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Shaker M, Mansour N, John BV. Primary Biliary Cholangitis in Males: Pathogenesis, Clinical Presentation, and Prognosis. Clin Liver Dis 2022; 26:643-655. [PMID: 36270721 DOI: 10.1016/j.cld.2022.06.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis (PBC) is an immune-mediated chronic liver disease characterized by progressive cholestasis, bile duct destruction, biliary fibrosis, and cirrhosis. Patients who respond to ursodeoxycholic acid have an expected survival similar to the general population. Although PBC primarily affects females, the prevalence in males is higher than was previously believed, with contemporary studies suggesting a female-to-male ratio of 4-6:1. A diagnosis of PBC is often delayed among males because of the myth that PBC is rare in males.
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Affiliation(s)
- Mina Shaker
- Division of Hepatology, Miami VA Medical Center 1201 NW 16th Street, Miami, FL 33125 USA.
| | - Natalie Mansour
- Division of Hepatology, Miami VA Medical Center 1201 NW 16th Street, Miami, FL 33125 USA
| | - Binu V John
- Division of Hepatology, Miami VA Medical Center 1201 NW 16th Street, Miami, FL 33125 USA; Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
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2
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Chen R, Tang R, Ma X, Gershwin ME. Immunologic Responses and the Pathophysiology of Primary Biliary Cholangitis. Clin Liver Dis 2022; 26:583-611. [PMID: 36270718 DOI: 10.1016/j.cld.2022.06.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis (PBC) is an autoimmune liver disease with a female predisposition and selective destruction of intrahepatic small bile ducts leading to nonsuppurative destructive cholangitis. It is characterized by seropositivity of antimitochondrial antibodies or PBC-specific antinuclear antibodies, progressive cholestasis, and typical liver histologic manifestations. Destruction of the protective bicarbonate-rich umbrella is attributed to the decreased expression of membrane transporters in biliary epithelial cells (BECs), leading to the accumulation of hydrophobic bile acids and sensitizing BECs to apoptosis. A recent X-wide association study reveals a novel risk locus on the X chromosome, which reiterates the importance of Treg cells.
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Affiliation(s)
- Ruiling Chen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Ruqi Tang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China.
| | - M Eric Gershwin
- Division of Rheumatology-Allergy and Clinical Immunology, University of California at Davis, 451 Health Sciences Drive, Suite 6510, Davis, CA 95616, USA.
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3
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The prognostic value of antibodies to gp210 among patients with primary biliary cholangitis in Northeast China. Dig Liver Dis 2022; 54:1094-1100. [PMID: 34789400 DOI: 10.1016/j.dld.2021.10.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 10/26/2021] [Accepted: 10/26/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Whether the anti-gp210 antibody can be used as a biomarker in patients with primary biliary cholangitis (PBC) remains controversial. AIMS We aimed to investigate the association between anti-gp210 antibodies and prognosis in ursodeoxycholic acid (UDCA)-treated PBC patients. METHODS We conducted a retrospective cohort study of 180 UDCA-treated PBC patients to assess the prognostic value of anti-gp210 antibodies using the Kaplan-Meier method and Cox proportional hazard regression analysis. RESULTS Of the patients included in our analysis, 50 (27.8%) were anti-gp210 positive, and 130 (72.2%) were anti-gp210 negative. The incidence of liver-related death or transplantation was more common in the anti-gp210 + group (22.0 vs. 9.2%, P=0.022). The five-year transplant-free survival rates of anti-gp210-positive patients vs. anti-gp210-negative patients were 77.0% and 90.3%, respectively. We found that the probability of transplant-free survival was significantly lower in the anti-gp210-positive patients than in the anti-gp210-negative patients (log-rank P=0.004). After adjusting for potential confounders using multivariable Cox regression model, positivity for anti-gp210 antibody (hazard ratio: 4.619, 95% confidence interval: 1.895-11.261, P=0.001) was found to be independently associated with an increase in liver-related mortality or transplantation. CONCLUSION In this cohort of UDCA-treated PBC patients, positivity for anti-gp210 antibody was independently associated with a higher risk of liver-related death or transplantation.
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4
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Nguyen HH, Fritzler MJ, Swain MG. A Review on Biomarkers for the Evaluation of Autoimmune Cholestatic Liver Diseases and Their Overlap Syndromes. FRONTIERS IN MOLECULAR MEDICINE 2022; 2:914505. [PMID: 39086971 PMCID: PMC11285550 DOI: 10.3389/fmmed.2022.914505] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 05/30/2022] [Indexed: 08/02/2024]
Abstract
Autoimmune cholestatic liver disease includes both Primary Biliary Cholangitis (PBC) and Primary Sclerosing Cholangitis (PSC). Both conditions result in impairment of hepatic bile flow ultimately leading to chronic liver injury, liver fibrosis and eventually end stage cirrhosis. Early and accurate diagnosis are important for the risk stratification, follow up and management of these patients. The underlying pathogenesis of these conditions have not been completely resolved and poses a barrier for the development of new diagnostic and prognostics tools. Current research work suggests that the pathogenesis of autoimmune cholestatic liver disease results from environmental, genetic, and a large component of underlying immune dysfunction. While the current available serum biomarkers and imaging modalities showcases progression in precision medicine for the management of autoimmune cholestatic liver disease, development of new biomarkers are still an area of need in this field. In this review, we will discuss the current and emerging biomarkers in patients with PBC, PSC, and a special population that exhibit overlap syndrome with autoimmune hepatitis (AIH). The use of these biomarkers for diagnosis and prognosis of these patients will be reviewed through the lens of the current understanding of the complex immune pathophysiology of these conditions.
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Affiliation(s)
- Henry H. Nguyen
- University of Calgary Liver Unit, Department of Medicine & Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Marvin J. Fritzler
- Department of Medicine, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Mark G. Swain
- University of Calgary Liver Unit, Department of Medicine, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
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5
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Gulamhusein AF, Hirschfield GM. Pathophysiology of primary biliary cholangitis. Best Pract Res Clin Gastroenterol 2018; 34-35:17-25. [PMID: 30343706 DOI: 10.1016/j.bpg.2018.05.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 05/22/2018] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis is a prototypical autoimmune disease characterized by an overwhelming female predominance, a distinct clinical phenotype, and disease specific anti-mitochondrial antibodies targeted against a well-defined auto-antigen. In a genetically susceptible host, multi-lineage loss of tolerance to the E2 component of the 2-oxo-dehydrogenase pathway and dysregulated immune pathways directed at biliary epithelial cells leads to cholestasis, progressive biliary fibrosis, and cirrhosis in a subset of patients. Several key insights have shed light on the complex pathogenesis of disease. First, characteristic anti-mitochondrial antibodies (AMAs) target lipoic acid containing immunodominant epitopes, particularly pyruvate dehydrogenase complex (PDC-E2), on the inner mitochondrial membrane of BECs. Next, breakdown of the protective apical bicarbonate rich umbrella may sensitize BECs to aberrant apoptotic pathways leaving the antigenic PDC-E2 epitope immunologically tact within an apoptotic bleb. A multi-lineage immune response ensues characterized by an imbalance between effector and regulatory activity resulting in progressive and self-perpetuating biliary injury. Genome wide studies shed light on important pathways involved in disease, key among them being IL-12. Epigenetic mechanisms and microRNAs may play help shed light on the missing heritability and female preponderance of disease. Taken together, these findings have dramatically advanced our understanding of disease and may lead to important therapeutic advances.
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Affiliation(s)
- Aliya F Gulamhusein
- Toronto Centre for Liver Disease, 200 Elizabeth Street, Toronto, ON, Canada.
| | - Gideon M Hirschfield
- Centre for Liver Research and NIHR Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK.
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6
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Gatselis NK, Dalekos GN. Molecular diagnostic testing for primary biliary cholangitis. Expert Rev Mol Diagn 2016; 16:1001-10. [DOI: 10.1080/14737159.2016.1217159] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Nikolaos K. Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
| | - George N. Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
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7
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Mitra S, Minz RW. Autoantibodies in Autoimmune Liver Diseases-Methods of Detection and Interpretation: An Update for the Reporting Pathologist. Int J Surg Pathol 2016; 24:576-85. [PMID: 27388199 DOI: 10.1177/1066896916657643] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Autoimmune liver disease (AILD) is a type of chronic liver disease with autoimmune etiology. The diagnosis of the disease is multipronged and detection of autoantibodies in AILDs is an important diagnostic tool and it also helps in the classification of the disease. There are multiple autoantibodies that are detected in AILDs but none is diagnostic. Moreover, these autoantibodies are detected in many other pathological and nonpathological conditions. So the significance of seropositivity for these autoantibodies should be known by both the pathologists as well as the clinicians. In addition, there is prognostic significance associated with some of the antibodies and they also sometimes help in the disease monitoring. The whole array of antibodies detected in AILDs is discussed in detail in this review along with their clinical significance and interpretation.
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Affiliation(s)
- Suvradeep Mitra
- PGIMER (Post-Graduate Institute of Medical Education and Research), Chandigarh, India
| | - Ranjana Walker Minz
- PGIMER (Post-Graduate Institute of Medical Education and Research), Chandigarh, India
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8
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Affiliation(s)
- Diego Vergani
- Institute of Liver Studies, King's College Hospital, London, UK
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9
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Saverino D, Pesce G, Antola P, Porcelli B, Brusca I, Villalta D, Tampoia M, Tozzoli R, Tonutti E, Alessio MG, Bagnasco M, Bizzaro N. High levels of soluble CTLA-4 are present in anti-mitochondrial antibody positive, but not in antibody negative patients with primary biliary cirrhosis. PLoS One 2014; 9:e112509. [PMID: 25383768 PMCID: PMC4226553 DOI: 10.1371/journal.pone.0112509] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Accepted: 10/19/2014] [Indexed: 12/15/2022] Open
Abstract
Primary biliary cirrhosis (PBC) is a chronic autoimmune cholestatic liver disease frequently characterized by anti-mitochondrial autoantibodies (AMA). A minority of patients are AMA-negative. Cytotoxic-T-Lymphocyte-Antigen-4 (CTLA-4) is a surface molecule expressed on activated T-cells delivering a critical negative immunoregulatory signal. A soluble form of CTLA-4 (sCTLA-4) has been detected at high concentrations in several autoimmune diseases, and its possible functional meaning has been suggested. We aimed to evaluate sCTLA-4 concentration in sera of patients with PBC and to correlate it to immunological abnormalities associated with the disease. Blood samples were collected from 82 PBC-patients diagnosed according to international criteria (44 AMA-positive/MIT3-positive and 38 AMA-negative-MIT3-negative), and 65 controls. sCTLA-4 levels were evaluated by ELISA and Western blot. Increased sCTLA-4 concentrations were found in all AMA-positive PBC-patients, but in none of the AMA-negative ones, nor in normal controls or in controls with unrelated liver diseases. sCTLA-4 presence was associated with autoantibodies against MIT3, but not with nuclear autoantibodies (sp100, gp210). This is the first study to demonstrate that levels of sCTLA-4 are elevated in sera of PBC patients. However, they are clearly restricted to patients with AMA positivity, suggesting an immunological difference with respect to AMA-negative ones.
