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Smyk DS, Rigopoulou EI, Darkhabani M, Invernizzi P, Bogdanos DP. Infection and Autoimmune Liver Diseases. INFECTION AND AUTOIMMUNITY 2024:857-875. [DOI: 10.1016/b978-0-323-99130-8.00025-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Gkoutzourelas A, Barmakoudi M, Bogdanos DP. A Bioinformatics Analysis Reveals Novel Pathogens as Molecular Mimicry Triggers of Systemic Sclerosis. Mediterr J Rheumatol 2020; 31:50-70. [PMID: 32411933 PMCID: PMC7219639 DOI: 10.31138/mjr.31.1.50] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 02/01/2020] [Accepted: 02/17/2020] [Indexed: 12/18/2022] Open
Abstract
A recent bioinformatic analysis revealing dominant B cell epitopes of systemic sclerosis-specific autoantibodies, including anti-centromere B, anti-topoisomerase I and anti-fibrillarin, has demonstrated the existence of several in silico antigenic mimics of pathogens that could act as triggers of the respective dominant autoepitopes. Based on those findings, the aim of the present study was to use a more comprehensive bioinformatic analysis. We demonstrated the presence of a plethora of novel microbial mimics, unnoticed by the studies so far conducted, which share remarkable amino acid similarities with the respective autoantigenic epitopes. This bioinformatic approach coupled by in vitro testing of the homologous self/non-self-mimics in serum samples from patients with systemic sclerosis may provide novel evidence of immunological cross-reactivity, implicating currently ignored or overlooked pathogens, which may indeed play a role in the induction of SSc-specific autoantibodies and assist efforts to understand the pathogenesis of this enigmatic disease.
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Affiliation(s)
- Athanasios Gkoutzourelas
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University of Thessaly, Larissa, Greece
| | - Maria Barmakoudi
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University of Thessaly, Larissa, Greece
| | - Dimitrios P Bogdanos
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University of Thessaly, Larissa, Greece
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Nilsson I, Palmer J, Apostolou E, Gottfries CG, Rizwan M, Dahle C, Rosén A. Metabolic Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Not Due to Anti-mitochondrial Antibodies. Front Med (Lausanne) 2020; 7:108. [PMID: 32296708 PMCID: PMC7136523 DOI: 10.3389/fmed.2020.00108] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Accepted: 03/10/2020] [Indexed: 12/11/2022] Open
Abstract
Metabolic profiling studies have recently indicated dysfunctional mitochondria in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This includes an impaired function of pyruvate dehydrogenase complex (PDC), possibly driven by serum factor(s), which leads to inadequate adenosine triphosphate generation and excessive lactate accumulation. A reminiscent energy blockade is likely to occur in primary biliary cholangitis (PBC), caused by anti-PDC autoantibodies, as recently proposed. PBC is associated with fatigue and post-exertional malaise, also signifying ME/CFS. We herein have investigated whether ME/CFS patients have autoreactive antibodies that could interfere with mitochondrial function. We found that only 1 of 161 examined ME/CFS patients was positive for anti-PDC, while all PBC patients (15/15) presented significant IgM, IgG, and IgA anti-PDC reactivity, as previously shown. None of fibromyalgia patients (0/14), multiple sclerosis patients (0/29), and healthy blood donors (0/44) controls showed reactivities. Anti-mitochondrial autoantibodies (inner and outer membrane) were negative in ME/CFS cohort. Anti-cardiolipin antibody levels in patients did not differ significantly from healthy blood donors. In conclusion, the impaired mitochondrial/metabolic dysfunction, observed in ME/CFS, cannot be explained by presence of circulating autoantibodies against the tested mitochondrial epitopes.
