). However, this association was not detected in replicative studies conducted in Chinese Han and Japanese populations.To verify contributions of genetic variants of IL12A to the pathogenesis of PBC in Chinese populations, a replicative study of 22 single nucleotide polymorphisms (SNPs) around the IL12A gene locus was performed in a cohort of 586 PBC cases and 726 healthy controls. Three out of the 22 SNPs were significantly associated with PBC. The 2 SNPs with the most significant association signal were rs4679868 (P = 6.59E-05, odds ratio [OR] = 1.554 [1.253-1.927]) and rs6441286 (P = 8.00E-05, OR = 1.551 [1.250-1.924]). These 2 SNPs were strongly linked to each other (r = 0.981), and both were found to be significantly associated with PBC in European populations.An expression quantitative trait loci (eQTL) analysis was performed based on the observation that these 2 SNPs were located in proximity to 2 enhancers verified by luciferase reporter systems in the HEK293 cell line. The results of eQTL analysis, conducted using the publically accessible data, showed that the risk alleles of rs4679868 and rs6441286 were significantly associated with decreased expression of IL12A in lymphoblastoid cell lines derived from individuals of Chinese Han ancestry (P = 0.0031 for rs4679868 and P = 0.0073 for rs6441286). In addition, the risk alleles of the 2 SNPs were significantly associated with down-regulation of SCHIP1, a celiac disease susceptible gene, 91.5 kb upstream of IL12A.These results not only demonstrated that IL12A is associated with PBC in the Chinese Han population but also identified a potential mechanism for its involvement in the pathogenesis of PBC.
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Affiliation(s)
- Ping Li
- From the Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing (PL, GL, ZW, SC, JL, XW, HZ, FZ, YL) and Department of Blood Transfusion, Tangdu Hospital, The Fourth Military Medical University, Xi'an (GL, YC, MJ), China
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Tang R, Wei Y, Li Z, Chen H, Miao Q, Bian Z, Zhang H, Wang Q, Wang Z, Lian M, Yang F, Jiang X, Yang Y, Li E, Seldin MF, Gershwin ME, Liao W, Shi Y, Ma X. A Common Variant in CLDN14 is Associated with Primary Biliary Cirrhosis and Bone Mineral Density. Sci Rep 2016; 6:19877. [PMID: 26842849 PMCID: PMC4740766 DOI: 10.1038/srep19877] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 12/16/2015] [Indexed: 12/22/2022] Open
Abstract
Primary biliary cirrhosis (PBC), a chronic autoimmune liver disease, has been associated with increased incidence of osteoporosis. Intriguingly, two PBC susceptibility loci identified through genome-wide association studies are also involved in bone mineral density (BMD). These observations led us to investigate the genetic variants shared between PBC and BMD. We evaluated 72 genome-wide significant BMD SNPs for association with PBC using two European GWAS data sets (n = 8392), with replication of significant findings in a Chinese cohort (685 cases, 1152 controls). Our analysis identified a novel variant in the intron of the CLDN14 gene (rs170183, Pfdr = 0.015) after multiple testing correction. The three associated variants were followed-up in the Chinese cohort; one SNP rs170183 demonstrated consistent evidence of association in diverse ethnic populations (Pcombined = 2.43 × 10(-5)). Notably, expression quantitative trait loci (eQTL) data revealed that rs170183 was correlated with a decline in CLDN14 expression in both lymphoblastoid cell lines and T cells (Padj = 0.003 and 0.016, respectively). In conclusion, our study identified a novel PBC susceptibility variant that has been shown to be strongly associated with BMD, highlighting the potential of pleiotropy to improve gene discovery.
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Affiliation(s)
- Ruqi Tang
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai 200001, China
| | - Yiran Wei
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai 200001, China
| | - Zhiqiang Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China
| | - Haoyan Chen
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai 200001, China
| | - Qi Miao
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai 200001, China
| | - Zhaolian Bian
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai 200001, China
| | - Haiyan Zhang
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai 200001, China
| | - Qixia Wang
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai 200001, China
| | - Zhaoyue Wang
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai 200001, China
| | - Min Lian
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai 200001, China
| | - Fan Yang
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai 200001, China
| | - Xiang Jiang
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai 200001, China
| | - Yue Yang
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai 200001, China
| | - Enling Li
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai 200001, China
| | - Michael F. Seldin
- Department of Biochemistry and Molecular Medicine, University of California at Davis, Davis, CA 95616, USA
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Genome and Biomedical Sciences Facility, 451 Health Sciences Drive, Suite 6510, Davis, CA 95616, USA
| | - M. Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Genome and Biomedical Sciences Facility, 451 Health Sciences Drive, Suite 6510, Davis, CA 95616, USA
| | - Wilson Liao
- Department of Dermatology, University of California San Francisco School of Medicine, 1701 Dividadero Street, San Francisco, CA 94415, USA
| | - Yongyong Shi
- Department of Biochemistry and Molecular Medicine, University of California at Davis, Davis, CA 95616, USA
| | - Xiong Ma
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai 200001, China
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Zhang AP, Yang JH. Advances in understanding pathogenesis of primary biliary cholangitis. Shijie Huaren Xiaohua Zazhi 2016; 24:169-175. [DOI: 10.11569/wcjd.v24.i2.169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by chronic and progressive cholestasis. In recent years, the incidence and prevalence of PBC are increasing year by year. However, the etiology and pathogenesis are not fully understood. It is believed that genetic susceptibility, environmental factors, and immunologic tolerance are related with the pathogenesis of PBC. This article reviews the progress in the understanding of the pathogenesis of PBC.
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Extrahepatic malignancies in primary biliary cirrhosis: a comparative study at two European centers. Clin Rev Allergy Immunol 2016; 48:254-62. [PMID: 25205363 DOI: 10.1007/s12016-014-8446-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Limited information and divergent results are available on the prevalence/incidence, survival, and risk factors for developing extrahepatic malignancies (EMs) in primary biliary cirrhosis (PBC). The aim of the study was to analyze the epidemiology and survival rates for EM in PBC patients. The study was conducted on two series of patients followed up at two European centers (361 in Padova, Italy, and 397 in Barcelona, Spain) for a mean 7.7 ± 7 and 12.2 ± 7 years, respectively. The cancer incidence was compared with the standardized incidence ratios (SIRs) calculated using the Cancer Registry of the Veneto Region (Italy) and the Cancer Registry of Tarragona (Spain). Seventy-two patients developed EM. The prevalence of cases was similar in Padova (9.7 %) and Barcelona (9.4 %). The overall cancer incidence was similar to the expected incidence for the general population in the same geographical area (SIR = 1.2), and so was the crude EM rate (855.01 vs 652.86 per 100,000 patient-years, respectively, RR = 1.3). Logistic regression analysis showed that advanced histological stage and extrahepatic autoimmune diseases were significantly associated with the onset of EM. Survival was similar for PBC patients with and without EM (p = n.s.), and actual survival was similar to the one predicted by the Mayo model. The incidence of EM in PBC patients was found similar in Italy and Spain and no different from that of the general population. Advanced histological stage and extrahepatic autoimmune disease were risk factors significantly associated with EM developing in PBC. The onset of cancer in PBC patients does not influence the natural history of their liver disease.
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Abstract
Genome-wide association studies (GWASs) have been a significant technological advance in our ability to evaluate the genetic architecture of complex diseases such as primary biliary cirrhosis (PBC). To date, six large-scale studies have been performed that have identified 27 risk loci in addition to human leukocyte antigen (HLA) associated with PBC. The identified risk variants emphasize important disease concepts; namely, that disturbances in immunoregulatory pathways are important in the pathogenesis of PBC and that such perturbations are shared among a diverse number of autoimmune diseases-suggesting the risk architecture may confer a generalized propensity to autoimmunity not necessarily specific to PBC. Furthermore, the impact of non-HLA risk variants, particularly in genes involved with interleukin-12 signaling, and ethnic variation in conferring susceptibility to PBC have been highlighted. Although GWASs have been a critical stepping stone in understanding common genetic variation contributing to PBC, limitations pertaining to power, sample availability, and strong linkage disequilibrium across genes have left us with an incomplete understanding of the genetic underpinnings of disease pathogenesis. Future efforts to gain insight into this missing heritability, the genetic variation that contributes to important disease outcomes, and the functional consequences of associated variants will be critical if practical clinical translation is to be realized.
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Affiliation(s)
- Aliya F. Gulamhusein
- Division of Gastroenterology and Hepatology and the Mayo Clinic Center for Cell Signaling, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905
| | - Brian D. Juran
- Division of Gastroenterology and Hepatology and the Mayo Clinic Center for Cell Signaling, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905
| | - Konstantinos N. Lazaridis
- Division of Gastroenterology and Hepatology and the Mayo Clinic Center for Cell Signaling, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905. Phone: (507) 538-4877. Fax: (507) 284-0762
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Drapkina OM, Bueverova EL. [Ursodeoxycholic acid: A therapeutic niche in an internist's practice]. TERAPEVT ARKH 2015; 87:84-90. [PMID: 26087640 DOI: 10.17116/terarkh201587484-90] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The paper shows more than 40 years' experience with ursodeoxycholic acid (UDCA) used as a drug; during this period it has demonstrated its rather high clinical efficacy. Due to the range of its inherent pleiotropic (choleretic, cytoprotective, immunomodulatory, antiapoptotic, hypocholesterolemic, and litholytic) properties, UDCA has a broad spectrum of therapeutic activity. The paper considers the issues associated with the mechanism of action and with the clinical effects of this bile acid. It gives the results of the most important randomized controlled trials determining currently the evidence base for the efficiency and safety of using UDCA in the clinical picture of visceral diseases.