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Affiliation(s)
- Daniele Saverino
- Department of Experimental Medicine – Section of Human Anatomy, University of Genova, Genova, Italy
| | - Giampaola Pesce
- Autoimmunity Unit, Department of Internal Medicine, University of Genova, Genova, Italy
| | - Princey Antola
- Autoimmunity Unit, Department of Internal Medicine, University of Genova, Genova, Italy
| | | | - Ignazio Brusca
- Department of Clinical Pathology, Buccheri La Ferla Hospital, Palermo, Italy
| | - Danilo Villalta
- Allergology and Clinical Immunology, S. Maria degli Angeli Hospital, Pordenone, Italy
| | - Marilina Tampoia
- Laboratory of Clinical Pathology, University Hospital, Bari, Italy
| | - Renato Tozzoli
- Clinical Pathology, Department of Laboratory Medicine, S. Maria degli Angeli Hospital, Pordenone, Italy
| | - Elio Tonutti
- Immunopathology and Allergology Unit, S. Maria della Misericordia Hospital, Udine, Italy
| | - Maria Grazia Alessio
- Department of Laboratory Medicine, Biochemistry Laboratory, Riuniti Hospital, Bergamo, Italy
| | - Marcello Bagnasco
- Autoimmunity Unit, Department of Internal Medicine, University of Genova, Genova, Italy
| | - Nicola Bizzaro
- Laboratory of Clinical Pathology, San Antonio Hospital, Tolmezzo, Udine, Italy
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Senécal JL, Isabelle C, Fritzler MJ, Targoff IN, Goldstein R, Gagné M, Raynauld JP, Joyal F, Troyanov Y, Dabauvalle MC. An autoimmune myositis-overlap syndrome associated with autoantibodies to nuclear pore complexes: description and long-term follow-up of the anti-Nup syndrome. Medicine (Baltimore) 2014; 93:383-394. [PMID: 25500708 PMCID: PMC4602431 DOI: 10.1097/md.0000000000000223] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Autoimmune myositis encompasses various myositis-overlap syndromes, each being identified by the presence of serum marker autoantibodies. We describe a novel myositis-overlap syndrome in 4 patients characterized by the presence of a unique immunologic marker, autoantibodies to nuclear pore complexes. The clinical phenotype was characterized by prominent myositis in association with erosive, anti-CCP, and rheumatoid factor-positive arthritis, trigeminal neuralgia, mild interstitial lung disease, Raynaud phenomenon, and weight loss. The myositis was typically chronic, relapsing, and refractory to corticosteroids alone, but remitted with the addition of a second immunomodulating drug. There was no clinical or laboratory evidence for liver disease. The prognosis was good with 100% long-term survival (mean follow-up 19.5 yr).By indirect immunofluorescence on HEp-2 cells, sera from all 4 patients displayed a high titer of antinuclear autoantibodies (ANA) with a distinct punctate peripheral (rim) fluorescent pattern of the nuclear envelope characteristic of nuclear pore complexes. Reactivity with nuclear pore complexes was confirmed by immunoelectron microscopy. In a cohort of 100 French Canadian patients with autoimmune myositis, the nuclear pore complex fluorescent ANA pattern was restricted to these 4 patients (4%). It was not observed in sera from 393 adult patients with systemic sclerosis (n = 112), mixed connective tissue disease (n = 35), systemic lupus (n = 94), rheumatoid arthritis (n = 45), or other rheumatic diseases (n = 107), nor was it observed in 62 normal adults.Autoantibodies to nuclear pore complexes were predominantly of IgG isotype. No other IgG autoantibody markers for defined connective tissue diseases or overlap syndromes were present, indicating a selective and highly focused immune response. In 3 patients, anti-nuclear pore complex autoantibody titers varied in parallel with myositis activity, suggesting a pathogenic link to pathophysiology. The nuclear pore complex proteins, that is, nucleoporins (nup), recognized by these sera were heterogeneous and included Nup358/RanBP2 (n = 2 patients), Nup90 (n = 1), Nup62 (n = 1), and gp210 (n = 1). Taken together the data suggest that nup autoantigens themselves drive the anti-nup autoimmune response. Immunogenetically, the 4 patients shared the DQA1*0501 allele associated with an increased risk for autoimmune myositis.In conclusion, we report an apparent novel subset of autoimmune myositis in our population of French Canadian patients with connective tissue diseases. This syndrome is recognized by the presence of a unique immunologic marker, autoantibodies to nuclear pore complexes that react with nups, consistent with an "anti-nup syndrome."
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Affiliation(s)
- Jean-Luc Senécal
- From the Department of Medicine, Divisions of Rheumatology (JLS, CI, JPR, YT) and Internal Medicine (FJ), and Laboratory for Research in Autoimmunity, Research Center of the Centre Hospitalier de l'Université de Montréal, University of Montreal Faculty of Medicine, Montreal, Quebec, Canada; Mitogen Advanced Diagnostics Laboratory (MJF), Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada; Veterans Affairs Medical Center (INT), University of Oklahoma Health Sciences Center, and Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States; McGill University (RG), Montreal, Quebec, Canada; Polyclinique Saint-Eustache (MG), Saint-Eustache, Quebec, Canada; Biocenter (MCD), Division of Electron Microscopy, University of Würzburg, Am Hubland, Würzburg, Germany
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Liberal R, Grant CR, Sakkas L, Bizzaro N, Bogdanos DP. Diagnostic and clinical significance of anti-centromere antibodies in primary biliary cirrhosis. Clin Res Hepatol Gastroenterol 2013; 37:572-85. [PMID: 23876351 DOI: 10.1016/j.clinre.2013.04.005] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Revised: 03/31/2013] [Accepted: 04/23/2013] [Indexed: 02/04/2023]
Abstract
Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver characterised by biochemical evidence of cholestasis, elevated alkaline phosphatase levels and the presence of the highly disease specific anti-mitochondrial autoantibodies. Extra-hepatic autoimmune manifestations are common, including rheumatic disorders, such as systemic sclerosis (SSc). Notably, PBC is the most frequent autoimmune liver disease in SSc patients. Based on skin lesion extension, two major SSc disease subgroups are recognised: limited cutaneous SSc (lSSc) and diffuse cutaneous SSc. Anti-centromere antibody (ACA) positivity is highly characteristic of SSc, with up to 90% prevalence in lSSc patients. ACA has also been found in up to 30% of PBC patients and 80% of patients with a PBC/SSc overlap syndrome. The diagnostic and clinical significance of ACA positivity in patients with PBC without SSc has recently been under investigation, with several studies highlighting links to severe bile duct injury and portal hypertension. This review discusses the diagnostic and clinical relevance of ACA in patients with PBC, with or without SSc.
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Affiliation(s)
- Rodrigo Liberal
- Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, Denmark Hill Campus, London SE5 9RS, UK; Faculty of Medicine, University of Porto, Porto, Portugal.
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12
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Smyk DS, Orfanidou T, Invernizzi P, Bogdanos DP, Lenzi M. Vitamin D in autoimmune liver disease. Clin Res Hepatol Gastroenterol 2013; 37:535-45. [PMID: 23845396 DOI: 10.1016/j.clinre.2013.05.016] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2013] [Revised: 04/27/2013] [Accepted: 05/28/2013] [Indexed: 02/04/2023]
Abstract
The development of autoimmune disease is based on the interaction of genetic susceptibility and environmental causes. Environmental factors include infectious and non-infectious agents, with some of these factors being implicated in several autoimmune diseases. Vitamin D is now believed to play a role in the development (or prevention) of several autoimmune diseases, based on its immunomodulatory properties. As well, the increasing incidence of autoimmune disease as one moves away from the equator, may be due to the lack of sunlight, which is crucial for the maintenance of normal vitamin D levels. A deficiency in vitamin D levels or vitamin D receptors is commonly indicated in autoimmune diseases, with multiple sclerosis (MS) being one of the best-studied and well-known examples. However, the role of vitamin D in other autoimmune diseases is not well defined, including autoimmune liver diseases such as primary biliary cirrhosis, autoimmune hepatitis, and primary sclerosing cholangitis. This review will examine the role of vitamin D as an immunomodulator, followed by a comparison of vitamin D in MS versus autoimmune liver disease. From this comparison, it will become clear that vitamin D likely plays a role in the development of autoimmune liver disease, but this area requires further investigation.
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Affiliation(s)
- Daniel S Smyk
- Institute of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, King's College London Medical School at King's College London Hospital, Denmark Hill Campus, London, SE5 9RS, UK.
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Sfakianaki O, Tzardi M, Voumvouraki A, Afgoustaki A, Koulentaki M, Kouroumalis E. Presence of disease specific autoantibodies against liver sinusoidal cells in primary biliary cirrhosis. World J Hepatol 2013; 5:568-576. [PMID: 24179616 PMCID: PMC3812459 DOI: 10.4254/wjh.v5.i10.568] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2013] [Revised: 07/20/2013] [Accepted: 09/13/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the presence of autoantibodies directed against liver sinusoidal cells in primary biliary cirrhosis (PBC).
METHODS: Liver biopsies from 21 PBC patients were studied and compared with 12 liver biopsies from disease controls [3 patients with hepatitis B (HBV) virus, 3 patients with hepatitis C virus (HCV), 3 patients with non-alcoholic steatohepatitis and 3 patients with acute alcoholic hepatitis (AAH)]. As healthy controls, we used tissue specimens adjacent to metastatic liver adenocarcinoma. Normal serum was taken from staff members of the unit. The determination of the cell type targeted by autoantibodies present in the patients sera was performed by indirect immunofluorescence (IIF) analysis using paraffin-embedded liver sections as a substrate. Sera from homologous or heterologous PBC patients or sera from the disease control group were used as primary antibodies. The presence of autoantibodies was identified using confocal microscopy.