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Affiliation(s)
- Isabell Nilsson
- Division of Cell Biology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Jeremy Palmer
- The Medical School, The University Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
| | - Eirini Apostolou
- Division of Cell Biology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | | | - Muhammad Rizwan
- Division of Cell Biology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Charlotte Dahle
- Division of Cell Biology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Anders Rosén
- Division of Cell Biology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
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Liberal R, Gaspar R, Lopes S, Macedo G. Primary biliary cholangitis in patients with inflammatory bowel disease. Clin Res Hepatol Gastroenterol 2020; 44:e5-e9. [PMID: 31171469 DOI: 10.1016/j.clinre.2019.05.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 04/24/2019] [Accepted: 05/09/2019] [Indexed: 02/04/2023]
Abstract
BACKGROUND & AIMS Inflammatory bowel diseases (IBD) are associated with various hepatobiliary disorders. There is a strong association for primary sclerosing cholangitis (PSC). Primary biliary cholangitis (PBC), another autoimmune cholestatic liver disease, is not usually associated with IBD. The aim of this study is to report cases of PBC-associated IBD, their clinical features, response to therapy, and long-term outcome. METHODS Retrospective analysis of a prospectively collated database identified patients presenting with PBC-associated IBD from 2006 to 2016. PBC has been diagnosed according to accepted criteria, and staged according to Ludwig classification. A magnetic resonance cholangiopancreatography (MRCP) was performed to rule out PSC. Response to ursodeoxycholic acid (UDCA) therapy has been assessed by using the Paris II criteria. RESULTS A total of six patients (five females) with PBC-associated IBD were identified. Median age at IBD diagnosis was 44.7 years (range 22.5-48.8). Three had Crohn's disease and three ulcerative colitis. PBC was diagnosed in all after IBD had been diagnosed. All patients presented with cholestasis, all were positive for anti-mitochondrial antibodies. MRCP was normal in all. Liver biopsy was consistent with PBC (stage I in one, stage II in five). One year after initiation of UDCA, all patients responded to therapy. CONCLUSION Herein we describe the largest series reported to date of PBC-associated IBD. Although the coexistence of the two conditions is rare, PBC should be considered during the work-up of abnormal liver function tests in patients with IBD.
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Affiliation(s)
- Rodrigo Liberal
- Gastroenterology and Hepatology Department, Centro Hospitalar Sao Joao, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal.
| | - Rui Gaspar
- Gastroenterology and Hepatology Department, Centro Hospitalar Sao Joao, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal
| | - Susana Lopes
- Gastroenterology and Hepatology Department, Centro Hospitalar Sao Joao, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal
| | - Guilherme Macedo
- Gastroenterology and Hepatology Department, Centro Hospitalar Sao Joao, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal
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Hou X, Yang Y, Chen J, Jia H, Zeng P, Lv L, Lu Y, Liu X, Diao H. TCRβ repertoire of memory T cell reveals potential role for Escherichia coli in the pathogenesis of primary biliary cholangitis. Liver Int 2019; 39:956-966. [PMID: 30721553 DOI: 10.1111/liv.14066] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 11/19/2018] [Accepted: 11/28/2018] [Indexed: 12/24/2022]
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is an organ-specific, T cell-mediated autoimmune disease which is characterized by the breakdown of self-tolerance to the highly conserved pyruvate dehydrogenase complex, especially the pyruvate dehydrogenase E2 complex (PDC-E2). However, the molecular mechanism of breakdown of self-tolerance is still unclear. METHODS A combination of multiplex-PCR and immune repertoire sequencing (IR-seq) was used for a standardized analysis of memory T cell receptor (TCR) β-chain repertoire of PBC patient and healthy volunteers. In vitro induction and expansion of human PDC-E2163-176 (human PDC-E2)-specific T cells and E coli PDC-E231-44/134-147/235-248 (E coli PDC-E2)-specific T cells, and identified the human (and E coli) PDC-E2-specific TCRβ repertoire by IR-seq. RESULTS Primary biliary cholangitis patients have shorter complementarity-determining region 3s (CDR3s), and higher degree of sequence overlap in the TCRβ repertoire of memory T cell. Moreover, altered insertion patterns and skewed TRBV segment usage were observed in PBC patients. With regard to the pathogenesis, the concentration of E coli was higher in PBC patients' faecal. The frequency of E coli (and human)-specific TCRs was higher in the memory TCRβ repertoire of PBC patients compared with healthy controls. Importantly, the TCRβ repertoire characteristics were almost identical between E coli PDC-E2-related TCRs and human PDC-E2-related TCRs, including the patterns of TRBV usage, CDR3 length and amino acid composition. CONCLUSION Our findings comprehensively revealed the TCRβ repertoire characterization of PBC patients, and provided a TCR molecular basis to understand the mechanism of cross-recognition between human PDC-E2 and E coli PDC-E2, and the imbalance of immune tolerance in PBC.