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Affiliation(s)
- O M Drapkina
- Department of Internal Propedeutics, Faculty of Therapeutics, I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow
| | - E L Bueverova
- Department of Internal Propedeutics, Faculty of Therapeutics, I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow
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Tang R, Chen H, Miao Q, Bian Z, Ma W, Feng X, Seldin MF, Invernizzi P, Gershwin ME, Liao W, Ma X. The cumulative effects of known susceptibility variants to predict primary biliary cirrhosis risk. Genes Immun 2015; 16:193-8. [PMID: 25569263 PMCID: PMC5553973 DOI: 10.1038/gene.2014.76] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Revised: 09/25/2014] [Accepted: 10/02/2014] [Indexed: 12/12/2022]
Abstract
Multiple genetic variants influence the risk for development of primary biliary cirrhosis (PBC). To explore the cumulative effects of known susceptibility loci on risk, we utilized a weighted genetic risk score (wGRS) to evaluate whether genetic information can predict susceptibility. The wGRS was created using 26 known susceptibility loci and investigated in 1840 UK PBC and 5164 controls. Our data indicate that the wGRS was significantly different between PBC and controls (P=1.61E-142). Moreover, we assessed predictive performance of wGRS on disease status by calculating the area under the receiver operator characteristic curve. The area under curve for the purely genetic model was 0.72 and for gender plus genetic model was 0.82, with confidence limits substantially above random predictions. The risk of PBC using logistic regression was estimated after dividing individuals into quartiles. Individuals in the highest disclosed risk group demonstrated a substantially increased risk for PBC compared with the lowest risk group (odds ratio: 9.3, P=1.91E-084). Finally, we validated our findings in an analysis of an Italian PBC cohort. Our data suggested that the wGRS, utilizing genetic variants, was significantly associated with increased risk for PBC with consistent discriminant ability. Our study is a first step toward risk prediction for PBC.
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Affiliation(s)
- Ruqi Tang
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, China
| | - Haoyan Chen
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, China
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
| | - Qi Miao
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, China
| | - Zhaolian Bian
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, China
| | - Wansu Ma
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA
| | - Xiaomei Feng
- Division of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Michael F. Seldin
- Department of Biochemistry and Molecular Medicine, University of California at Davis, Davis, CA, USA
- Department of Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - Pietro Invernizzi
- Clinical Immunology, IRCCS Istituto Clinico Humanitas, Rozzano, Milan, Italy
| | - M. Eric Gershwin
- Department of Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - Wilson Liao
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
| | - Xiong Ma
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, China
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Wang Y, Qu A, Wang H. Signal transducer and activator of transcription 4 in liver diseases. Int J Biol Sci 2015; 11:448-55. [PMID: 25798064 PMCID: PMC4366643 DOI: 10.7150/ijbs.11164] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Accepted: 01/24/2015] [Indexed: 12/14/2022] Open
Abstract
STAT4 is a member of the signal transducer and activator of transcription (STAT) family of molecules that localizes to the cytoplasm. STAT4 regulates various genes expression as a transcription factor after it is phosphorylated, dimerizes and translocates to the nucleus. STAT4 activation is detected virtually in the liver of several mouse models of liver injury, as well as the human liver of chronic liver diseases. STAT4 gene polymorphism has been shown to be associated with the antiviral response in chronic hepatitis C and drug-induced liver injury (DILI), primary biliary cirrhosis (PBC), HCV-associated liver fibrosis and in hepatocellular carcinoma (HCC). However, the roles of STAT4 in the pathogeneses of liver diseases are still not understood entirely. This review summarizes the recent advances on the functional roles of STAT4 and its related cytokines in liver diseases, especially in regulating hepatic anti-viral responses, inflammation, proliferation, apoptosis and tumorigenesis. Targeting STAT4 signaling pathway might be a promising strategy in developing therapeutic approaches for treating hepatitis in order to prevent further injury like cirrhosis and liver cancer.
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Affiliation(s)
- Yan Wang
- 1. Department of Infectious Diseases, Peking University First Hospital, Beijing 100034
| | - Aijuan Qu
- 3. Institute of Hypoxic Disease, School of Basic Medical Sciences, Capital Medical University, Beijing 100069 ; 4. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Hua Wang
- 2. Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei 230032
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Ali AH, Carey EJ, Lindor KD, Chen Y, Lin Y, Zheng Q, Zhu K, Pan J. Recent advances in the development of farnesoid X receptor agonists. ANNALS OF TRANSLATIONAL MEDICINE 2015. [PMID: 25705637 DOI: 10.3978/j.issn.2305-5839] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Farnesoid X receptors (FXRs) are nuclear hormone receptors expressed in high amounts in body tissues that participate in bilirubin metabolism including the liver, intestines, and kidneys. Bile acids (BAs) are the natural ligands of the FXRs. FXRs regulate the expression of the gene encoding for cholesterol 7 alpha-hydroxylase, which is the rate-limiting enzyme in BA synthesis. In addition, FXRs play a critical role in carbohydrate and lipid metabolism and regulation of insulin sensitivity. FXRs also modulate live growth and regeneration during liver injury. Preclinical studies have shown that FXR activation protects against cholestasis-induced liver injury. Moreover, FXR activation protects against fatty liver injury in animal models of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and improved hyperlipidemia, glucose intolerance, and insulin sensitivity. Obeticholic acid (OCA), a 6α-ethyl derivative of the natural human BA chenodeoxycholic acid (CDCA) is the first-in-class selective FXR agonist that is ~100-fold more potent than CDCA. Preliminary human clinical trials have shown that OCA is safe and effective. In a phase II clinical trial, administration of OCA was well-tolerated, increased insulin sensitivity and reduced markers of liver inflammation and fibrosis in patients with type II diabetes mellitus and NAFLD. In two clinical trials of OCA in patients with primary biliary cirrhosis (PBC), a progressive cholestatic liver disease, OCA significantly reduced serum alkaline phosphatase (ALP) levels, an important disease marker that correlates well with clinical outcomes of patients with PBC. Together, these studies suggest that FXR agonists could potentially be used as therapeutic tools in patients suffering from nonalcoholic fatty and cholestatic liver diseases. Larger and Longer-term studies are currently ongoing.
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Affiliation(s)
- Ahmad H Ali
- Division of Gastroenterology and Hepatology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA
| | - Elizabeth J Carey
- Division of Gastroenterology and Hepatology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA
| | - Keith D Lindor
- Division of Gastroenterology and Hepatology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA
| | - Yuanmei Chen
- 1 Department of Oncological Surgery, 2 Department of Radiation Oncology, 3 Department of Pathology, The Teaching Hospital of Fujian Medical University, Fujian Provincial Cancer Hospital, Fuzhou 350014, China
| | - Yu Lin
- 1 Department of Oncological Surgery, 2 Department of Radiation Oncology, 3 Department of Pathology, The Teaching Hospital of Fujian Medical University, Fujian Provincial Cancer Hospital, Fuzhou 350014, China
| | - Qingfeng Zheng
- 1 Department of Oncological Surgery, 2 Department of Radiation Oncology, 3 Department of Pathology, The Teaching Hospital of Fujian Medical University, Fujian Provincial Cancer Hospital, Fuzhou 350014, China
| | - Kunshou Zhu
- 1 Department of Oncological Surgery, 2 Department of Radiation Oncology, 3 Department of Pathology, The Teaching Hospital of Fujian Medical University, Fujian Provincial Cancer Hospital, Fuzhou 350014, China
| | - Jianji Pan
- 1 Department of Oncological Surgery, 2 Department of Radiation Oncology, 3 Department of Pathology, The Teaching Hospital of Fujian Medical University, Fujian Provincial Cancer Hospital, Fuzhou 350014, China
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Ali AH, Carey EJ, Lindor KD. Recent advances in the development of farnesoid X receptor agonists. ANNALS OF TRANSLATIONAL MEDICINE 2015; 3:5. [PMID: 25705637 DOI: 10.3978/j.issn.2305-5839.2014.12.06] [Citation(s) in RCA: 102] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Accepted: 11/21/2014] [Indexed: 12/13/2022]
Abstract
Farnesoid X receptors (FXRs) are nuclear hormone receptors expressed in high amounts in body tissues that participate in bilirubin metabolism including the liver, intestines, and kidneys. Bile acids (BAs) are the natural ligands of the FXRs. FXRs regulate the expression of the gene encoding for cholesterol 7 alpha-hydroxylase, which is the rate-limiting enzyme in BA synthesis. In addition, FXRs play a critical role in carbohydrate and lipid metabolism and regulation of insulin sensitivity. FXRs also modulate live growth and regeneration during liver injury. Preclinical studies have shown that FXR activation protects against cholestasis-induced liver injury. Moreover, FXR activation protects against fatty liver injury in animal models of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and improved hyperlipidemia, glucose intolerance, and insulin sensitivity. Obeticholic acid (OCA), a 6α-ethyl derivative of the natural human BA chenodeoxycholic acid (CDCA) is the first-in-class selective FXR agonist that is ~100-fold more potent than CDCA. Preliminary human clinical trials have shown that OCA is safe and effective. In a phase II clinical trial, administration of OCA was well-tolerated, increased insulin sensitivity and reduced markers of liver inflammation and fibrosis in patients with type II diabetes mellitus and NAFLD. In two clinical trials of OCA in patients with primary biliary cirrhosis (PBC), a progressive cholestatic liver disease, OCA significantly reduced serum alkaline phosphatase (ALP) levels, an important disease marker that correlates well with clinical outcomes of patients with PBC. Together, these studies suggest that FXR agonists could potentially be used as therapeutic tools in patients suffering from nonalcoholic fatty and cholestatic liver diseases. Larger and Longer-term studies are currently ongoing.