RESULTS: In total, 18/21 (85.7%) PBC patients exhibited positive staining in the sinusoidal cells, 10/21 (47.6%) in lymphocytes, 8/21 (38%) in cholangiocytes and 7/21 (33.3%) in hepatocytes, when homologous serum and fluorescein isothiocyanate-conjugated immunoglobulin type G (IgG) secondary antibody were used. PBC sections incubated with heterologous PBC serum showed reduced staining (20% for sinusoidal cells, 20% for lymphocytes, 20% for cholangiocytes and 13.3% for hepatocytes). When IgM immunoglobulin, instead of IgG, was used as secondary antibody, positive staining was observed in 75% of lymphocytes, 62.5% of cholangiocytes, 37.5% of hepatocytes and 50% of the sinusoidal cells with a much stronger staining intensity. No staining was observed when either normal or PBC sera were used as a primary antibody on liver sections from the disease control group. When PBC sera were incubated with healthy control sections, weak positive staining of cholangiocytes was observed in 3/21 (14.3%) PBC serum samples. Steatohepatitis serum on PBC sections gave a positive staining of some hepatocytes and lymphocytes but no staining on viral hepatitis sections. Incubation with HBV sera stained some hepatocytes, cholangiocytes and intra-sinusoidal or portal lymphocytes of PBC, HBV and AAH patients but not HCV patients.
CONCLUSION: In this study, for the first time in diseased liver tissue, we have demonstrated that a large proportion of PBC patients have disease specific autoantibodies against liver sinusoidal cells.
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Gressner AM, Arndt T. A. LEXIKON DER MEDIZINISCHEN LABORATORIUMSDIAGNOSTIK 2013. [PMCID: PMC7123472 DOI: 10.1007/978-3-642-12921-6_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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15
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P. LEXIKON DER MEDIZINISCHEN LABORATORIUMSDIAGNOSTIK 2013. [PMCID: PMC7123940 DOI: 10.1007/978-3-642-12921-6_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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16
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Koutsoumpas AL, Kriese S, Rigopoulou EI. Popular and unpopular infectious agents linked to primary biliary cirrhosis. AUTO- IMMUNITY HIGHLIGHTS 2012; 3:95-104. [PMID: 26000132 PMCID: PMC4389080 DOI: 10.1007/s13317-012-0039-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/24/2012] [Accepted: 10/03/2012] [Indexed: 12/12/2022]
Abstract
Primary biliary cirrhosis (PBC) is a progressive cholestatic liver disease characterized by the autoimmune destruction of the biliary epithelial cells of the small and medium-size bile ducts. The disease affects middle aged women and usually affects more than one member within a family. The pathognomonic serological hallmark of the disease is the presence of circulating anti-mitochondrial antibodies, and disease-specific anti-nuclear antibodies. Susceptibility genes and environmental risk factors such as infections and smoking have been reported as important for the development of the disease. Among the environmental agents, infectious triggers are the best studied. Most of the work published so far has investigated the role of infections caused by Novosphingobium aromaticivorans and Escherichia coli. This review will discuss the popular and unpopular infectious agents causatively linked to PBC. It will also examine reports investigating the epidemiological aspects of the disease and their direct or indirect implications to bacterial-induced PBC.
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Affiliation(s)
| | | | - Eirini I. Rigopoulou
- Department of Medicine, University of Thessaly Medical School, Viopolis, Mezourlo, 41110 Larissa, Greece
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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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Smyk D, Rigopoulou EI, Zen Y, Abeles RD, Billinis C, Pares A, Bogdanos DP. Role for mycobacterial infection in pathogenesis of primary biliary cirrhosis? World J Gastroenterol 2012; 18:4855-65. [PMID: 23002357 PMCID: PMC3447267 DOI: 10.3748/wjg.v18.i35.4855] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2011] [Revised: 04/16/2012] [Accepted: 05/06/2012] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cirrhosis (PBC) is a progressive cholestatic liver disease characterized by the immune-mediated destruction of biliary epithelial cells in small intrahepatic bile ducts. The disease is characterized by circulating antimitochondrial antibodies (AMAs) as well as disease-specific antinuclear antibodies, cholestatic liver function tests, and characteristic histological features, including granulomas. A variety of organisms are involved in granuloma formation, of which mycobacteria are the most commonly associated. This has led to the hypothesis that mycobacteria may be involved in the pathogenesis of PBC, along with other infectious agents. Additionally, AMAs are found in a subgroup of patients with mycobacterial infections, such as leprosy and pulmonary tuberculosis. Antibodies against species-specific mycobacterial proteins have been reported in patients with PBC, but it is not clear whether these antibodies are specific for the disease. In addition, data in support of the involvement of the role of molecular mimicry between mycobacterial and human mitochondrial antigens as triggers of cross-reactive immune responses leading to the loss of immunological tolerance, and the induction of pathological features have been published. Thus, antibodies against mycobacterial heat shock protein appear to cross-recognize AMA-specific autoantigens, but it is not clear whether these autoantibodies are mycobacterium-species-specific, and whether they are pathogenic or incidental. The view that mycobacteria are infectious triggers of PBC is intriguing, but the data provided so far are not conclusive.
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Smyk D, Rigopoulou EI, Baum H, Burroughs AK, Vergani D, Bogdanos DP. Autoimmunity and environment: am I at risk? Clin Rev Allergy Immunol 2012; 42:199-212. [PMID: 21337133 DOI: 10.1007/s12016-011-8259-x] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The complex interplay between environmental factors and genetic susceptibility plays an essential role in disease pathogenesis. This is especially true for autoimmunity, where clinical reports, genomic and epidemiological studies, as well as animal models have identified several environmental and genetic risk factors associated with autoimmune disease. The complexity of this relationship is demonstrated by the vast array of environmental factors that have now been implicated in the induction, and possibly the maintenance of autoimmune disease. The multitude of environmental factors implicated includes both infectious and non-infectious agents. Here, we review one specific autoimmune disease, primary biliary cirrhosis (PBC), as a model for environmental risk factors acting in concert with genetic susceptibility in the disease pathogenesis. PBC is an ideal model, as both infectious and non-infectious environmental agents have been identified as risk factors, and their study provides clues for unravelling the pathogenesis of the disease.
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Affiliation(s)
- Daniel Smyk
- Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, UK.
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20
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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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21
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Epstein-barr virus as a trigger of autoimmune liver diseases. Adv Virol 2012; 2012:987471. [PMID: 22693505 PMCID: PMC3368154 DOI: 10.1155/2012/987471] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2012] [Accepted: 03/09/2012] [Indexed: 02/08/2023] Open
Abstract
The pathogenesis of autoimmune diseases includes a combination of genetic factors and environmental exposures including infectious agents. Infectious triggers are commonly indicated as being involved in the induction of autoimmune disease, with Epstein-Barr virus (EBV) being implicated in several autoimmune disorders. EBV is appealing in the pathogenesis of autoimmune disease, due to its high prevalence worldwide, its persistency throughout life in the host's B lymphocytes, and its ability to alter the host's immune response and to inhibit apoptosis. However, the evidence in support of EBV in the pathogenesis varies among diseases. Autoimmune liver diseases (AiLDs), including autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC), have a potential causative link with EBV. The data surrounding EBV and AiLD are scarce. The lack of evidence surrounding EBV in AiLD may also be reflective of the rarity of these conditions. EBV infection has also been linked to other autoimmune conditions, which are often found to be concomitant with AiLD. This paper will critically examine the literature surrounding the link between EBV infection and AiLD development. The current evidence is far from being conclusive of the theory of a link between EBV and AiLD.
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Duarte-Rey C, Bogdanos D, Yang CY, Roberts K, Leung PSC, Anaya JM, Worman HJ, Gershwin ME. Primary biliary cirrhosis and the nuclear pore complex. Autoimmun Rev 2012; 11:898-902. [PMID: 22487189 DOI: 10.1016/j.autrev.2012.03.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2012] [Accepted: 03/19/2012] [Indexed: 12/15/2022]
Abstract
Experimental models of autoimmune diseases have led to the conclusion that an immune response to nuclear antigens is a sentinel marker for loss of tolerance and potential tissue damage. Various proteins are targets of antinuclear antibodies in a variety of autoimmune diseases, ranging from systemic rheumatologic disorders to diseases affecting specific organs such as the liver. Autoantibodies against specific nuclear constituents have also been used as probes to understand the structure and the function of the targeted components and their relevance to disease pathogenesis. Approximately a quarter of patients with primary biliary cirrhosis (PBC) have antibodies targeting proteins of the nuclear pore complex (NPC), a multi-protein structure that mediates molecular transport across the nuclear envelope. Autoantibodies against the integral membrane glycoprotein gp210 and nucleoporin p62 appear to be highly specific for PBC, an autoimmune disease characterized by progressive destruction of intrahepatic biliary epithelial cells. This review discusses the diagnostic and clinical relevance of anti-NPC antibodies in PBC and the possibility that this autoimmune response may arise as a result of molecular mimicry.
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Affiliation(s)
- Carolina Duarte-Rey
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616, USA
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23
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Smyk D, Rigopoulou EI, Bizzaro N, Bogdanos DP. Hair dyes as a risk for autoimmunity: from systemic lupus erythematosus to primary biliary cirrhosis. AUTOIMMUNITY HIGHLIGHTS 2012; 4:1-9. [PMID: 26000137 PMCID: PMC4389085 DOI: 10.1007/s13317-011-0027-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/19/2011] [Accepted: 10/17/2011] [Indexed: 12/12/2022]
Abstract
Environmental and genetic factors appear to be involved in the pathogenesis of primary biliary cirrhosis (PBC), a chronic cholestatic liver disease characterized by immune-mediated destruction of the small and medium sized intrahepatic bile ducts. Environmental factors include exposure to various infectious, xenobiotic and chemical compounds. These exposures may occur occupationally, through water or air contamination, pharmacological administration or by elective exposure, to name a few. Hair dyes are compounds that have been implicated in the development of several autoimmune diseases, including systemic lupus erythematosus (SLE) and PBC. So far, only epidemiological studies have addressed the role of hair dyes in PBC, with limited results. Hair dyes in SLE have been examined, and have recently demonstrated an association, both epidemiologically and immunologically. This follows a series of negative studies, which may not have taken into account several features of hair dye use. This review will examine the literature surrounding hair dye use and SLE, and compare this to data surrounding PBC. Treating physicians should be prepared for questions surrounding the need to take precautions against repeated hair dye use and this topic is discussed further.