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Affiliation(s)
- Xianliang Hou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yida Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jianing Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Hongyu Jia
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Ping Zeng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Longxian Lv
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yingfeng Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xiangdong Liu
- College of Materials and Textile, Zhejiang Sci-Tech University, Xiasha Higher Education Zone, Hangzhou, China
| | - Hongyan Diao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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The Role of Invariant NKT in Autoimmune Liver Disease: Can Vitamin D Act as an Immunomodulator? Can J Gastroenterol Hepatol 2018; 2018:8197937. [PMID: 30046564 PMCID: PMC6038587 DOI: 10.1155/2018/8197937] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 05/16/2018] [Indexed: 12/18/2022] Open
Abstract
Natural killer T (NKT) cells are a distinct lineage of T cells which express both the T cell receptor (TCR) and natural killer (NK) cell markers. Invariant NKT (iNKT) cells bear an invariant TCR and recognize a small variety of glycolipid antigens presented by CD1d (nonclassical MHC-I). CD1d-restricted iNKT cells are regulators of immune responses and produce cytokines that may be proinflammatory (such as interferon-gamma (IFN-γ)) or anti-inflammatory (such as IL-4). iNKT cells also appear to play a role in B cell regulation and antibody production. Alpha-galactosylceramide (α-GalCer), a derivative of the marine sponge, is a potent stimulator of iNKT cells and has been proposed as a therapeutic iNKT cell activator. Invariant NKT cells have been implicated in the development and perpetuation of several autoimmune diseases such as multiple sclerosis and systemic lupus erythematosus (SLE). Animal models of SLE have shown abnormalities in iNKT cells numbers and function, and an inverse correlation between the frequency of NKT cells and IgG levels has also been observed. The role of iNKT cells in autoimmune liver disease (AiLD) has not been extensively studied. This review discusses the current data with regard to iNKT cells function in AiLD, in addition to providing an overview of iNKT cells function in other autoimmune conditions and animal models. We also discuss data regarding the immunomodulatory effects of vitamin D on iNKT cells, which may serve as a potential therapeutic target, given that deficiencies in vitamin D have been reported in various autoimmune disorders.
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Blomberg J, Gottfries CG, Elfaitouri A, Rizwan M, Rosén A. Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model. Front Immunol 2018; 9:229. [PMID: 29497420 PMCID: PMC5818468 DOI: 10.3389/fimmu.2018.00229] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 01/26/2018] [Indexed: 12/13/2022] Open
Abstract
Myalgic encephalomyelitis (ME) often also called chronic fatigue syndrome (ME/CFS) is a common, debilitating, disease of unknown origin. Although a subject of controversy and a considerable scientific literature, we think that a solid understanding of ME/CFS pathogenesis is emerging. In this study, we compiled recent findings and placed them in the context of the clinical picture and natural history of the disease. A pattern emerged, giving rise to an explanatory model. ME/CFS often starts after or during an infection. A logical explanation is that the infection initiates an autoreactive process, which affects several functions, including brain and energy metabolism. According to our model for ME/CFS pathogenesis, patients with a genetic predisposition and dysbiosis experience a gradual development of B cell clones prone to autoreactivity. Under normal circumstances these B cell offsprings would have led to tolerance. Subsequent exogenous microbial exposition (triggering) can lead to comorbidities such as fibromyalgia, thyroid disorder, and orthostatic hypotension. A decisive infectious trigger may then lead to immunization against autoantigens involved in aerobic energy production and/or hormone receptors and ion channel proteins, producing postexertional malaise and ME/CFS, affecting both muscle and brain. In principle, cloning and sequencing of immunoglobulin variable domains could reveal the evolution of pathogenic clones. Although evidence consistent with the model accumulated in recent years, there are several missing links in it. Hopefully, the hypothesis generates testable propositions that can augment the understanding of the pathogenesis of ME/CFS.