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Affiliation(s)
- Ahmad H Ali
- Division of Gastroenterology and Hepatology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA
| | - Elizabeth J Carey
- Division of Gastroenterology and Hepatology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA
| | - Keith D Lindor
- Division of Gastroenterology and Hepatology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA
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Ali AH, Carey EJ, Lindor KD. Diagnosis and management of primary biliary cirrhosis. Expert Rev Clin Immunol 2014; 10:1667-78. [DOI: 10.1586/1744666x.2014.979792] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Biochemical response to ursodeoxycholic acid predicts survival in a North American cohort of primary biliary cirrhosis patients. J Gastroenterol 2014; 49:1414-20. [PMID: 24317935 PMCID: PMC4048793 DOI: 10.1007/s00535-013-0903-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2013] [Accepted: 10/20/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND Biochemical response to ursodeoxycholic acid among patients with primary biliary cirrhosis remains variable, and there is no agreement of an ideal model. Novel assessment of response coupled to histologic progression was recently defined by the Toronto criteria. We retrospectively assessed transplant-free survival and clinical outcomes associated with ursodeoxycholic acid response to evaluate the Toronto criteria using a large North American cohort of PBC patients. METHODS Three hundred and ninety-eight PBC patients from the Mayo Clinic PBC Genetic Epidemiology Registry were assessed for ursodeoxycholic acid treatment and biochemical response per the Toronto criteria. Responders were defined by reduction in alkaline phosphatase to less than or equal to 1.67 times the upper normal limit by 2 years of treatment, whereas non-responders had alkaline phosphatase values greater than 1.67 times the upper normal limit. Probability of survival was estimated using the Kaplan-Meier method. RESULTS Three hundred and two (76 %) patients were responders and 96 (24 %) were non-responders. Significantly more non-responders developed adverse events related to chronic liver disease compared to responders (hazard ratio (HR) 2.77, P = 0.001). Biochemical responders and early-stage disease at treatment start was associated with improved overall transplant-free survival compared to non-responders (HR 1.9) and patients with late-stage disease (HR 2.7) after age and sex adjustment. CONCLUSIONS The Toronto criteria are capable of identifying ursodeoxycholic acid-treated primary biliary cirrhosis patients at risk of poor transplant-free survival and adverse clinical outcomes. Our data reveal that despite advanced disease at diagnosis, biochemical response per the Toronto criteria associates with improved overall transplant-free survival.
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Tanaka T, Yamashiki N, Sugawara Y, Tamura S, Nakamura M, Kaneko J, Aoki T, Sakamoto Y, Hasegawa K, Kokudo N. Chronologic changes of explanted liver volume and the use of ursodeoxycholic acid in patients with end-stage primary biliary cirrhosis. Hepatol Res 2014; 44:993-999. [PMID: 24298893 DOI: 10.1111/hepr.12283] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Revised: 11/12/2013] [Accepted: 11/26/2013] [Indexed: 12/13/2022]
Abstract
AIM The clinical presentation of Primary biliary cirrhosis (PBC) at the time of liver transplantation (LT) may have changed, due to the long-term use of ursodeoxycholic acid (UDCA). The aim of this retrospective study was to investigate whether the clinical characteristics of LT recipients with PBC have changed over the years. METHODS Of all 421 adults undergoing LT from 1997 to 2012 at our center, we included 85 recipients with PBC into the present study. The 85 recipients were divided into three groups according to the year LT was performed: group 1 (1997-2001, n = 29), group 2 (2002-2005, n = 29) and group 3 (2006-2012, n = 27). RESULTS There were no significant differences in sex, recipient age, Model for End-Stage Liver Disease score, updated Mayo risk score for PBC, or liver-related complications except for esophageal varices among the three groups. Patients in group 1 were complicated with esophageal varices less frequently than those in the other two groups. In older cases, the ratio of explanted liver volume to standard liver volume (ELV/SLV) was significantly higher, and the duration of pre-LT UDCA treatment was significantly shorter. The duration of UDCA treatment was significantly correlated with ELV/SLV. CONCLUSION Recent LT patients were characterized by more frequent portal hypertension and more severe liver atrophy, with longer UDCA therapy prior to LT, which might have prevented the somewhat rapid progression of liver failure characterized by hepatomegaly with insignificant fibrosis or portal hypertension.
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Affiliation(s)
- Tomohiro Tanaka
- Organ Transplantation Service, The University of Tokyo Hospital, Tokyo, Japan
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Boonstra K, Kunst AE, Stadhouders PH, Tuynman HA, Poen AC, van Nieuwkerk KMJ, Witteman EM, Hamann D, Witteman BJ, Beuers U, Ponsioen CY. Rising incidence and prevalence of primary biliary cirrhosis: a large population-based study. Liver Int 2014; 34:e31-8. [PMID: 24387641 DOI: 10.1111/liv.12434] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Accepted: 12/03/2013] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Large population-based studies are much needed to accurately establish the epidemiology of primary biliary cirrhosis (PBC). We aimed to collect all PBC patients in a geographically defined area to evaluate the epidemiology of PBC and examine the possible association of PBC with smoking, age at menarche, age at first pregnancy and number of pregnancies. METHODS All PBC patients between 2000 and 2008 were identified in a geographically defined area of the Netherlands, comprising 50% of the Dutch population. Four independent hospital databases were searched in 44 hospitals. Medical records were reviewed on site verifying diagnosis and for collection of clinical data. Age- and gender matched controls were recruited from the outpatient clinics of four participating hospitals. Patients and controls were asked to fill out a questionnaire regarding family history, previous and current smoking behaviour and fertility status. RESULTS Nine hundred and ninety-two PBC patients fulfilled all inclusion criteria, resulting in a mean incidence of 1.1 per 100 000; 0.3 in men and 1.9 in women. On January 1st 2008 the point prevalence was 13.2 per 100 000 inhabitants. Incidence and prevalence rates were increasing over time (P < 0.001). No geographical differences in disease distribution were observed. Smoking behaviour, age at menarche, age at first pregnancy, gravidity and number of children were not significantly different between cases and controls. CONCLUSION Incidence and prevalence rates of PBC are increasing over time. PBC was not found to be associated with smoking, age at menarche, age at first pregnancy or number of pregnancies.
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Affiliation(s)
- Kirsten Boonstra
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands
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Zeng L, Cui J, Wu H, Lu Q. The emerging role of circulating microRNAs as biomarkers in autoimmune diseases. Autoimmunity 2014; 47:419-29. [PMID: 24953646 DOI: 10.3109/08916934.2014.929667] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The highly conserved RNAs known as microRNAs (miRNAs) are a class of small, single-stranded, non-coding RNAs that play a critical role in the regulation of host genome expression at the posttranscriptional level. MiRNA-mediated gene regulation is vital for normal cellular functions, such as the cell differentiation, proliferation and apoptosis, and nearly one-third of human messenger RNAs might be miRNA targets. Increasing evidence has suggested that miRNAs play a critical role in the regulating the immune system and preventing autoimmune disorders. Circulating miRNAs, which can be easily detected by a non-invasive methods, have been proven to be able to distinguish diseased individuals from healthy subjects. In addition, these circulating miRNAs have relatively high sensitivity and specificity and thus have been developed as biomarkers for the diagnosis and monitoring of human diseases. To date, nearly 100 circulating miRNAs have been proven to be biomarkers for various diseases, and this number continues to rise. This review aims to summarize the most promising identified circulating miRNAs as potential biomarkers in autoimmune diseases and to discuss current challenges and future directions in the field.