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Affiliation(s)
- Daniel Smyk
- Institute of Liver Studies and Liver Unit, Transplantation Immunology and Mucosal Biology, King's College London, School of Medicine, King's College Hospital, Denmark Hill Campus, London, SE5 9RS UK
| | - Eirini I Rigopoulou
- Department of Medicine, University of Thessaly Medical School, Thessaly, Mezourlo, 41222 Larissa, Greece
| | - Nicola Bizzaro
- Laboratorio di Patologia Clinica, Ospedale Civile, Tolmezzo, Italy
| | - Dimitrios P Bogdanos
- Institute of Liver Studies and Liver Unit, Transplantation Immunology and Mucosal Biology, King's College London, School of Medicine, King's College Hospital, Denmark Hill Campus, London, SE5 9RS UK
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24
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Primary biliary cirrhosis associated with systemic sclerosis: diagnostic and clinical challenges. Int J Rheumatol 2011; 2011:976427. [PMID: 22187566 PMCID: PMC3236477 DOI: 10.1155/2011/976427] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2011] [Accepted: 09/07/2011] [Indexed: 12/14/2022] Open
Abstract
Patients with primary biliary cirrhosis (PBC) often have concurrent limited systemic sclerosis (SSc). Conversely, up to one-fourth of SSc patients are positive for PBC-specific antimitochondrial antibodies (AMA). The mechanisms responsible for the co-occurrence of these diseases are largely unknown. Genetic, epigenetic, environmental, and infectious factors appear to be important for the pathogenesis of the disease, but the hierarchy of events are not well defined. Patients with SSc and PBC have an increased morbidity and mortality compared with the general population, but whether the presence of both diseases in an affected individual worsens the prognosis and/or outcome of either disease is not clear. Some case reports suggested that the presence of SSc in PBC patents is associated with a more favorable prognosis of the liver disease, whereas others report an increased mortality in patients with PBC and SSc compared to patients with PBC alone. This paper discusses the features of patients with PBC-associated SSc. Our aims are to clarify some of the pathogenetic, diagnostic, and clinical challenges that are currently faced in the routine management of these patients. We also intend to provide some practical hints for practitioners that will assist in the early identification of patients with PBC-associated SSc.
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Smyk DS, Mytilinaiou MG, Milkiewicz P, Rigopoulou EI, Invernizzi P, Bogdanos DP. Towards systemic sclerosis and away from primary biliary cirrhosis: the case of PTPN22. AUTOIMMUNITY HIGHLIGHTS 2011; 3:1-9. [PMID: 26000122 PMCID: PMC4389021 DOI: 10.1007/s13317-011-0023-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/16/2011] [Accepted: 07/29/2011] [Indexed: 12/12/2022]
Abstract
Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized by immune-mediated destruction of the small and medium size intrahepatic bile ducts. PBC patients often have concomitant autoimmune diseases, which are most often autoimmune thyroid disease, as well as Sicca syndrome. Occasionally, some PBC patients will also have systemic sclerosis of the limited cutaneous type (lcSSc). Conversely, up to one-fourth of SSc patients are positive for antimitochondrial antibody, the serologic hallmark of PBC. It is also common for SSc patients to have concomitant autoimmune disease, which may include PBC in rare cases. This has led to speculation of shared environmental and/or genetic factors, which lead to the development of PBC in SSc patients and vice versa. Recent genetic studies have revealed associations with several genes in both SSc and PBC. PTPN22 is one gene that has been associated with SSc, but not with PBC. It may be argued that some SSc patients with a particular genotype, which shares genes found in both conditions may develop PBC. Likewise, particular genes such as PTPN22 may infer susceptibility to SSc alone. The presence of PTPN22 may also contribute to the development of SSc in PBC patients. The lack of a large number of overlapping genes may, in part, explain the relative rarity of PBC with SSc and vice versa. This review will examine the literature surrounding the genetic associations of PBC and SSc, and the role of PTPN22 in particular.
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Affiliation(s)
- Daniel S. Smyk
- Institute of Liver Studies, King’s College London School of Medicine at King’s College Hospital, Denmark Hill Campus, London, SE5 9RS UK
| | - Maria G. Mytilinaiou
- Institute of Liver Studies, King’s College London School of Medicine at King’s College Hospital, Denmark Hill Campus, London, SE5 9RS UK
| | - Piotr Milkiewicz
- Liver Unit, Liver Unit and Liver Research Laboratories, Pomeranian Medical University, SPSK2, Powstancow Wlkp, 7270-111 Szczecin, Poland
| | - Eirini I. Rigopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, University of Thessaly Medical School, Thessaly, Mezourlo, Larissa, 41222 Greece
| | - Pietro Invernizzi
- Center for Autoimmune Liver Diseases, Division of Internal Medicine, IRCCS Istituto Clinico Humanitas, Rozzano, Italy
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA USA
| | - Dimitrios P. Bogdanos
- Institute of Liver Studies, King’s College London School of Medicine at King’s College Hospital, Denmark Hill Campus, London, SE5 9RS UK
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26
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Smyk D, Cholongitas E, Kriese S, Rigopoulou EI, Bogdanos DP. Primary biliary cirrhosis: family stories. Autoimmune Dis 2011; 2011:189585. [PMID: 21687641 PMCID: PMC3112499 DOI: 10.4061/2011/189585] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2010] [Revised: 02/09/2011] [Accepted: 03/07/2011] [Indexed: 01/03/2023] Open
Abstract
Primary biliary cirrhosis (PBC) is a chronic immune-mediated cholestatic liver disease of unknown aetiology which affects mostly women in middle age. Familial PBC is when PBC affects more than one member of the same family, and data suggest that first-degree relatives of PBC patients have an increased risk of developing the disease. Most often, these familial clusters involve mother-daughter pairs, which is consistent with the female preponderance of the disease. These clusters provide evidence towards a genetic basis underlying PBC. However, clusters of nonrelated individuals have also been reported, giving strength to an environmental component. Twin studies have demonstrated a high concordance for PBC in monozygotic twins and a low concordance among dizygotic twins. In conclusion, studies of PBC in families clearly demonstrate that genetic, epigenetic, and environmental factors play a role in the development of the disease.
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Affiliation(s)
- Daniel Smyk
- Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, Denmark Hill Campus, London SE5 9RS, UK
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27
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Performance parameters of the conventional serological markers for autoimmune hepatitis. Dig Dis Sci 2011; 56:545-54. [PMID: 21127976 DOI: 10.1007/s10620-010-1501-1] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2010] [Accepted: 11/15/2010] [Indexed: 12/15/2022]
Abstract
BACKGROUND Autoimmune hepatitis is defined by a conventional battery of autoantibodies that may also be present in other liver diseases. AIMS To define the performance parameters of the conventional autoantibodies for autoimmune hepatitis, determine the diagnostic implications of simultaneous autoantibody production, and assess the performances of serological assays based on indirect immunofluorescence and enzyme immunoassay. METHODS In this study, 265 adults satisfying codified criteria for autoimmune hepatitis and 342 adults who satisfied conventional diagnostic criteria for another chronic liver disease were each assessed for the conventional autoantibodies. RESULTS Antinuclear antibodies, smooth muscle antibodies, and antibodies to liver kidney type 1 had sensitivities of only 32, 16, and 1%, respectively, for the diagnosis of autoimmune hepatitis, and their diagnostic accuracy ranged from 56 to 61%. The combination of antinuclear antibodies and smooth muscle antibodies at presentation had superior sensitivity (43%), specificity (99%), positive (97%) and negative (69%) predictabilities, and diagnostic accuracy (74%) than each marker alone. The occurrence of multiple autoantibodies was lower in other chronic liver diseases than in autoimmune hepatitis (8% versus 51%, p < 0.000001). The enzyme immunoassay for antinuclear antibodies had an accuracy that was not discriminative for autoimmune hepatitis (p = 0.06). CONCLUSIONS Isolated autoantibodies have a low diagnostic accuracy for autoimmune hepatitis. Concurrent antinuclear antibodies and smooth muscle antibodies have superior performance parameters. The enzyme immunoassay for antinuclear antibodies performs less well than the assay based on indirect immunofluorescence.
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Czaja AJ. Autoantibodies as prognostic markers in autoimmune liver disease. Dig Dis Sci 2010; 55:2144-61. [PMID: 20464491 DOI: 10.1007/s10620-010-1268-4] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2010] [Accepted: 04/23/2010] [Indexed: 01/25/2023]
Abstract
Certain autoantibodies in autoimmune liver disease have prognostic implications that are under-utilized and under-developed. The goals of this review are to indicate progress in characterizing the autoantibodies with prognostic connotations and to indicate the feasibility and importance of discovering other markers. Prime source and review articles in English were selected by a Medline search through 2010. Antibodies to soluble liver antigen, actin, liver cytosol type 1, asialoglycoprotein receptor, chromatin, cyclic citrullinated peptide, and uridine glucuronosyltransferases have been associated with the occurrence, severity, and progression of autoimmune hepatitis, and antibodies to Sp100, gp210, and centromere have had similar implications in primary biliary cirrhosis. Antibodies to soluble liver antigen have shown the most promise in autoimmune hepatitis as they have been associated with severe histological changes, long durations of treatment, relapse after drug withdrawal, and high frequency of liver failure. Antibodies to the nuclear rim pore protein, gp210, have shown the most promise in primary biliary cirrhosis as they have been associated with severe interface hepatitis, lobular inflammation, and progression to liver failure. The major limitations of the autoantibodies have been their lack of standardized assays, low negative predictabilities, and fluctuating levels. Performance parameters will improve as critical pathogenic pathways, comprehensive testing batteries, and standardized assays through international exchange workshops are developed. Progress has been made in identifying the serological markers of prognosis in autoimmune liver disease, and they promise to reflect critical disease mechanisms and enhance patient management.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
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29
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Nakamura M, Yasunami M, Kondo H, Horie H, Aiba Y, Komori A, Migita K, Yatsuhashi H, Ito M, Shimoda S, Ishibashi H. Analysis of HLA-DRB1 polymorphisms in Japanese patients with primary biliary cirrhosis (PBC): The HLA-DRB1polymorphism determines the relative risk of antinuclear antibodies for disease progression in PBC. Hepatol Res 2010; 40:494-504. [PMID: 20374297 DOI: 10.1111/j.1872-034x.2010.00631.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIMS Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis (PBC). However, the association of human leukocyte antigen (HLA) polymorphisms with these risk factors is unknown. METHODS We determined the HLA-DRB1 genotype in 334 Japanese PBC patients and studied their serum antibodies to gp210 and centromere during the 1-452-month observation period. RESULTS Anti-gp210 (odds ratio [OR] 46.56, 95% confidence interval [CI], 9.20-850.1) and anti-centromere antibodies (OR, 2.36, 95% CI, 1.28-4.35) were significant risk factors for jaundice- and nonjaundice-type progression, respectively. HLA-DRB1*0405 and *0803 predisposed patients to anti-gp210 (OR, 1.61, 95% CI, 1.08-2.39) and anti-centromere (OR, 2.30, 95% CI, 1.41-3.73) antibody production, respectively. HLA-DRB1*1502 and *0901 patients were predisposed to nonjaundice-type progression (OR, 1.98, 95% CI, 1.13-3.40 and OR, 1.78, 95% CI, 1.02-3.03), while HLA-DRB1*0803 and *0405 patients were predisposed to disease development (OR, 2.24, 95% CI, 1.48-3.41 and OR, 1.53, 95% CI, 1.11-2.11, respectively). Stratifying patients by HLA-DRB1 alleles revealed that anti-gp210 antibodies was a strong risk factor, regardless of the HLA-DRB1 alleles for jaundice-type progression, while anti-centromere antibodies was a significant risk factor for nonjaundice-type progression in patients with HLA-DRB1*0405 (OR, 6.89, 95% CI, 2.18-26.56) and -DRB1*0803 (OR, 5.42, 95% CI, 1.47-24.62) but not other HLA-DRB1 alleles. CONCLUSIONS HLA-DRB1 polymorphisms are significantly associated with not only disease development and progression but also antinuclear antibody production and the determination of the relative risk of antinuclear antibodies that contribute to PBC disease progression.