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Affiliation(s)
- Jonas Blomberg
- Department of Medical Sciences, Uppsala University, Clinical Microbiology, Academic Hospital, Uppsala, Sweden
| | | | - Amal Elfaitouri
- Department of Infectious Disease and Tropical Medicine, Faculty of Public Health, Benghazi University, Benghazi, Libya
| | - Muhammad Rizwan
- Department of Medical Sciences, Uppsala University, Clinical Microbiology, Academic Hospital, Uppsala, Sweden
| | - Anders Rosén
- Department of Clinical and Experimental Medicine, Division of Cell Biology, Linköping University, Linköping, Sweden
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Patel A, Seetharam A. Primary Biliary Cholangitis: Disease Pathogenesis and Implications for Established and Novel Therapeutics. J Clin Exp Hepatol 2016; 6:311-318. [PMID: 28003721 PMCID: PMC5157913 DOI: 10.1016/j.jceh.2016.10.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Accepted: 10/10/2016] [Indexed: 02/07/2023] Open
Abstract
Primary Biliary Cholangitis is a progressive, autoimmune cholestatic liver disorder. Cholestasis with disease progression may lead to dyslipidemia, osteodystrophy and fat-soluble vitamin deficiency. Portal hypertension may develop prior to advanced stages of fibrosis. Untreated disease may lead to cirrhosis, hepatocellular cancer and need for orthotopic liver transplantation. Classically, diagnosis is made with elevation of alkaline phosphatase, demonstration of circulating antimitochondrial antibody, and if performed: asymmetric destruction/nonsupperative cholangitis of intralobular bile ducts on biopsy. Disease pathogenesis is complex and results from innate and adaptive (cell-mediated and humoral) responses that lead to inflammation of biliary duct epithelium. Ongoing damage is amplified and sustained through bile acid toxicity. Use of weight based (13-15mg/kg) ursodeoxycholic acid is well established in retarding disease progression and improving survival; however, is ineffective in achieving complete biochemical remission in many. Recently, a Farnesoid X Receptor agonist, obeticholic acid, has been approved for use. A number of ongoing clinical studies are underway to evaluate utility of fibric acid derivatives, biologics, antifibrotics, and stem cells as monotherapy or in combination with ursodeoxycholic acid for primary biliary cholangitis. The aim of this review is to discuss disease pathogenesis and highlight rationale/implications for both established and novel therapeutics.
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Key Words
- ALP, alkaline phosphatase
- ALT, alanine aminotransferase
- AMAbs, anti-mitochondrial antibodies
- ASBT, apical sodium BA transporter
- BA, bile acids
- CDCA, chenodeoxycholic acid
- FGF-19, fibroblast growth factor
- FXR, farnesoid X receptor
- GGT, gamma-glutamyltranspeptidase
- IL, interleukin
- MHC, major histocompatibility complex
- OCA, obeticholic acid
- PBC
- PBC, primary biliary cholangitis
- PPARα, peroxisome proliferator-activated α-receptor
- UC-MSC, umbilical cord mesenchymal stem cells
- ULN, upper limit of normal
- biologic
- fibric acid
- liver transplantation
- obeticholic acid
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Affiliation(s)
- Amitkumar Patel
- University of Arizona College of Medicine-Phoenix, Department of Gastroenterology, 1111 E. McDowell Road, Phoenix, AZ 85006, United States
| | - Anil Seetharam
- University of Arizona College of Medicine-Phoenix, Banner Transplant and Advanced Liver Disease Center, 1300 N. 12th Street Suite 404, Phoenix, AZ 85006, United States,Address for correspondence: University of Arizona College of Medicine-Phoenix, Banner Transplant and Advanced Liver Disease Center, 1300 N. 12th Street Suite 404, Phoenix, AZ 85006, United States. Fax: +1 602 839 2606.University of Arizona College of Medicine-Phoenix, Banner Transplant and Advanced Liver Disease Center1300 N. 12th Street Suite 404PhoenixAZ85006United States
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Mattner J. Impact of Microbes on the Pathogenesis of Primary Biliary Cirrhosis (PBC) and Primary Sclerosing Cholangitis (PSC). Int J Mol Sci 2016; 17:1864. [PMID: 27834858 PMCID: PMC5133864 DOI: 10.3390/ijms17111864] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 11/02/2016] [Accepted: 11/04/2016] [Indexed: 02/07/2023] Open
Abstract
Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) represent the major clinical entities of chronic cholestatic liver diseases. Both disorders are characterized by portal inflammation and slowly progress to obliterative fibrosis and eventually liver cirrhosis. Although immune-pathogenic mechanisms have been implicated in the pathogenesis of PBC and PSC, neither disorder is considered to be a classical autoimmune disease, as PSC and PBC patients do not respond to immune-suppressants. Furthermore, the decreased bile flow resulting from the immune-mediated tissue assault and the subsequent accumulation of toxic bile products in PBC and PSC not only perpetuates biliary epithelial damage, but also alters the composition of the intestinal and biliary microbiota and its mutual interactions with the host. Consistent with the close association of PSC and inflammatory bowel disease (IBD), the polyclonal hyper IgM response in PBC and (auto-)antibodies which cross-react to microbial antigens in both diseases, an expansion of individual microbes leads to shifts in the composition of the intestinal or biliary microbiota and a subsequent altered integrity of epithelial layers, promoting microbial translocation. These changes have been implicated in the pathogenesis of both devastating disorders. Thus, we will discuss here these recent findings in the context of novel and alternative therapeutic options.