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Affiliation(s)
- Li Zeng
- Department of Dermatology, The 2nd Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenetics , Changsha , China
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Abstract
PURPOSE OF REVIEW Primary biliary cirrhosis (PBC) was first described in the 1950s as a clinical syndrome of progressive cholestatic liver disease resulting from chronic inflammatory destruction of the intrahepatic bile ducts. In the 1980s, the autoimmune nature of the disease was appreciated with the discovery of disease-specific loss of immune tolerance to the pyruvate dehydrogenase complex and subsequent development of antimitochondrial antibodies and autoreactive T cells. Then, in the 1990s, multiple clinical trials demonstrating the efficacy of ursodiol as a treatment for PBC were published, although it has been clear that ursodiol is not a cure and only delays progression in some patients. RECENT FINDINGS The study of PBC in the 2000s has been buoyed by two basic science advances: rapid sequencing technologies that have led to genome wide association studies, and elucidation of the role of nuclear hormone receptors in the regulation of bile salt metabolism, which has led to novel therapies under study for cholestatic diseases. SUMMARY Today's clinician should be able to determine which patients with PBC are likely to progress despite treatment with ursodiol and understand the putative new bile acid and immunosuppressant treatment strategies under development, as well as be aware of the recently described genetic factors at play in the development of PBC.
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Ohira H, Watanabe H. Pathophysiology and recent findings of primary biliary cirrhosis complicated by systemic sclerosis. Hepatol Res 2014; 44:377-83. [PMID: 24308674 DOI: 10.1111/hepr.12285] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2013] [Revised: 12/02/2013] [Accepted: 12/02/2013] [Indexed: 02/08/2023]
Abstract
Primary biliary cirrhosis (PBC) can be complicated by systemic sclerosis (SSc) and, more specifically, limited cutaneous SSc (lcSSc), which was previously called CREST syndrome. Moreover, combined PBC and SSc has been described in many case reports. Although neither the etiology of PBC nor that of SSc has been elucidated, some genetic and immunological factors are known to be shared. Both disorders are autoimmune fibrotic diseases characterized by increased levels of profibrotic cytokines transforming growth factor β (TGFβ) and interleukin-6, which have recently been suggested to influence T-helper 17 cells and regulatory T cells involved in acquired immunity. lcSSc is accompanied by CREST symptoms, although complete CREST cases are rare, with relatively high prevalence of Raynaud's phenomenon, sclerodactyly and telangiectasia, and lower prevalence of calcinosis and esophageal dysmotility. Because patients with anticentromere antibody positive PBC-SSc are at a high risk of developing portal hypertension, particular attention should be paid to the management of gastroesophageal varices. In addition, the management of SSc-related non-hepatic disorders, such as pulmonary fibrosis, pulmonary hypertension, heart disorder, infection and malignancy, is also important for improved outcomes. Because PBC is often complicated by rheumatic disease, hepatologists should keep the possibility of systemic disorder in mind when examining PBC patients.
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Affiliation(s)
- Hiromasa Ohira
- Department of Gastroenterology and Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hiroshi Watanabe
- Department of Gastroenterology and Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
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31
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STAT4 gene polymorphisms are associated with susceptibility and ANA status in primary biliary cirrhosis. DISEASE MARKERS 2014; 2014:727393. [PMID: 24648611 PMCID: PMC3932279 DOI: 10.1155/2014/727393] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2013] [Revised: 11/27/2013] [Accepted: 12/16/2013] [Indexed: 12/25/2022]
Abstract
Recent genome-wide association studies suggest that genetic factors contribute to primary biliary cirrhosis (PBC) susceptibility. Although several reports have demonstrated that the interleukin (IL) 12 signaling pathway is involved in PBC pathogenesis, its precise genetic factors have not been fully clarified. Here, we performed an association analysis between IL12A, IL12RB, and signal transducer and activator of transcription 4 (STAT4) genetic variations and susceptibility to PBC. Single nucleotide polymorphisms (SNPs) were genotyped in 395 PBC patients and 458 healthy subjects of Japanese ethnicity and evaluated for associations with PBC susceptibility, anti-nuclear antibody (ANA) status, and anti-mitochondrial antibody (AMA) status. We detected significant associations with PBC susceptibility for several STAT4 SNPs (rs10168266; P = 9.4 × 10−3, rs11889341; P = 1.2 × 10−3, rs7574865; P = 4.0 × 10−4, rs8179673; P = 2.0 × 10−4, and rs10181656; P = 4.2 × 10−5). Three risk alleles (rs7574865; P = 0.040, rs8179673; P = 0.032, and rs10181656; P = 0.031) were associated with ANA status, but not with AMA positivity. Our findings confirm that STAT4 is involved in PBC susceptibility and may play a role in ANA status in the Japanese population.
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Abstract
We recently introduced the concept of the infectome as a means of studying all infectious factors which contribute to the development of autoimmune disease. It forms the infectious part of the exposome, which collates all environmental factors contributing to the development of disease and studies the sum total of burden which leads to the loss of adaptive mechanisms in the body. These studies complement genome-wide association studies, which establish the genetic predisposition to disease. The infectome is a component which spans the whole life and may begin at the earliest stages right up to the time when the first symptoms manifest, and may thus contribute to the understanding of the pathogenesis of autoimmunity at the prodromal/asymptomatic stages. We provide practical examples and research tools as to how we can investigate disease-specific infectomes, using laboratory approaches employed from projects studying the “immunome” and “microbiome”. It is envisioned that an understanding of the infectome and the environmental factors that affect it will allow for earlier patient-specific intervention by clinicians, through the possible treatment of infectious agents as well as other compounding factors, and hence slowing or preventing disease development.
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Podda M, Selmi C, Lleo A, Moroni L, Invernizzi P. The limitations and hidden gems of the epidemiology of primary biliary cirrhosis. J Autoimmun 2013; 46:81-87. [PMID: 23871640 DOI: 10.1016/j.jaut.2013.06.015] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2013] [Accepted: 06/23/2013] [Indexed: 12/28/2022]
Abstract
Epidemiology is expected to provide important clues to our understanding of the enigmatic etiopathogenesis of primary biliary cirrhosis (PBC). First, a systematic review of population based studies indicated a wide range in the yearly incidence (0.33-5.8/100.000) and point prevalence (1.91-40.2/100.000) rates. Though different ethnic representations may also contribute it is likely that methodological issues, based on the retrospective survey of diagnosed cases, and time trend play a major role, also in view of the prolonged asymptomatic period of the disease. Of note, the highest prevalence rates (35-40/100.000) were found in areas characterized by high medical awareness and easier access to healthcare. Second, the search for serum AMA in unselected population sera may identify the largest possible number of patients who have or will develop the disease. Indeed, a surprisingly high AMA prevalence rate, ranging between 0.43 and 1%, appears likely in the general population despite the lack of adequate work-up in most studies. Third, the median female to male ratio for PBC is classically accepted as 9-10:1 but is significantly lower for AMA prevalence (2.5:1), death certificates for PBC (4.3:1) and liver transplantation (6:1), thus suggesting that PBC in men may be underdiagnosed in early stages or manifest a more severe progression. Lastly, studies of both PBC and serum AMA prevalence among family members and monozygotic twins strongly support the role played by genetic factors in the etiopathogenesis of the disease. In conclusion, PBC epidemiology is far from being a closed case and the numerous open issues will be solved through a collaborative effort and powerful data mining tools.
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Affiliation(s)
- Mauro Podda
- Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
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Invernizzi P. Liver auto-immunology: the paradox of autoimmunity in a tolerogenic organ. J Autoimmun 2013; 46:1-6. [PMID: 24012346 DOI: 10.1016/j.jaut.2013.08.006] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2013] [Accepted: 08/14/2013] [Indexed: 02/07/2023]
Abstract
The study of the liver as a lymphoid organ is a growing field fueled by our better knowledge of the different component of the immune system and how they orchestrate an immune-related response. The liver have highly specialized mechanisms of immune tolerance, mainly because is continuously exposed to microbial and environmental antigens, and dietary components from the gut. Accordingly, the liver contains specialized lymphoid subpopulations acting as antigen-presenting cells. Growing evidences show that the liver is also associated with obesity-associated diseases because of its immune-related capacity to sense metabolic stress induced by nutritional surplus. Finally, the liver produces a pletora of neo-antigens being the primary metabolic organ of the body. Common immune mechanisms play a key pathogenetic role in most of acute and chronic liver diseases and in the rejection of liver allografts. Any perturbations of liver-related immune functions have important clinical implications. This issue of the Journal of Autoimmunity is focused on the more recent advances in our knowledge related to the loss of liver tolerance, a paradox for a tolerogenic organ, that leads to overactivation of the innate and adaptive immune response and the development of autoimmune liver diseases, such as autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis. The invited expert review articles capture the underlying immunomolecular mechanisms of the development and progression of autoimmune liver diseases, the novel field of the immune-related "liver-gut" axis influences to the development of liver autoimmunity, the predominant role of genetic factors, and the increasingly effective immuno-therapeutic possibilities.
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Affiliation(s)
- Pietro Invernizzi
- Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA.