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Affiliation(s)
- Minoru Nakamura
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center
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30
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Bogdanos DP, Invernizzi P, Mackay IR, Vergani D. Autoimmune liver serology: Current diagnostic and clinical challenges. World J Gastroenterol 2008; 14:3374-87. [PMID: 18528935 PMCID: PMC2716592 DOI: 10.3748/wjg.14.3374] [Citation(s) in RCA: 141] [Impact Index Per Article: 8.3] [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
Liver-related autoantibodies are crucial for the correct diagnosis and classification of autoimmune liver diseases (AiLD), namely autoimmune hepatitis types 1 and 2 (AIH-1 and 2), primary biliary cirrhosis (PBC), and the sclerosing cholangitis variants in adults and children. AIH-1 is specified by anti-nuclear antibody (ANA) and smooth muscle antibody (SMA). AIH-2 is specified by antibody to liver kidney microsomal antigen type-1 (anti-LKM1) and anti-liver cytosol type 1 (anti-LC1). SMA, ANA and anti-LKM antibodies can be present in de-novo AIH following liver transplantation. PBC is specified by antimitochondrial antibodies (AMA) reacting with enzymes of the 2-oxo-acid dehydrogenase complexes (chiefly pyruvate dehydrogenase complex E2 subunit) and disease-specific ANA mainly reacting with nuclear pore gp210 and nuclear body sp100. Sclerosing cholangitis presents as at least two variants, first the classical primary sclerosing cholangitis (PSC) mostly affecting adult men wherein the only (and non-specific) reactivity is an atypical perinuclear antineutrophil cytoplasmic antibody (p-ANCA), also termed perinuclear anti-neutrophil nuclear antibodies (p-ANNA) and second the childhood disease called autoimmune sclerosing cholangitis (ASC) with serological features resembling those of type 1 AIH. Liver diagnostic serology is a fast-expanding area of investigation as new purified and recombinant autoantigens, and automated technologies such as ELISAs and bead assays, become available to complement (or even compete with) traditional immunofluorescence procedures. We survey for the first time global trends in quality assurance impacting as it does on (1) manufacturers/purveyors of kits and reagents, (2) diagnostic service laboratories that fulfill clinicians’ requirements, and (3) the end-user, the physician providing patient care, who must properly interpret test results in the overall clinical context.
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31
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Meda F, Zuin M, Invernizzi P, Vergani D, Selmi C. Serum autoantibodies: a road map for the clinical hepatologist. Autoimmunity 2008; 41:27-34. [PMID: 18176862 DOI: 10.1080/08916930701619227] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
The widespread use of serum autoantibodies in the practice of clinical hepatology has led to novel challenges in the interpretation of results obtained with routine techniques, such as indirect immunofluorescence (IIF) or with recombinant antigens. In fact, the laboratory methods are often overlooked factors in the interpretation of data by the bedside clinician despite being critical in the interpretation of data. Importantly, the sensitivity and specificity of these serum hallmarks are not defined in all cases. Taken altogether, these observations point towards the need for a systematic discussion of autoimmune serology in the clinical setting of everyday practice. The target of this review article is therefore, to illustrate the current knowledge and available experimental evidence to guide the diagnostic and prognostic decision making in autoimmune and viral chronic liver diseases.
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Affiliation(s)
- Francesca Meda
- Division of Internal Medicine and Liver Unit, San Paolo Hospital School of Medicine, University of Milan, Milan, Italy
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32
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Nakamura M, Komori A, Ito M, Kondo H, Aiba Y, Migita K, Nagaoka S, Ohata K, Yano K, Abiru S, Daikoku M, Yatsuhashi H, Shimoda S, Ishibashi H. Predictive role of anti-gp210 and anticentromere antibodies in long-term outcome of primary biliary cirrhosis. Hepatol Res 2007; 37 Suppl 3:S412-9. [PMID: 17931196 DOI: 10.1111/j.1872-034x.2007.00244.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Because some of the autoreactive T-cell clones specific for human PDC-E2 cross-react to mimicry peptides having an EIExDK motif derived from nuclear antigens such as human gp210 and sp100, we studied the clinical significance of antinuclear antibodies (ANA) in primary biliary cirrhosis (PBC) patients registered to the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ). We found that there are two different types of progression in PBC; one is a hepatic failure-type progression which is represented by positive anti-gp210 antibodies and the other is a portalhypertension-type progression which is represented by positive anticentromere antibodies. We discuss the predictive role of these ANA in the long-term outcome of PBC and the mechanisms by which two different PBC progression types occur based on molecular mimicry and aberrant expression of nuclear antigens.
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Affiliation(s)
- Minoru Nakamura
- National Hospital Organization (NHO) Nagasaki Medical Center, Omura; Nagasaki University Graduate School of Biomedical Sciences, Nagasaki; and National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Fukuoka, Japan
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Nakamura M, Kondo H, Mori T, Komori A, Matsuyama M, Ito M, Takii Y, Koyabu M, Yokoyama T, Migita K, Daikoku M, Abiru S, Yatsuhashi H, Takezaki E, Masaki N, Sugi K, Honda K, Adachi H, Nishi H, Watanabe Y, Nakamura Y, Shimada M, Komatsu T, Saito A, Saoshiro T, Harada H, Sodeyama T, Hayashi S, Masumoto A, Sando T, Yamamoto T, Sakai H, Kobayashi M, Muro T, Koga M, Shums Z, Norman GL, Ishibashi H. Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis. Hepatology 2007; 45:118-127. [PMID: 17187436 DOI: 10.1002/hep.21472] [Citation(s) in RCA: 249] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
UNLABELLED The predictive role of antinuclear antibodies (ANAs) remains elusive in the long-term outcome of primary biliary cirrhosis (PBC). The progression of PBC was evaluated in association with ANAs using stepwise Cox proportional hazard regression and an unconditional stepwise logistic regression model based on the data of 276 biopsy-proven, definite PBC patients who have been registered to the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ). When death of hepatic failure/liver transplantation (LT) was defined as an end-point, positive anti-gp210 antibodies (Hazard ratio (HR) = 6.742, 95% confidence interval (CI): 2.408, 18.877), the late stage (Scheuer's stage 3, 4) (HR = 4.285, 95% CI:1.682,10.913) and male sex (HR = 3.266, 95% CI: 1.321,8.075) were significant risk factors at the time of initial liver biopsy. When clinical progression to death of hepatic failure/LT (i.e., hepatic failure type progression) or to the development of esophageal varices or hepatocellular carcinoma without developing jaundice (Total bilirubin < 1.5 mg/dL) (i.e., portal hypertension type progression) was defined as an end-point in the early stage (Scheuer's stage 1, 2) PBC patients, positive anti-gp210 antibodies was a significant risk factor for hepatic failure type progression [odds ratio (OR) = 33.777, 95% CI: 5.930, 636.745], whereas positive anti-centromere antibodies was a significant risk factor for portal hypertension type progression (OR = 4.202, 95% CI: 1.307, 14.763). Histologically, positive anti-gp210 antibodies was most significantly associated with more severe interface hepatitis and lobular inflammation, whereas positive anticentromere antibodies was most significantly associated with more severe ductular reaction. CONCLUSION These results indicate 2 different progression types in PBC, hepatic failure type and portal hypertension type progression, which may be represented by positive-anti-gp210 and positive-anticentromere antibodies, respectively.
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Affiliation(s)
- Minoru Nakamura
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center and Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Nagasaki, Japan.
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34
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Granito A, Muratori P, Muratori L, Pappas G, Cassani F, Worthington J, Guidi M, Ferri S, DE Molo C, Lenzi M, Chapman RW, Bianchi FB. Antinuclear antibodies giving the 'multiple nuclear dots' or the 'rim-like/membranous' patterns: diagnostic accuracy for primary biliary cirrhosis. Aliment Pharmacol Ther 2006; 24:1575-1583. [PMID: 17206945 DOI: 10.1111/j.1365-2036.2006.03172.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Serum antinuclear antibodies giving the 'multiple nuclear dots' or the 'rim-like/membranous' patterns are frequently detected by indirect immunofluorescence on HEp-2 cells in patients with primary biliary cirrhosis. AIM To assess the accuracy of multiple nuclear dot and rim-like/membranous antinuclear antibodies for the diagnosis of primary biliary cirrhosis. METHODS Sera from 4371 consecutive patients referred to our laboratory were analysed under code for antinuclear antibodies testing by indirect immunofluorescence on HEp-2 cells. RESULTS Review of the clinical records of the 4371 patients allowed identification of 101 patients with antimitochondrial antibody-positive primary biliary cirrhosis and 22 with antimitochondrial antibody-negative variant. Multiple nuclear dot and/or rim-like/membranous patterns were found in 59 (1.3%) of the 4371 patients: 31 antimitochondrial antibody-positive primary biliary cirrhosis, 17 antimitochondrial antibody-negative primary biliary cirrhosis and 11 non-primary biliary cirrhosis. The specificity for primary biliary cirrhosis of both the antinuclear antibodies pattern was 99%. Positive predictive value and likelihood ratio for a positive test were 86% (95% CI: 72.7-94) and 221 (95% CI: 91.7-544) for multiple nuclear dot, 79% (95% CI: 62.2-90.1) and 132 (95% CI: 56.8-312.7) for rim-like/membranous, respectively. CONCLUSIONS Multiple nuclear dot and rim-like/membranous antinuclear antibodies are rare findings. Their positivity strongly suggests the diagnosis of primary biliary cirrhosis, irrespective of antimitochondrial antibody status. The high specificity for primary biliary cirrhosis makes them a useful diagnostic tool especially in antimitochondrial antibody-negative patients.