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MESH Headings
- Anti-Bacterial Agents/therapeutic use
- Antibodies, Bacterial/biosynthesis
- Bacterial Translocation
- Bile/drug effects
- Bile/microbiology
- Cholangiopancreatography, Endoscopic Retrograde
- Cholangitis, Sclerosing/diagnostic imaging
- Cholangitis, Sclerosing/drug therapy
- Cholangitis, Sclerosing/immunology
- Cholangitis, Sclerosing/microbiology
- Gastrointestinal Microbiome/drug effects
- Host-Pathogen Interactions
- Humans
- Immunoglobulin M/biosynthesis
- Liver Cirrhosis, Biliary/diagnostic imaging
- Liver Cirrhosis, Biliary/drug therapy
- Liver Cirrhosis, Biliary/immunology
- Liver Cirrhosis, Biliary/microbiology
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Affiliation(s)
- Jochen Mattner
- Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Wasserturmstr. 3/5, D-91054 Erlangen, Germany.
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Liberal R, Grant CR. Cirrhosis and autoimmune liver disease: Current understanding. World J Hepatol 2016; 8:1157-1168. [PMID: 27729952 PMCID: PMC5055585 DOI: 10.4254/wjh.v8.i28.1157] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 05/14/2016] [Accepted: 08/08/2016] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) constitute the classic autoimmune liver diseases (AILDs). While AIH target the hepatocytes, in PBC and PSC the targets of the autoimmune attack are the biliary epithelial cells. Persistent liver injury, associated with chronic AILD, leads to un-resolving inflammation, cell proliferation and the deposition of extracellular matrix proteins by hepatic stellate cells and portal myofibroblasts. Liver cirrhosis, and the resultant loss of normal liver function, inevitably ensues. Patients with cirrhosis have higher risks or morbidity and mortality, and that in the decompensated phase, complications of portal hypertension and/or liver dysfunction lead to rapid deterioration. Accurate diagnosis and monitoring of cirrhosis is, therefore of upmost importance. Liver biopsy is currently the gold standard technique, but highly promising non-invasive methodology is under development. Liver transplantation (LT) is an effective therapeutic option for the management of end-stage liver disease secondary to AIH, PBC and PSC. LT is indicated for AILD patients who have progressed to end-stage chronic liver disease or developed intractable symptoms or hepatic malignancy; in addition, LT may also be indicated for patients presenting with acute liver disease due to AIH who do not respond to steroids.
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Purohit T, Cappell MS. Primary biliary cirrhosis: Pathophysiology, clinical presentation and therapy. World J Hepatol 2015; 7:926-941. [PMID: 25954476 PMCID: PMC4419097 DOI: 10.4254/wjh.v7.i7.926] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Revised: 02/09/2015] [Accepted: 03/05/2015] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cirrhosis (PBC) is an autoimmune, slowly progressive, cholestatic, liver disease characterized by a triad of chronic cholestasis, circulating anti-mitochondrial antibodies (AMA), and characteristic liver biopsy findings of nonsuppurative destructive cholangitis and interlobular bile duct destruction. About 10% of PBC patients, however, lack AMA. A variant, called PBC-autoimmune hepatitis (AIH) overlap, is characterized by the above findings of PBC together with findings of elevated serum alanine aminotransferase, elevated serum immunoglobulin G, and circulating anti-smooth muscle antibodies, with liver biopsy demonstrating periportal or periseptal, lymphocytic, piecemeal necrosis. PBC is hypothesized to be related to environmental exposure in genetically vulnerable individuals. It typically occurs in middle-aged females. Prominent clinical features include fatigue, pruritis, jaundice, xanthomas, osteoporosis, and dyslipidemia. The Mayo Risk score is the most widely used and best prognostic system. Ursodeoxycholic acid is the primary therapy. It works partly by reducing the concentration and injury from relatively toxic bile acids. PBC-AIH overlap syndrome is treated with ursodeoxycholic acid and corticosteroids, especially budesonide. Obeticholic acid and fibrate are promising new, but incompletely tested, therapies. Liver transplantation is the definitive therapy for advanced disease, with about 70% 10-year survival after transplantation. Management of pruritis includes local skin care, dermatologist referral, avoiding potential pruritogens, cholestyramine, and possibly opioid antagonists, sertraline, or rifaximin. Management of osteoporosis includes life-style modifications, administration of calcium and vitamin D, and alendronate. Statins are relatively safe to treat the osteopenia associated with PBC. Associated Sjogren's syndrome is treated by artificial tears, cyclosporine ophthalmic emulsion to stimulate tear production; and saliva substitutes, cholinergic agents, and scrupulous oral and dental care. Complications of cirrhosis from advanced PBC include esophageal varices, ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, and hepatoma formation.