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Abstract
Cholestasis develops as a consequence of impaired bile formation and/or bile flow and can be classified as intra- or extrahepatic. Chronic cholestatic diseases are mostly intrahepatic with the exception of primary and secondary sclerosing cholangitis affecting intra- and extrahepatic bile ducts. Recent genome-wide association studies have confirmed major histocompatibility complex associations and discovered multiple susceptibility loci in primary biliary cirrhosis and primary sclerosing cholangitis, providing new insights into disease pathogenesis, which may translate into more precise therapeutic prevention and intervention in the future. Diagnostic steps in cholestatic conditions comprise a thorough patient history, abdominal imaging and distinct serological studies including antimitochondrial antibodies and IgG4 levels; if the diagnosis remains unclear, liver biopsy is warranted. Genetic testing should also be considered, as mutations in the hepatobiliary transporters ATP8B1, ABCB11 and ABCB4 are causative for three different forms of familial intrahepatic cholestasis. Disease severity is dependent on the genotypic variants of these transporters, ranging from mildly elevated liver enzymes in adults to cirrhosis in early childhood. Ligands of nuclear receptors, which represent important regulators of hepatobiliary transporters, and modified bile salts are new promising therapeutic options in cholestatic liver disease and are currently being investigated in clinical trials.
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Affiliation(s)
- Christoph Jüngst
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
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36
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Ninomiya M, Kondo Y, Funayama R, Nagashima T, Kogure T, Kakazu E, Kimura O, Ueno Y, Nakayama K, Shimosegawa T. Distinct microRNAs expression profile in primary biliary cirrhosis and evaluation of miR 505-3p and miR197-3p as novel biomarkers. PLoS One 2013; 8:e66086. [PMID: 23776611 PMCID: PMC3680413 DOI: 10.1371/journal.pone.0066086] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Accepted: 05/03/2013] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND AIMS MicroRNAs are small endogenous RNA molecules with specific expression patterns that can serve as biomarkers for numerous diseases. However, little is known about the expression profile of serum miRNAs in PBC. METHODS First, we employed Illumina deep sequencing for the initial screening to indicate the read numbers of miRNA expression in 10 PBC, 5 CH-C, 5 CH-B patients and 5 healthy controls. Comparing the differentially expressed miRNAs in the 4 groups, analysis of variance was performed on the number of sequence reads to evaluate the statistical significance. Hierarchical clustering was performed using an R platform and we have found candidates for specific miRNAs in the PBC patients. Second, a quantitative reverse transcription PCR validation study was conducted in 10 samples in each group. The expression levels of the selected miRNAs were presented as fold-changes (2(-ΔΔCt)). Finally, computer analysis was conducted to predict target genes and biological functions with MiRror 2.0 and DAVID v6.7. RESULTS We obtained about 12 million 32-mer short RNA reads on average per sample and the mapping rates to miRBase were 16.60% and 81.66% to hg19. In the statistical significance testing, the expression levels of 81 miRNAs were found to be differentially expressed in the 4 groups. The heat map and hierarchical clustering demonstrated that the miRNA profiles from PBC clustered with those of CH-B, CH-C and healthy controls. Additionally, the circulating levels of hsa-miR-505-3p, 197-3p, and 500a-3p were significantly decreased in PBC compared with healthy controls and the expression levels of hsa-miR-505-3p, 139-5p and 197-3p were significantly reduced compared with the viral hepatitis group. CONCLUSIONS Our results indicate that sera from patients with PBC have a unique miRNA expression profile and that the down-regulated expression of hsa-miR-505-3p and miR-197-3p can serve as clinical biomarkers of PBC.
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Affiliation(s)
- Masashi Ninomiya
- Division of Gastroenterology, Tohoku University Hospital, Sendai, Japan
| | - Yasuteru Kondo
- Division of Gastroenterology, Tohoku University Hospital, Sendai, Japan
| | - Ryo Funayama
- Division of Cell Proliferation, Tohoku University School of Medicine, Sendai, Japan
| | - Takeshi Nagashima
- Division of Cell Proliferation, Tohoku University School of Medicine, Sendai, Japan
| | - Takayuki Kogure
- Division of Gastroenterology, Tohoku University Hospital, Sendai, Japan
| | - Eiji Kakazu
- Division of Gastroenterology, Tohoku University Hospital, Sendai, Japan
| | - Osamu Kimura
- Division of Gastroenterology, Tohoku University Hospital, Sendai, Japan
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Keiko Nakayama
- Division of Cell Proliferation, Tohoku University School of Medicine, Sendai, Japan
| | - Tooru Shimosegawa
- Division of Gastroenterology, Tohoku University Hospital, Sendai, Japan
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HIRSCHFIELD GIDEONM, CHAPMAN ROGERW, KARLSEN TOMH, LAMMERT FRANK, LAZARIDIS KONSTANTINOSN, MASON ANDREWL. The genetics of complex cholestatic disorders. Gastroenterology 2013; 144:1357-74. [PMID: 23583734 PMCID: PMC3705954 DOI: 10.1053/j.gastro.2013.03.053] [Citation(s) in RCA: 104] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2013] [Revised: 03/24/2013] [Accepted: 03/27/2013] [Indexed: 02/07/2023]
Abstract
Cholestatic liver diseases are caused by a range of hepatobiliary insults and involve complex interactions among environmental and genetic factors. Little is known about the pathogenic mechanisms of specific cholestatic diseases, which has limited our ability to manage patients with these disorders. However, recent genome-wide studies have provided insight into the pathogenesis of gallstones, primary biliary cirrhosis, and primary sclerosing cholangitis. A lithogenic variant in the gene that encodes the hepatobiliary transporter ABCG8 has been identified as a risk factor for gallstone disease; this variant has been associated with altered cholesterol excretion and metabolism. Other variants of genes encoding transporters that affect the composition of bile have been associated with cholestasis, namely ABCB11, which encodes the bile salt export pump, and ABCB4, which encodes hepatocanalicular phosphatidylcholine floppase. In contrast, studies have associated primary biliary cirrhosis and primary sclerosing cholangitis with genes encoding major histocompatibility complex proteins and identified loci associated with microbial sensing and immune regulatory pathways outside this region, such as genes encoding IL12, STAT4, IRF5, IL2 and its receptor (IL2R), CD28, and CD80. These discoveries have raised interest in the development of reagents that target these gene products. We review recent findings from genetic studies of patients with cholestatic liver disease. Future characterization of genetic variants in animal models, stratification of risk alleles by clinical course, and identification of interacting environmental factors will increase our understanding of these complex cholestatic diseases.
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Affiliation(s)
- GIDEON M. HIRSCHFIELD
- Centre for Liver Research, National Institute for Health Research Biomedical Research Unit, University of Birmingham, Birmingham, England
| | - ROGER W. CHAPMAN
- Department of Gastroenterology, John Radcliffe Hospital, Oxford, England
| | - TOM H. KARLSEN
- Research Institute for Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - FRANK LAMMERT
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - KONSTANTINOS N. LAZARIDIS
- Center for Basic Research in Digestive Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - ANDREW L. MASON
- Centre of Excellence in Gastrointestinal Inflammation and Immunity Research, University of Alberta, Edmonton, Alberta, Canada
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Hirschfield GM, Gershwin ME. The immunobiology and pathophysiology of primary biliary cirrhosis. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2013; 8:303-30. [PMID: 23347352 DOI: 10.1146/annurev-pathol-020712-164014] [Citation(s) in RCA: 225] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Primary biliary cirrhosis (PBC) is an autoimmune disease characterized by clinical homogeneity among patients, an overwhelming female predominance, production of a multilineage immune response to mitochondrial autoantigens, inflammation of small bile ducts, and in some patients the development of fibrosis and cirrhosis. The targets in this disease are small bile ducts, and the prototypic serologic response includes antimitochondrial antibodies (AMAs). Several key observations have greatly advanced our understanding of PBC. First, the multilineage immune response, including AMAs, is directed at the E2 component of the 2-oxo-dehydrogenase pathway, particularly PDC-E2. Second, such autoantibodies may be identified years before the clinical diagnosis of disease. Third, the autoreactive T cell precursor frequency for both CD4 and CD8 cells is significantly higher in liver and regional lymph node than in blood, so the multilineage antimitochondrial response may be required for the development of this disease. Fourth, the apotope of biliary cells contains intact PDC-E2; this apotope, in a setting that includes granulocyte macrophage colony-stimulating factor-stimulated macrophages and AMAs, produces an intense proinflammatory response. Fifth, several mouse models of PBC highlight the importance of loss of tolerance to PDC-E2 as well as a critical role for the interleukin (IL)-12 signaling pathway. Finally, genome-wide association studies suggest an important role for the IL-12 pathway in disease susceptibility. Taken together, these findings have resulted in a better understanding of the mechanism for selective biliary cell destruction and have also suggested unique pathways for therapeutic intervention.