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Affiliation(s)
- A Granito
- Department of Internal Medicine, Cardioangiology, Hepatology, Alma Mater Studiorum, University of Bologna, Sant'Orsola-Malpighi Hospital, Bologna, Italy.
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35
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Miyachi K, Hosaka H, Nakamura N, Miyakawa H, Mimori T, Shibata M, Matsushima S, Chinoh H, Horigome T, Hankins RW, Zhang M, Fritzler MJ. Anti-p97/VCP antibodies: an autoantibody marker for a subset of primary biliary cirrhosis patients with milder disease? Scand J Immunol 2006; 63:376-82. [PMID: 16640662 DOI: 10.1111/j.1365-3083.2006.01747.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
We previously reported that 12.5% of primary biliary cirrhosis (PBC) sera reacted with a 95 kDa cytosol protein (p95c) that was subsequently identified as a p97/valosin-containing protein (VCP). The clinical features and course of the six anti-p97/VCP-positive PBC patients with Scheuer's stage 1 and 2 liver biopsies were monitored for an average of 15 years. This group was compared with 50 PBC patients that did not have detectable anti-VCP. Autoantibodies to a full-length recombinant p97/VCP were assayed by immunoprecipitation. All six PBC patients with anti-VCP had antibodies to the mitochondrial pyruvate dehydrogenase complex-E2 antigen as measured by an addressable laser bead immunoassay. The first was a male with no evidence of liver failure that died of cerebral infarction at the age of 85. The second was a 73-year-old female with Hashimoto's thyroiditis who has remained clinically stable without ursodeoxycolic acid (UDCA) treatment. Although the third had no HCV antibodies, he developed hepatocellular carcinoma at the age of 76 and died of renal failure at 78. The fourth was a 50-year-old female who remained clinically stable during follow-up and the fifth with Hashimoto's thyroiditis and stable liver function following UCDA treatment. The sixth was a male patient presenting a mild clinical course. The clinical course of these patients was in contrast to the 50 comparison group PBC patients who did not have anti-p97/VCP. As the six PBC patients with anti-p97/VCP antibodies had slowly progressive liver disease and no mortality related to autoimmune liver disease, our observations suggest that this autoantibody might be an indicator of a favourable prognosis.
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Affiliation(s)
- K Miyachi
- First Diagnostic Division, Health Sciences Research Institute, Inc., Yokohama, Japan.
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36
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Terjung B, Spengler U. Role of auto-antibodies for the diagnosis of chronic cholestatic liver diseases. Clin Rev Allergy Immunol 2006; 28:115-33. [PMID: 15879618 DOI: 10.1385/criai:28:2:115] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Auto-antibodies are an integral part of the diagnostic armentarium in chronic cholestatic liver disorders, such as primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC),auto-immune cholangitis, or overlap syndromes among these disorders. However, care should be taken not to overestimate the diagnostic specificity. Auto-antibodies to mitochondrial antigens(AMAs) with reactivity to the E2 subunit of the pyruvate dehydrogenase complex represent the hallmark antibody for the diagnosis of PBC, whereas antinuclear antibodies (ANAs)with low disease specificity are found in up to 50% of these sera. Antibodies that recognize nuclear envelope proteins exert a similarly high diagnostic specificity as AMA in PBC but occur at a rather low prevalence. The role of auto-antibodies is less well-studied for patients with PSC, but there is growing evidence that only antineutrophil cytoplasmic antibodies(ANCAs) are of relevant diagnostic significance. In contrast, auto-antibodies-particularlyAMAs-do not contribute to the diagnosis of auto-immune cholangitis, whereas ANCAs,ANAs, smooth muscle antibodies, and AMAs are of varying significance in PBC-auto-immune hepatitis (AIH) or PSC-AIH overlap syndromes. It has been widely accepted that the course of the auto-antibody serum end point titers are not suited for the clinical management of patients with chronic cholestatic liver disorders. Additionally, auto-antibodies in these disorders usually do not contribute to the immunopathogenesis of the disease.
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MESH Headings
- Antigens, Bacterial/immunology
- Antigens, Nuclear/immunology
- Autoantibodies/blood
- Autoantibodies/immunology
- Autoantigens/immunology
- Autoimmune Diseases/diagnosis
- Autoimmune Diseases/immunology
- Cholangitis, Sclerosing/diagnosis
- Cholangitis, Sclerosing/immunology
- Hepatitis, Autoimmune/diagnosis
- Hepatitis, Autoimmune/immunology
- Humans
- Liver Cirrhosis, Biliary/diagnosis
- Liver Cirrhosis, Biliary/immunology
- Mitochondria, Liver/immunology
- Muscle, Smooth/immunology
- Transglutaminases/immunology
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Affiliation(s)
- Birgit Terjung
- Department of Internal Medicine I, University of Bonn, Bonn, Germany.
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Abstract
Autoantibodies indicate an immune reactive state, but in liver disease they lack pathogenicity and disease specificity. Antinuclear antibodies, smooth muscle antibodies, antibodies to liver/kidney microsome type 1, antimitochondrial antibodies, and perinuclear antineutrophil cytoplasmic antibodies constitute the standard serological repertoire that should be assessed in all liver diseases of undetermined cause. Antibodies to soluble liver antigen/liver pancreas, asialoglycoprotein receptor, actin, liver cytosol type 1, nuclear antigens specific to primary biliary cirrhosis, and pore complex antigens constitute an investigational repertoire that promises to have prognostic and diagnostic value. These autoantibodies may emerge as predictors of treatment response and outcome. Antibodies to histones, doubled-stranded DNA, chromatin, and lactoferrin constitute a supplemental repertoire, and they support the immune nature of the liver disease. Final diagnoses and treatment strategies do not depend solely on serological markers. Autoantibodies are floating variables, and their behavior does not correlate closely with disease activity. There are no minimum levels of significant seropositivity, especially in children. Over-interpretation is the major pitfall in the clinical application of the serological results. New autoantibodies will emerge as the search for target antigens and key pathogenic pathways continues.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
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38
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Nakamura M, Takii Y, Ito M, Komori A, Yokoyama T, Shimizu-Yoshida Y, Koyabu M, Matsuyama M, Mori T, Kamihira T, Daikoku M, Migita K, Yatsuhashi H, Nozaki N, Shimoda S, Ishibashi H. Increased expression of nuclear envelope gp210 antigen in small bile ducts in primary biliary cirrhosis. J Autoimmun 2005; 26:138-45. [PMID: 16337775 DOI: 10.1016/j.jaut.2005.10.007] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2005] [Revised: 10/19/2005] [Accepted: 10/26/2005] [Indexed: 02/07/2023]
Abstract
The sustained antibody response to nuclear envelope gp210 antigen indicates a group of primary biliary cirrhosis (PBC) patients at high risk for the progression to end-stage hepatic failure. To address this issue, we immunohistochemically studied the expression of gp210 antigen in needle liver biopsy specimens from PBC patients using a monoclonal antibody specific for gp210 antigen. The specimens from autoimmune hepatitis (AIH), chronic viral hepatitis B (CHB) and C (CHC) patients served as disease controls. The expression of gp210 antigen was apparently increased on the nuclear envelope of biliary epithelial cells (BECs) of small bile ducts in almost all specimens from PBC. In contrast, the expression of gp210 antigen was negative in BECs of small bile ducts in normal liver, while relatively weak anti-gp210 immunostaining was observed in AIH, CHC and CHB. In addition, the degree of gp210 expression in BECs of small bile ducts was positively correlated to that of portal inflammation, interface hepatitis and lobular inflammation in PBC. These results indicate that the increased expression of gp210 in small bile ducts, which is probably associated with damage to BECs by inflammation, is possibly involved in autoimmune response to gp210 leading to the progression to end-stage hepatic failure in PBC.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Amino Acid Sequence
- Antibodies/blood
- Antibodies, Monoclonal/immunology
- Bile Canaliculi/immunology
- Biopsy, Needle
- Female
- Hepatitis B, Chronic/immunology
- Hepatitis B, Chronic/pathology
- Hepatitis C, Chronic/immunology
- Hepatitis C, Chronic/pathology
- Hepatitis, Autoimmune/immunology
- Hepatitis, Autoimmune/pathology
- Humans
- Liver Cirrhosis, Biliary/complications
- Liver Cirrhosis, Biliary/immunology
- Liver Cirrhosis, Biliary/pathology
- Liver Failure/diagnosis
- Liver Failure/etiology
- Liver Failure/pathology
- Male
- Membrane Glycoproteins/analysis
- Membrane Glycoproteins/chemistry
- Membrane Glycoproteins/immunology
- Middle Aged
- Molecular Sequence Data
- Nuclear Pore Complex Proteins
- Nuclear Proteins/analysis
- Nuclear Proteins/chemistry
- Nuclear Proteins/immunology
- Prognosis
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Affiliation(s)
- Minoru Nakamura
- Clinical Research Center, National Hospital Organization, Nagasaki Medical Center, Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Kubara 2-1001-1, Omura, Nagasaki 856-8562, Japan.
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39
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Nakamura M. [The significance of anti-nuclear envelope (gp210) antibody in primary biliary cirrhosis]. ACTA ACUST UNITED AC 2005; 28:117-22. [PMID: 15997174 DOI: 10.2177/jsci.28.117] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Primary biliary cirrhosis (PBC) is considered to be an autoimmune disease selectively targeted for interlobular bile ducts. While anti-mitochondrial antibodies are specifically detected in more than 90% of PBC patients, anti-nuclear envelope-gp210 antibodies are also specifically detected in 20-30% of PBC patients. In this review, we present 1, T cells specific for mitochondrial major epitope, PDC-E2 163-176, cross-react with peptides derived from nuclear envelope-gp210 protein, 2, PBC patients who have sustained high antibody titers to gp210 are at high risk for the progression to end-stage hepatic failure. These evidences may be very important for the epitope spreading of autoantigens from PDC-E2 to nuclear antigens and for the identification of target antigens on biliary epithelial cells which are recognized by cytotoxic T cells in PBC.