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Affiliation(s)
- Gideon M Hirschfield
- Centre for Liver Research, NIHR Biomedical Research Unit, University of Birmingham, Birmingham, United Kingdom
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Bogdanos DP, Smyk DS, Invernizzi P, Rigopoulou EI, Blank M, Pouria S, Shoenfeld Y. Infectome: a platform to trace infectious triggers of autoimmunity. Autoimmun Rev 2012; 12:726-40. [PMID: 23266520 PMCID: PMC7105216 DOI: 10.1016/j.autrev.2012.12.005] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2012] [Accepted: 12/12/2012] [Indexed: 02/06/2023]
Abstract
The "exposome" is a term recently used to describe all environmental factors, both exogenous and endogenous, which we are exposed to in a lifetime. It represents an important tool in the study of autoimmunity, complementing classical immunological research tools and cutting-edge genome wide association studies (GWAS). Recently, environmental wide association studies (EWAS) investigated the effect of environment in the development of diseases. Environmental triggers are largely subdivided into infectious and non-infectious agents. In this review, we introduce the concept of the "infectome", which is the part of the exposome referring to the collection of an individual's exposures to infectious agents. The infectome directly relates to geoepidemiological, serological and molecular evidence of the co-occurrence of several infectious agents associated with autoimmune diseases that may provide hints for the triggering factors responsible for the pathogenesis of autoimmunity. We discuss the implications that the investigation of the infectome may have for the understanding of microbial/host interactions in autoimmune diseases with long, pre-clinical phases. It may also contribute to the concept of the human body as a superorganism where the microbiome is part of the whole organism, as can be seen with mitochondria which existed as microbes prior to becoming organelles in eukaryotic cells of multicellular organisms over time. A similar argument can now be made in regard to normal intestinal flora, living in symbiosis within the host. We also provide practical examples as to how we can characterise and measure the totality of a disease-specific infectome, based on the experimental approaches employed from the "immunome" and "microbiome" projects.
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Affiliation(s)
- Dimitrios P Bogdanos
- Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, Denmark Hill Campus, London, UK.
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40
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Bianchi I, Lleo A, Bernuzzi F, Caliari L, Smyk DS, Invernizzi P. The X-factor in primary biliary cirrhosis: monosomy X and xenobiotics. AUTO- IMMUNITY HIGHLIGHTS 2012; 3:127-132. [PMID: 26000136 PMCID: PMC4389075 DOI: 10.1007/s13317-012-0043-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/20/2012] [Accepted: 10/24/2012] [Indexed: 12/12/2022]
Abstract
Primary biliary cirrhosis (PBC) is a chronic, cholestatic, autoimmune liver disease characterised by the destruction of small- and medium-sized bile ducts. The serological hallmark of PBC includes antimitochondrial antibodies (AMA). The disease has a striking female predominance, and primarily affects women of middle-age. First-degree relatives, and in particular female relatives, are known to have an increased risk of developing the disease. Several studies have attempted to explain the female predominance of PBC, and autoimmune diseases in general. Two components that are of interest in PBC include monosomy X and xenobiotics. Monosomy X has been noted to be prevalent in the peripheral blood mononuclear cells of PBC patients. Xenobiotics, which are exogenous chemicals not normally found within the body, have been implicated in the modification of, and loss of, tolerance to AMA. Several cosmetics are known to contain these xenobiotics, which is of interest given the information provided in regards to known risk factors for PBC development. This review will focus on X monosomy and xenobiotics, which appear to constitute the X-factor of PBC.
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Affiliation(s)
- Ilaria Bianchi
- Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano (MI), Italy
| | - Ana Lleo
- Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano (MI), Italy
| | - Francesca Bernuzzi
- Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano (MI), Italy
| | - Lisa Caliari
- Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano (MI), Italy
| | - Dan S. Smyk
- Institute of Liver Transplantation, Division of Transplantation Immunology and Mucosal Biology, King’s College London School of Medicine at King’s College Hospital, London, SE5 9RJ UK
| | - Pietro Invernizzi
- Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano (MI), Italy
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, USA
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Qin B, Liang Y, Yang Z, Zhong R. Effect of the polymorphisms of tumor necrosis factor-α gene on the susceptibility to primary biliary cirrhosis: a meta-analysis. Eur J Gastroenterol Hepatol 2012; 24:1386-92. [PMID: 23011034 DOI: 10.1097/meg.0b013e3283581f2e] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Previous studies have shown the genetic association of tumor necrosis factor (TNF)-α polymorphisms and susceptibility to primary biliary cirrhosis (PBC), but the results of individual studies have remained contradictory. Therefore, a meta-analysis was carried out to evaluate comprehensively the association of TNF-α polymorphisms and susceptibility to PBC. METHODS The relevant published articles were searched in PubMed, EMBASE, and Cochrane library. Data were extracted using standardized forms and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for each study. Pooled data were estimated by fixed-effects and random-effects models when appropriate. We analyzed the association between the 'A' allele at position -308(rs1800629) and -238(rs361525) and the risk of PBC. RESULTS We examined eight publications, showing that all eight studies discussed the TNF-α -308(rs1800629) polymorphism; four studies were relevant with -238(rs361525). No significant associations were found between the 'A' allele frequency of rs1800629 and rs361525 and the risk of PBC in the overall population (OR=0.89, 95% CI 0.71-1.11, P=0.91; OR=0.98, 95% CI 0.66-1.47, P=0.93) and in Whites (OR=0.94, 95% CI 0.74-1.19, P=0.58; OR=1.01, 95% CI 0.64-1.59, P=0.97). Besides, it was also found that the genotype (AA+AG vs. GG, GG+AG vs. AA) was not linked to susceptibility to PBC. CONCLUSION The meta-analysis indicated that none of these two polymorphisms (-308G/A and -238G/A) showed any significant association with the risk of PBC.
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Affiliation(s)
- Baodong Qin
- Department of Laboratory Diagnostics, Changzheng Hospital, Second Military Medical University, Shanghai, China
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Juran BD, Hirschfield GM, Invernizzi P, Atkinson EJ, Li Y, Xie G, Kosoy R, Ransom M, Sun Y, Bianchi I, Schlicht EM, Lleo A, Coltescu C, Bernuzzi F, Podda M, Lammert C, Shigeta R, Chan LL, Balschun T, Marconi M, Cusi D, Heathcote EJ, Mason AL, Myers RP, Milkiewicz P, Odin JA, Luketic VA, Bacon BR, Bodenheimer HC, Liakina V, Vincent C, Levy C, Franke A, Gregersen PK, Bossa F, Gershwin ME, deAndrade M, Amos CI, The Italian PBC Genetics Study Group, Lazaridis KN, Seldin MF, Siminovitch KA. Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants. Hum Mol Genet 2012; 21:5209-5221. [PMID: 22936693 PMCID: PMC3490520 DOI: 10.1093/hmg/dds359] [Citation(s) in RCA: 122] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2012] [Revised: 08/09/2012] [Accepted: 08/21/2012] [Indexed: 12/17/2022] Open
Abstract
To further characterize the genetic basis of primary biliary cirrhosis (PBC), we genotyped 2426 PBC patients and 5731 unaffected controls from three independent cohorts using a single nucleotide polymorphism (SNP) array (Immunochip) enriched for autoimmune disease risk loci. Meta-analysis of the genotype data sets identified a novel disease-associated locus near the TNFSF11 gene at 13q14, provided evidence for association at six additional immune-related loci not previously implicated in PBC and confirmed associations at 19 of 22 established risk loci. Results of conditional analyses also provided evidence for multiple independent association signals at four risk loci, with haplotype analyses suggesting independent SNP effects at the 2q32 and 16p13 loci, but complex haplotype driven effects at the 3q25 and 6p21 loci. By imputing classical HLA alleles from this data set, four class II alleles independently contributing to the association signal from this region were identified. Imputation of genotypes at the non-HLA loci also provided additional associations, but none with stronger effects than the genotyped variants. An epistatic interaction between the IL12RB2 risk locus at 1p31and the IRF5 risk locus at 7q32 was also identified and suggests a complementary effect of these loci in predisposing to disease. These data expand the repertoire of genes with potential roles in PBC pathogenesis that need to be explored by follow-up biological studies.
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MESH Headings
- Alleles
- Case-Control Studies
- Chromosomes, Human, Pair 1
- Chromosomes, Human, Pair 13
- Chromosomes, Human, Pair 7
- Epistasis, Genetic
- Gene Frequency
- Genetic Loci
- Genetic Predisposition to Disease
- Genotype
- HLA Antigens/genetics
- HLA Antigens/immunology
- Humans
- Liver Cirrhosis, Biliary/genetics
- Liver Cirrhosis, Biliary/immunology
- Oligonucleotide Array Sequence Analysis
- Polymorphism, Single Nucleotide
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Affiliation(s)
| | - Gideon M. Hirschfield
- Centre for Liver Research, University of Birmingham, Birmingham, UK
- Department of Medicine
| | - Pietro Invernizzi
- University of California - Davis, Davis, CA, USA
- Center for Autoimmune Liver Diseases, IRCCS Istituto Clinico Humanitas, Rozzano, Italy
| | | | - Yafang Li
- University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Gang Xie
- Mount Sinai Hospital, Samuel Lunenfeld Research Institute and Toronto General Research Institute, Toronto, Ontario, Canada
| | - Roman Kosoy
- University of California - Davis, Davis, CA, USA
| | | | | | - Ilaria Bianchi
- Center for Autoimmune Liver Diseases, IRCCS Istituto Clinico Humanitas, Rozzano, Italy
| | | | - Ana Lleo
- Center for Autoimmune Liver Diseases, IRCCS Istituto Clinico Humanitas, Rozzano, Italy
- Department of Translational Medicine, Università degli Studi di Milano, Rozzano, Italy
| | - Catalina Coltescu
- University Health Network, Liver Centre, Toronto Western Hospital, Toronto, Ontario, Canada
| | - Francesca Bernuzzi
- Center for Autoimmune Liver Diseases, IRCCS Istituto Clinico Humanitas, Rozzano, Italy
| | - Mauro Podda
- Center for Autoimmune Liver Diseases, IRCCS Istituto Clinico Humanitas, Rozzano, Italy
| | | | | | - Landon L. Chan
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Tobias Balschun
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Maurizio Marconi
- Centre of Blood Transfusion and Immuno Hematology, Fondazione CaGranda, Ospedale Maggiore Policlinico, Milano, Italy
| | - Daniele Cusi
- Department of Medicine, Surgery and Dentistry, University of Milano, Milano, Italy
- Genomics and Bioinformatics Unit, Fondazione Filarete, Milan, Italy
| | - E. Jenny Heathcote
- Department of Medicine
- University Health Network, Liver Centre, Toronto Western Hospital, Toronto, Ontario, Canada
| | - Andrew L. Mason
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Robert P. Myers
- Liver Unit, Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
| | | | - Joseph A. Odin
- Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY, USA
| | - Velimir A. Luketic
- Department of Gastroenterology, Virginia Commonwealth University, Richmond, VA, USA
| | - Bruce R. Bacon
- Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St Louis, MO, USA
| | - Henry C. Bodenheimer
- Department of Medicine, Beth Israel Medical Center, Albert Einstein College of Medicine, New York, NY, USA
| | - Valentina Liakina
- Centre of Hepatology, Gastroenterology and Dietetics, Vilnius University, Vilnius, Lithuania
| | - Catherine Vincent
- Universite de Montreal Hospital Centre, Saint-Luc Hospital, Montreal, Quebec, Canada
| | - Cynthia Levy
- Center for Liver Diseases Division of Hepatology, University of Miami School of Medicine, Miami, FL, USA
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Peter K. Gregersen
- Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY, USA and
| | - Fabrizio Bossa
- Division of Gastroenterology, IRCCS-CSS Hospital, San Giovanni Rotondo, Italy
| | | | - Mariza deAndrade
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | | | | | | | | | - Katherine A. Siminovitch
- Department of Medicine
- Department of Immunology and
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
- Mount Sinai Hospital, Samuel Lunenfeld Research Institute and Toronto General Research Institute, Toronto, Ontario, Canada
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Rheumatoid arthritis and primary biliary cirrhosis: cause, consequence, or coincidence? ARTHRITIS 2012; 2012:391567. [PMID: 23150824 PMCID: PMC3488395 DOI: 10.1155/2012/391567] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/28/2012] [Accepted: 09/28/2012] [Indexed: 12/14/2022]
Abstract
Primary biliary cirrhosis (PBC) is a progressive cholestatic liver disease characterized serologically by cholestasis and the presence of high-titre antimitochondrial antibodies and histologically by chronic nonsuppurative cholangitis and granulomata. PBC patients often have concomitant autoimmune diseases, including arthropathies. This raises the question as to whether there are shared features in the pathogenesis of those diseases with the pathogenesis of PBC. Epidemiological and large case studies have indicated that although the incidence of rheumatoid arthritis (RA) is not significantly raised in PBC patients, there appears to be a higher rate of RA in PBC patients and their relatives. Genetic studies have demonstrated that several genes implicated in PBC have also been implicated in RA. Epigenetic studies provided a wealth of data regarding RA, but the findings on epigenetic changes in PBC are very limited. As well, certain infectious agents identified in the pathogenesis of PBC may also play a role in the pathogenesis of RA. These data suggest that although RA is not significantly present in PBC, some individuals with certain genetic traits and environmental exposures may develop both conditions. This concept may also apply to other concomitant diseases found in PBC patients.
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Abstract
Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic autoimmune liver disease characterized by the destruction of small intrahepatic bile ducts and the presence of highly specific serum antimitochondrial antibodies (AMAs). The human leukocyte antigen (HLA) gene has been proved to have strongest association with PBC susceptibility, and non-HLA genes, including IL12A, IL12RB2, STAT4, IRF5-TNPO3, ORMDL3/IKZF3, MMEL1, SPIB, CTLA-4, FCRL3 and A2BP1, are also closely associated with PBC susceptibility. Four AMAs including anti-M2, anti-M4, anti-M8 and anti-M9, and antinuclear antibodies (ANAs), such as antinuclear dot antibodies (SP100, PML, NDP52, SP140), antinuclear pore antibodies (gp210, p62), antinuclear envelope antibodies (Lamin and Lamin B receptor), and anti-centromere antibodies, may also be involved in the pathogenesis of PBC. The imbalance between Th17 cells and regulatory T lymphocytes (Treg) may also play an important role in the pathogenesis of PBC. In addition, senescence, autophagy, apoptosis of biliary epithelial cells (BECs), and environmental factors, such as Epstein-Barr virus (EBV) infection and smoking, may also contribute to the pathogenesis of PBC. Understanding of the mechanisms responsible for the pathogenesis of PBC has important implications for the treatment of PBC.
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45
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Milkiewicz M, Caballería L, Smyk DS, Milkiewicz P. Predicting and preventing autoimmunity: the case of anti-mitochondrial antibodies. AUTOIMMUNITY HIGHLIGHTS 2012; 3:105-12. [PMID: 26000133 PMCID: PMC4389078 DOI: 10.1007/s13317-012-0038-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/22/2012] [Accepted: 10/03/2012] [Indexed: 12/12/2022]
Abstract
To be able to predict who will develop autoimmune disease would allow for early treatment which may dramatically alter the course of the disease. In some cases, it may also lead to prevention of the disease development. The prediction of disease development is based on the analysis of risk factors which have been associated with the disease in question. These factors include genetic susceptibility, as well as immunological and environmental factors. One autoimmune disease that may serve as a model for disease prediction is primary biliary cirrhosis (PBC), an autoimmune liver disease affecting the small- and medium-sized bile ducts. PBC could be an ideal model due to recent advances in elucidating its genetic associations. As well, a variety of immunological and environmental risk factors have been well established. Indeed, the presence of PBC-specific antimitochondrial antibodies and/or antinuclear antibodies has been shown to be predictor of disease development and possibly prognosis. This review will examine the current evidence which suggests that we may potentially be able to predict the development of PBC in some individuals. These concepts may also be applied to autoimmune diseases in general.
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Affiliation(s)
| | | | - Daniel S Smyk
- Institute of Liver Studies, King's College London School of Medicine, London, UK
| | - Piotr Milkiewicz
- Liver Unit, Pomeranian Medical University, Al. Powstancow Wlkp. 72, 70-111 Szczecin, Poland
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Trivedi PJ, Hirschfield GM. Review article: overlap syndromes and autoimmune liver disease. Aliment Pharmacol Ther 2012; 36:517-33. [PMID: 22817525 DOI: 10.1111/j.1365-2036.2012.05223.x] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2012] [Revised: 03/30/2012] [Accepted: 07/01/2012] [Indexed: 12/12/2022]
Abstract
BACKGROUND Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) all nestle within the family of autoimmune liver diseases, whereby the result of immune-mediated liver injury gives rise to varied clinical presentations. Some patients demonstrate a phenotype whereby there is evidence of either PBC or PSC together with overlapping features of AIH. Due to an absence of well-validated diagnostic criteria and a lack of large therapeutic trials, treatment of overlap conditions is empiric and extrapolated from data derived from the primary autoimmune liver diseases. AIMS To review overlaps in the context of autoimmune liver diseases. METHODS General and specific review of published articles using PubMed, Medline and Ovid search engines, alongside pre-existing clinical management protocols, guidelines, and the authors' own knowledge of the published literature. RESULTS The challenges in diagnosis, clinical presentation, determining natural history and outcome of overlaps are presented, as well as present-day management suggestions, some based on evidence, others on consensus and opinion. CONCLUSIONS Overlapping autoimmune features, be they clinical, serological, histological or radiological are not infrequent, but appropriate diagnosis remains hindered by a lack of standardised diagnostic criteria. Optimum care for those with suspected overlap should thus focus on attention to detail over the fundamental aspects of timely secure diagnosis of the dominant disease entity. Clinicians should counsel patients carefully with regard to the risks and benefits of treatment, bearing in mind the paucity of randomised and controlled outcome data for medical interventions.