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Affiliation(s)
- Minoru Nakamura
- Clinical Research Center, NHO Nagasaki Medical Center and Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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40
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Nakamura M, Shimizu-Yoshida Y, Takii Y, Komori A, Yokoyama T, Ueki T, Daikoku M, Yano K, Matsumoto T, Migita K, Yatsuhashi H, Ito M, Masaki N, Adachi H, Watanabe Y, Nakamura Y, Saoshiro T, Sodeyama T, Koga M, Shimoda S, Ishibashi H. Antibody titer to gp210-C terminal peptide as a clinical parameter for monitoring primary biliary cirrhosis. J Hepatol 2005; 42:386-392. [PMID: 15710222 DOI: 10.1016/j.jhep.2004.11.016] [Citation(s) in RCA: 99] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2004] [Revised: 10/26/2004] [Accepted: 11/03/2004] [Indexed: 12/12/2022]
Abstract
BACKGROUND/AIMS The presence of antibodies to the 210-kDa glycoprotein of the nuclear pore complex (gp210) is highly indicative of primary biliary cirrhosis (PBC). However, the significance of anti-gp210 antibody titers for monitoring PBC remains unresolved. METHODS We used an ELISA with a gp210 C-terminal peptide as an antigen to assess serum antibody titers in 71 patients with PBC. RESULTS Patients were classified into three groups: Group A in whom anti-gp210 titers were sustained at a high level, Group B in whom anti-gp210 status changed from positive to negative under ursodeoxycholic acid (UDCA) therapy, Group C in whom anti-gp210 antibodies were negative at the time of diagnosis. The rate of progression to end-stage hepatic failure was significantly higher in group A (60%) as compared to groups B (0%) and C (4.2%). The sustained antibody response to gp210 was closely associated with the severity of interface hepatitis. The significance of anti-gp210 antibody was confirmed by National Hospital Organization Study Group for Liver Disease in Japan. CONCLUSIONS The serial quantitation of serum anti-gp210-C-terminal peptide antibodies is useful for monitoring the effect of UDCA and for the early identification of patients at high risk for end-stage hepatic failure.
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Affiliation(s)
- Minoru Nakamura
- Department of Hepatology, Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Nagasaki University Graduate School of Biomedical Sciences, Kubara 2-1001-1, Omura, Nagasaki 856-8562, Japan.
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41
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Sivakamasundari P, Kalaiselvi P, Sakthivel R, Selvam R, Varalakshmi P. Nuclear pore complex oxalate binding protein p62: expression in different kidney disorders. Clin Chim Acta 2004; 347:111-9. [PMID: 15313148 DOI: 10.1016/j.cccn.2004.04.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2004] [Revised: 04/12/2004] [Accepted: 04/13/2004] [Indexed: 11/28/2022]
Abstract
BACKGROUND Urolithiasis is a multifactorial process that starts with the formation of microcrystals in the urine and terminates as mature renal calculi. The oxalate binding protein plays a vital role in the transport of oxalate. The physiological significance of the presence of oxalate binding protein in the nuclear pore complex is not well understood. METHODS The nuclear envelope was extracted from human cadaver kidneys. 14C oxalate was labeled, nuclear pore complex proteins were extracted and loaded onto Sephadex G-200, and further purified in DEAE-Sephadex A-50 column. The radioactive protein peak was pooled, concentrated and checked for purity in SDS-PAGE. The purified protein showed cross-reactivity with the monoclonal antibody (MAb 414) and was homogeneous. Urine samples of healthy individuals with no history of kidney disease served as control. Blood and urine samples were collected from kidney and autoimmune disorder patients and checked for the expression of p62 protein by ELISA. RESULTS Extracted and purified nuclear pore complex oxalate binding protein had a molecular weight of 62 kDa. A threefold increase in oxalate excretion was observed in hyperoxaluric patients compared to control subjects. The protein expression was found to be higher in hyperoxaluric patients vs. controls, chronic renal failure (CRF) and acute renal failure (ARF), whereas decreased expression was observed in nephrotic syndrome (NS) patients. p62 autoantibodies was observed in hyperoxaluria (HO), systemic lupus erythematosus (SLE) and primary biliary cirrhosis (PBC), whereas it was absent in controls. CONCLUSION Increased expression of p62 may be due to membrane damage induced by oxalate stress, and may be used as a diagnostic marker. This study also confirms the presence of p62 autoantibodies in HO patients.
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Affiliation(s)
- P Sivakamasundari
- Department of Medical Biochemistry, University of Madras, Taramani, Chennai-113, India
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42
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Sivakamasundari P, Varalakshmi P, Kannabiran M. Nuclear pore complex oxalate binding protein p62: its expression on oxalate exposure to VERO cells. J Cell Biochem 2004; 93:1099-106. [PMID: 15449314 DOI: 10.1002/jcb.20269] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Oxalate rich stones are the most common among the various stones. Oxalate binding protein plays a vital role in the transport of oxalate. Nuclear pore complex (NPC) contains a protein of molecular weight 62 kDa and it has maximum oxalate binding activity. The physiological significance of the presence of oxalate binding protein in the NPC is not well understood. In order to study its function, the expression of this protein during oxalate stress condition and the morphological changes on oxalate exposure to synchronized VERO cells have been determined. VERO cells were synchronized at different stages of cell cycle using cell cycle blockers and expression of the NPC p62 was assessed using enzyme linked immunosorbent assay (ELISA) technique with p62 antibody (MAb 414). Expression of NPC p62 was more pronounced in 1.0 mM oxalate concentration in mitotic phase than in S phase, suggesting cell cycle dependency. During oxalate exposure there is cell aggregation and complete degeneration of cell morphology occurs, which in turn lead to the expression of certain genes, including the NPC oxalate binding protein p62. Thus, oxalate induces degeneration of cells (may be due to the lipid peroxidation) and leads to the expression of NPC oxalate binding protein and the expression is of cell cycle dependent manner.
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Affiliation(s)
- P Sivakamasundari
- Department of Medical Biochemistry, Dr. ALM Post Graduate Institute of Basic Medical Sciences, Taramani, Chennai 113, India
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43
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Romero-Gómez M, Wichmann I, Crespo J, Parés A, Rodrigo L, Alvarez A, Diago M, Pons-Romero F, Sanchez-Munoz D, Aguilar-Reina J, Andrade RJ, Salmeron J, Sánchez-Pobre P, Rebollo JM, Martin-Vivaldi R, Castellano-Megias V, Nuñez-Roldan A, Bruguera M. Serum immunological profile in patients with chronic autoimmune cholestasis. Am J Gastroenterol 2004; 99:2150-7. [PMID: 15554996 DOI: 10.1111/j.1572-0241.2004.40416.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
AIM To compare patients who had biochemical and histological features of chronic autoimmune cholestasis (CAIC) using serological autoantibody profiling. METHODS Patients (n = 174 CAIC; 79 AMA(-) and 95 AMA(+)) were profiled for the following antibodies: antinuclear antibodies (ANAs), antimitochondrial antibodies (AMAs), antismooth muscle actin (SMA, mainly F-actin), antiperinuclear cytoplasmic neutrophil antibodies (pANCAs), anti-SP100, anti-GP210, anti-M2 (2-oxo-acid dehydrogenase complexes), and antisoluble liver antigen (SLA). Liver specimens were reviewed according to staging, biliary interface activity, lobular hepatitis, granulomas, cholestasis, and florid ductal lesion. RESULTS In patients who were AMA(-) by indirect immunofluorescence (IIF), 34.6% were positive for anti-M2 by immunoblotting. In 49 definitively AMA(-) patients, 24 (48.9%) showed ANA-primary biliary cirrhosis (PBC)-related antibodies (rim-like, multiple nuclear dots, anti-SP100, or anti-GP210). There were no differences in immunological, biochemical, or histopathological features between IIF-AMA(+) patients and AMA(-) patients with anti-M2 or ANA-PBC-related antibodies. AIH-related autoantibodies were found in 13 patients (7.5%). Patients with AMAs or ANA-PBC-related antibodies had higher IgM levels, whereas patients with antibodies highly specific for AIH had higher AST, bilirubin, and IgG levels, and AIH scores, and higher grades of lobular hepatitis. Overall, three distinct categories of patients were observed: AMA(+) or AMA(-) patients with ANA-PBC-related antibodies; AMA(-) patients with non-PBC-related ANAs; and patients with AIH-related antibodies together with serum PBC markers. CONCLUSION Since these three groups had immunological, biochemical, and histopathological differences, they ought to be considered as separate clinical subentities rather than as merely AMA(-) or AMA(+) patients with autoimmune cholestasis.
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44
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Coppo P, Clauvel JP, Bengoufa D, Fuentes V, Gouilleux-Gruart V, Courvalin JC, Lassoued K. Autoimmune cytopenias associated with autoantibodies to nuclear envelope polypeptides. Am J Hematol 2004; 77:241-9. [PMID: 15495255 DOI: 10.1002/ajh.20188] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
A subset of anti-nuclear autoantibodies (ANA) are directed against nuclear envelope (NE) polypeptides and display by indirect immunofluorescence (IIF) a ring-like fluorescent pattern. We report herein 19 patients with autoimmune cytopenias associated with antibodies (Abs) to NE polypeptides. Anti-NE specificity was determined by immunoblot, using NE preparations and purified lamina fractions. Eleven sera reacted with lamin B(1), and two reacted with both lamin B(1) and an unidentified 150-kDa protein (p150). One serum reacted with only p150. Four sera reacted with lamins A and C, and one reacted with and an unidentified 52-kDa NE polypeptide (p52). Autoimmune cytopenias included hemolytic anemia (7 cases), thrombocytopenia (13 cases), and neutropenia (6 cases). Five patients had 2 (3 cases) or 3 (2 cases) different cytopenias. Antiphospholipid antibodies (APLA) were detected in 14 patients, 2 of whom experienced thromboembolic events. A liver disorder was present in 7 patients. Systemic lupus erythematosus and lupus-like syndrome were diagnosed in 11 and 2 patients, respectively. Cytopenias responded to steroids alone (13 patients), or together with intravenous immunoglobulins (2 patients), or cyclophosphamide (2 patients). Two patients did not require treatment. Our results suggest that anti-NE Abs need to be sought for in patients with peripheral cytopenias, particularly when they are associated with APLA and/or liver disorders. Their detection strongly suggests an autoimmune process. Such cytopenias are often manifestations of a lupus or lupus-like disease and are responsive to steroids.