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Affiliation(s)
- P J Trivedi
- Centre for Liver Research and NIHR Biomedical Research Unit, University of Birmingham, Birmingham, UK
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47
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Invernizzi P, Alessio MG, Smyk DS, Lleo A, Sonzogni A, Fabris L, Candusso M, Bogdanos DP, Iorio R, Torre G. Autoimmune hepatitis type 2 associated with an unexpected and transient presence of primary biliary cirrhosis-specific antimitochondrial antibodies: a case study and review of the literature. BMC Gastroenterol 2012; 12:92. [PMID: 22816667 PMCID: PMC3464927 DOI: 10.1186/1471-230x-12-92] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2012] [Accepted: 07/20/2012] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Unlike other autoimmune liver diseases, primary biliary cirrhosis (PBC) has never been reported in early childhood, while type 2 autoimmune hepatitis (AIH) is eminently a paediatric disease. CASE PRESENTATION We describe a case of type 2 AIH with serological positivity for PBC-specific anti-mitochondrial antibodies (AMA) in a 3-year old girl. We found this observation intriguing as AMA and indeed an overlap with PBC are virtually absent in Type 2 AIH, a pediatric form of AIH which is distinct precisely because it is characterized by pathognomonic anti-liver kidney microsomal type 1 (LKM-1) showing a remarkable antigen-specificity directed against cytochrome P4502D6. We also review the literature in relation to AMA positivity in paediatric age and adolescence. In our case, the presence of AIH-2-specific anti-LKM-1 and PBC-specific AMA was confirmed by indirect immunofluorescence (IIF), and immunoblotting and ELISA based on recombinant mitochondrial antigens. The clinical, laboratory and histological features of the child are given in detail. Interestingly the mother was AMA positive without other features of PBC. The child was successfully treated with immunosuppression and five years after the original diagnosis is on a low dose of prednisolone and azathioprine, with no signs of relapse. Anti-LKM-1 antibodies are still present in low titres. AMA were detectable for the first 4 years after the diagnosis and disappeared later. CONCLUSION This is the first case report in the literature of AIH type 2 with an unexpected PBC-specific AMA positivity in a young child. Response to immunosuppressive treatment was satisfactory and similar to that described in AIH. A review of published reports on AMA positivity in paediatric age shows that the antibody may arise in the context of immunodeficiency and is variably associated with liver damage.
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Affiliation(s)
- Pietro Invernizzi
- Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano(MI), Italy
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | | | - Daniel S Smyk
- Institute of Liver Studies, King’s College London School of Medicine at King’s College Hospital, Denmark Hill Campus, London, UK
| | - Ana Lleo
- Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano(MI), Italy
| | - Aurelio Sonzogni
- Department of Medicine and Transplantation, Ospedali Riuniti, Bergamo, Italy
| | - Luca Fabris
- Department of Surgical and Gastroenterological Sciences, University of Padova, Padova, Italy
- Center for Liver Research (CeLiveR), Ospedali Riuniti, Bergamo, Italy
| | | | - Dimitrios P Bogdanos
- Institute of Liver Studies, King’s College London School of Medicine at King’s College Hospital, Denmark Hill Campus, London, UK
| | - Raffaele Iorio
- Department of Pediatrics, Federico II University, Naples, Italy
| | - Giuliano Torre
- Division of Pediatrics, Ospedali Riuniti, Bergamo, Italy
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Hirschfield GM, Xie G, Lu E, Sun Y, Juran BD, Chellappa V, Coltescu C, Mason AL, Milkiewicz P, Myers RP, Odin JA, Luketic VA, Bacon B, Bodenheimer H, Liakina V, Vincent C, Levy C, Pillai S, Lazaridis KN, Amos CI, Siminovitch KA. Association of primary biliary cirrhosis with variants in the CLEC16A, SOCS1, SPIB and SIAE immunomodulatory genes. Genes Immun 2012; 13:328-335. [PMID: 22257840 PMCID: PMC3360983 DOI: 10.1038/gene.2011.89] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2011] [Revised: 11/29/2011] [Accepted: 12/05/2011] [Indexed: 12/21/2022]
Abstract
We fine mapped two primary biliary cirrhosis (PBC) risk loci, CLEC16A (C-type lectin domain family 16 member A)-suppressor of cytokine signaling 1 (SOCS1) and Spi-B protein (SPIB) and sequenced a locus, sialic acid acetylesterase (SIAE), proposed to harbor autoimmunity-associated mutations. In all, 1450 PBC cases and 2957 healthy controls were genotyped for 84 single-nucleotide polymorphisms (SNPs) across the CLEC16A-SOCS1 and SPIB loci. All 10 exons of the SIAE gene were resequenced in 381 cases and point substitutions of unknown significance assayed for activity and secretion. Fine mapping identified 26 SNPs across the CLEC16A-SOCS1 and 11 SNPs across the SPIB locus with significant association to PBC, the strongest signals at the CLEC16A-SOCS1 locus emanating from a SOCS1 intergenic SNP (rs243325; P=9.91 × 10(-9)) and at the SPIB locus from a SPIB intronic SNP (rs34944112; P=3.65 × 10(-9)). Among the associated SNPs at the CLEC16A-SOCS1 locus, two within the CLEC16A gene as well as one SOCS1 SNP (rs243325) remained significant after conditional logistic regression and contributed independently to risk. Sequencing of the SIAE gene and functional assays of newly identified variants revealed six patients with functional non-synonymous SIAE mutations (Fisher's P=9 × 10(-4) vs controls) We demonstrate independent effects on risk of PBC for CLEC16A, SOCS1 and SPIB variants, while identifying functionally defective SIAE variants as potential factors in risk for PBC.
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Affiliation(s)
- GM Hirschfield
- Liver Centre, Toronto Western Hospital, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - G Xie
- Mount Sinai Hospital, Samuel Lunenfeld Research Institute and Toronto General Research Institute, Toronto, Ontario, Canada
| | - E Lu
- Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Y Sun
- Mount Sinai Hospital, Samuel Lunenfeld Research Institute and Toronto General Research Institute, Toronto, Ontario, Canada
| | - BD Juran
- Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN; USA
| | - V Chellappa
- Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - C Coltescu
- Liver Centre, Toronto Western Hospital, Toronto, Ontario, Canada
| | - AL Mason
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - P Milkiewicz
- Liver Unit, Pomeranian Medical School, Szczecin, Poland
| | - RP Myers
- Liver Unit, University of Calgary, Calgary, Alberta, Canada
| | - JA Odin
- Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY, USA
| | - VA Luketic
- Department of Gastroenterology, Virginia Commonwealth University, Richmond, VA, USA
| | - B Bacon
- Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St Louis, MO, USA
| | - H Bodenheimer
- Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA
| | - V Liakina
- Centre of Gastroenterology and Dietetics, Vilnius University, Vilnius, Lithuania
| | - C Vincent
- Université de Montréal Hospital Centre, Saint-Luc Hospital, Montréal, Quebec, Canada
| | - C Levy
- Center for Liver Diseases Division of Hepatology, University of Miami School of Medicine, Miami, FL, USA
| | - S Pillai
- Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - KN Lazaridis
- Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN; USA
| | - CI Amos
- Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - KA Siminovitch
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Mount Sinai Hospital, Samuel Lunenfeld Research Institute and Toronto General Research Institute, Toronto, Ontario, Canada
- Departments of Immunology and Molecular Genetics, University of Toronto, Ontario, Canada
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49
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Sex differences associated with primary biliary cirrhosis. Clin Dev Immunol 2012; 2012:610504. [PMID: 22693524 PMCID: PMC3369468 DOI: 10.1155/2012/610504] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2012] [Accepted: 02/27/2012] [Indexed: 12/14/2022]
Abstract
Primary biliary cirrhosis (PBC) is a cholestatic liver disease of autoimmune origin, characterised by the destruction of small intrahepatic bile ducts. The disease has an unpredictable clinical course but may progress to fibrosis and cirrhosis. The diagnostic hallmark of PBC is the presence of disease-specific antimitochondrial antibodies (AMA), which are pathognomonic for the development of PBC. The disease overwhelmingly affects females, with some cases of male PBC being reported. The reasons underlying the low incidence of males with PBC are largely unknown. Epidemiological studies estimate that approximately 7–11% of PBC patients are males. There does not appear to be any histological, serological, or biochemical differences between male and female PBC, although the symptomatology may differ, with males being at higher risk of life-threatening complications such as gastrointestinal bleeding and hepatoma. Studies on X chromosome and sex hormones are of interest when studying the low preponderance of PBC in males; however, these studies are far from conclusive. This paper will critically analyze the literature surrounding PBC in males.
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50
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Uibo R, Kisand K, Yang CY, Gershwin ME. Primary biliary cirrhosis: a multi-faced interactive disease involving genetics, environment and the immune response. APMIS 2012; 120:857-71. [PMID: 23009110 DOI: 10.1111/j.1600-0463.2012.02914.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2012] [Accepted: 04/10/2012] [Indexed: 12/12/2022]
Abstract
Primary biliary cirrhosis (PBC) is considered a model autoimmune disease based on several features, including the presence of a highly directed and very specific immune response to mitochondrial autoantigens, a female predominance, a targeted destruction of the biliary epithelium, and homogeneity between patients. It is essentially a chronic progressive cholestatic liver disease characterized by immune-mediated destruction of small- and medium-sized intrahepatic bile ducts. There is considerable variation in the incidence and prevalence of the disease between regions of the world, although such differences likely reflect not only a true disparity in disease but also differences in awareness; for example, in the United States, PBC is often detected in an asymptomatic stage based on multi-phasic clinical testing. There has been considerable progress at defining the immune response in this disease, including quantitation of autoreactive T cells against PDC-E2, the major mitochondrial autoantigen. The overwhelming data suggests that patients develop PBC based on a genetic predisposition and loss of tolerance to one or more environmental agents. In this review, we will present an updated overview of PBC and place it in the context of autoimmunity.
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Affiliation(s)
- Raivo Uibo
- Institute of General and Molecular Pathology, Centre of Excellence for Translational Medicine, University of Tartu, Tartu, Estonia.
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