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MESH Headings
- Adolescent
- Adult
- Aged
- Anemia, Hemolytic, Autoimmune/complications
- Anemia, Hemolytic, Autoimmune/drug therapy
- Anemia, Hemolytic, Autoimmune/immunology
- Anemia, Hemolytic, Autoimmune/pathology
- Autoantibodies/immunology
- Autoimmune Diseases/complications
- Autoimmune Diseases/drug therapy
- Autoimmune Diseases/immunology
- Autoimmune Diseases/pathology
- Coombs Test
- Female
- Follow-Up Studies
- Humans
- Immunoblotting
- Liver Diseases/complications
- Liver Diseases/pathology
- Male
- Middle Aged
- Neutropenia/complications
- Neutropenia/drug therapy
- Neutropenia/immunology
- Neutropenia/pathology
- Nuclear Envelope/immunology
- Nuclear Proteins/immunology
- Pancytopenia/complications
- Pancytopenia/drug therapy
- Pancytopenia/immunology
- Pancytopenia/pathology
- Peptides/immunology
- Purpura, Thrombocytopenic/complications
- Purpura, Thrombocytopenic/drug therapy
- Purpura, Thrombocytopenic/immunology
- Purpura, Thrombocytopenic/pathology
- Retrospective Studies
- Treatment Outcome
- Vasculitis/complications
- Vasculitis/pathology
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Affiliation(s)
- Paul Coppo
- Service d'Immuno-Hématologie, Hôpital Saint-Louis, Paris, France
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Czaja AJ, Muratori P, Muratori L, Carpenter HA, Bianchi FB. Diagnostic and therapeutic implications of bile duct injury in autoimmune hepatitis. Liver Int 2004; 24:322-329. [PMID: 15287855 DOI: 10.1111/j.1478-3231.2004.0924.x] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Bile duct injury is not a feature of classical autoimmune hepatitis (AIH), but it has been described in variant forms of the disease. AIMS Our goals were to assess the similarity of AIH with bile duct injury to classical disease and to evaluate the possibility of concurrent primary biliary cirrhosis (PBC). METHODS Fifteen patients with bile duct injury were compared with 151 patients with classical AIH. Patterns of nuclear immunofluorescence and the frequency and nature of autoantibodies associated with AIH and PBC were determined. RESULTS Patients with bile duct injury had the same nuclear-staining patterns, frequency and nature of autoantibodies, and genetic risk factors as the comparison group. Features specific for PBC, including the multiple nuclear dot pattern of immunofluorescence and antibodies to the M2 antigens, Sp100 and nuclear pore complex antigen, gp210, did not distinguish them from classical disease. Remission and treatment failure occurred with similar frequencies in both groups. CONCLUSIONS Patients with AIH and bile duct injury lack features of PBC, and they respond as well to corticosteroid therapy as patients with classical disease. Background bile duct changes should not alter the diagnosis or treatment of AIH.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA.
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Strassburg CP, Manns MP. [Primary biliary liver cirrhosis and overlap syndrome. Diagnosis and therapy]. Internist (Berl) 2004; 45:16-26. [PMID: 14735240 DOI: 10.1007/s00108-003-1127-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Primary biliary cirrhosis represents a chronic cholestatic liver disease of unknown etiology. It primarily affects females, is associated with extrahepatic immune-mediated syndromes, shows an immunogenetic association with HLA DR8, and displays serum autoantibodies, which makes an autoimmune etiology likely. The diagnosis is reached in patients with elevated alkaline phosphatase, gamma glutamyl transferase and bilirubin levels who exhibit normal bile ducts upon ultrasound examination, and in whom specific antimitochondrial autoantibodies are detectable. Half of all PBC patients additionally show specific antinuclear autoantibodies. Immunosuppressive therapy is ineffective; steroids, transplant immunosuppressants, colchicine, d-penicillamine and methotrexate are of limited clinical benefit. Ursodeoxycholic acid has few side effects and leads to a biochemical response and a delay of disease progression in most cases. When ursodeoxycholic acid therapy is ineffective an overlap syndrome with autoimmune hepatitis can be present, which can respond to steroid treatment. The only curative option is liver transplantation which should be considered when bilirubin levels exceed 100 microM/l.
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Affiliation(s)
- C P Strassburg
- Abteilung für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover.
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Miyachi K, Hirano Y, Horigome T, Mimori T, Miyakawa H, Onozuka Y, Shibata M, Hirakata M, Suwa A, Hosaka H, Matsushima S, Komatsu T, Matsushima H, Hankins RW, Fritzler MJ. Autoantibodies from primary biliary cirrhosis patients with anti-p95c antibodies bind to recombinant p97/VCP and inhibit in vitro nuclear envelope assembly. Clin Exp Immunol 2004; 136:568-73. [PMID: 15147362 PMCID: PMC1809050 DOI: 10.1111/j.1365-2249.2004.02456.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
We have reported previously that p95c, a novel 95-kDa cytosolic protein, was the target of autoantibodies in sera of patients with autoimmune hepatic diseases. We studied 30 sera that were shown previously to immunoprecipitate a 95 kDa protein from [(35)S]-methionine-labelled HeLa lysates and had a specific precipitin band in immunodiffusion. Thirteen sera were available to test the ability of p95c antibodies to inhibit nuclear envelope assembly in an in vitro assay in which confocal fluorescence microscopy was also used to identify the stages at which nuclear assembly was inhibited. The percentage inhibition of nuclear envelope assembly of the 13 sera ranged from 7% to 99% and nuclear envelope assembly and the swelling of nucleus was inhibited at several stages. The percentage inhibition of nuclear assembly was correlated with the titre of anti-p95c as determined by immunodiffusion. To confirm the identity of this autoantigen, we used a full-length cDNA of the p97/valosin-containing protein (VCP) to produce a radiolabelled recombinant protein that was then used in an immunoprecipitation (IP) assay. Our study demonstrated that 12 of the 13 (93%) human sera with antibodies to p95c immunoprecipitated recombinant p97/VCP. Because p95c and p97 have similar molecular masses and cell localization, and because the majority of sera bind recombinant p97/VCP and anti-p95c antibodies inhibit nuclear assembly, this is compelling evidence that p95c and p97/VCP are identical.
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Affiliation(s)
- K Miyachi
- Health Sciences Research Institute, Yokohama, Kanagawa, Japan.
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Bogdanos DP, Baum H, Butler P, Rigopoulou EI, Davies ET, Ma Y, Burroughs AK, Vergani D. Association between the primary biliary cirrhosis specific anti-sp100 antibodies and recurrent urinary tract infection. Dig Liver Dis 2003; 35:801-5. [PMID: 14674671 DOI: 10.1016/s1590-8658(03)00466-3] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Recurrent urinary tract infections (rUTI) have been suggested to be involved in the induction of anti-mitochondrial antibodies (AMA), the serological hallmark of primary biliary cirrhosis (PBC), in view of the presence of AMA in rUTI women without liver disease and conversely of a high prevalence of rUTI in women with PBC. This prompted us to investigate whether PBC-specific anti-nuclear antibodies (ANA) to sp100, gp210 and lamin B receptor (LBR) antigens may also be related to rUTI. METHODS AND SUBJECTS PBC-specific ANA reactivities were investigated in 20 women with rUTI but without liver disease, some of whom were AMA-seropositive; 40 women with PBC, with or without rUTI; and 104 pathological and 23 healthy controls. RESULTS Among the women with rUTI but without liver disease, 8 (80%) of 10 AMA-positive women reacted with sp100 compared with none of the 10 AMA-negative women. Among the PBC patients, 14 (74%) of 19 with rUTI and 1 (4.8%) of the 21 without rUTI reacted with sp100. None of the rUTI women without liver disease reacted with gp210 or LBR. None of 127 pathological and healthy controls had PBC-specific ANA reactivity. CONCLUSIONS Anti-sp100 reactivity strongly correlates with AMA seropositivity in rUTI women, with or without evidence of primary biliary cirrhosis. These findings provide additional support to the notion that E. coli infection is involved in the induction of PBC-specific autoimmunity. Additional factors must be involved in the progression to overt autoimmune disease.
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Affiliation(s)
- D P Bogdanos
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE5 9RS, UK
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Abstract
Primary biliary cirrhosis (PBC) is characterized by the presence of high-titer disease specific autoantibodies directed against mitochondrial antigens (AMA) of the inner mitochondrial membrane, that are members of the 2-oxo acid complex. Among numerous other autoantibodies found in PBC the focus of ongoing studies is on the PBC-specific anti-nuclear antibodies, that are of diagnostic and clinical relevance since they can be used as a 'positive tool' in the diagnosis of AMA-negative PBC while at the same time identifying a subgroup of patients with more advanced liver disease.
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Abstract
Autoantibodies are nonpathogenic manifestations of immune reactivity, and they may occur in acute and chronic liver diseases. Autoantibodies may be consequences rather than causes of the liver injury, and they should be regarded as diagnostic clues rather than etiologic markers. Conventional autoantibodies used in the categorization of autoimmune liver disease are antinuclear antibodies, smooth muscle antibodies, antibodies to liver/kidney microsome type 1, antimitochondrial antibodies, and atypical perinuclear anti-neutrophil cytoplasmic antibodies. Ancillary autoantibodies that enhance diagnostic specificity, have prognostic connotation, or direct treatment are antibodies to endomysium, tissue transglutaminase, histones, doubled-stranded DNA, and actin. Autoantibodies that have an emerging diagnostic and prognostic significance are antibodies to soluble liver antigen/liver pancreas, asialoglycoprotein receptor, liver cytosol type 1, and nuclear pore complex antigens. Autoantibodies of uncertain clinical value that remain under investigation are antibodies to chromatin, lactoferrin, and Saccharomyces cervisiae. Continued recognition and characterization of autoantibodies should improve diagnostic precision, provide prognostic indices, and elucidate target autoantigens. These advances may in turn clarify pathogenic mechanisms, facilitate the development of animal models, and generate novel site-specific therapies.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.
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