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Affiliation(s)
- Treta Purohit
- Treta Purohit, Mitchell S Cappell, Division of Gastroenterology and Hepatology, William Beaumont Hospital, Royal Oak, MI 48073, United States
| | - Mitchell S Cappell
- Treta Purohit, Mitchell S Cappell, Division of Gastroenterology and Hepatology, William Beaumont Hospital, Royal Oak, MI 48073, United States
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Rigopoulou EI, Bogdanos DP. Is primary biliary cirrhosis rare or common? The truth lies somewhere in between. Liver Int 2014; 34:e165-7. [PMID: 24517310 DOI: 10.1111/liv.12488] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2014] [Accepted: 02/03/2014] [Indexed: 12/11/2022]
Affiliation(s)
- Eirini I Rigopoulou
- Department of Internal Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
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Abstract
We recently introduced the concept of the infectome as a means of studying all infectious factors which contribute to the development of autoimmune disease. It forms the infectious part of the exposome, which collates all environmental factors contributing to the development of disease and studies the sum total of burden which leads to the loss of adaptive mechanisms in the body. These studies complement genome-wide association studies, which establish the genetic predisposition to disease. The infectome is a component which spans the whole life and may begin at the earliest stages right up to the time when the first symptoms manifest, and may thus contribute to the understanding of the pathogenesis of autoimmunity at the prodromal/asymptomatic stages. We provide practical examples and research tools as to how we can investigate disease-specific infectomes, using laboratory approaches employed from projects studying the “immunome” and “microbiome”. It is envisioned that an understanding of the infectome and the environmental factors that affect it will allow for earlier patient-specific intervention by clinicians, through the possible treatment of infectious agents as well as other compounding factors, and hence slowing or preventing disease development.
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Mattner J. Natural killer T (NKT) cells in autoimmune hepatitis. Curr Opin Immunol 2013; 25:697-703. [PMID: 24148235 PMCID: PMC4013545 DOI: 10.1016/j.coi.2013.09.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Revised: 09/15/2013] [Accepted: 09/27/2013] [Indexed: 02/08/2023]
Abstract
Natural killer T (NKT) cells represent an innate-like lymphocyte population endowed with unique antigen recognition and tissue distribution features. Their abundance in the microvascular compartments of the liver allows NKT cells to immediately respond to lipid antigens and soluble factors circulating through the portal vein system by releasing tremendous amounts of different cytokines and chemokines. Subsequently, dependent on the nature of the lipid antigen encountered as well as the accessory signal(s) provided, NKT cells not only contribute to the maintenance of immune tolerance, but also direct adverse immune reactions locally and systemically. Focusing on their potent immunomodulatory features and their interactions with various innate and adaptive immune cells, the role of NKT cells in perpetuating the loss of liver-specific immune tolerance will be discussed.
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Affiliation(s)
- Jochen Mattner
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen und Friedrich-Alexander Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany; Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital, Cincinnati, OH 45229, USA.
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15
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Rashid T, Wilson C, Ebringer A. The link between ankylosing spondylitis, Crohn's disease, Klebsiella, and starch consumption. Clin Dev Immunol 2013; 2013:872632. [PMID: 23781254 PMCID: PMC3678459 DOI: 10.1155/2013/872632] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2012] [Accepted: 04/23/2013] [Indexed: 12/22/2022]
Abstract
Both ankylosing spondylitis (AS) and Crohn's disease (CD) are chronic and potentially disabling interrelated conditions, which have been included under the group of spondyloarthropathies. The results of a large number of studies support the idea that an enteropathic pathogen, Klebsiella pneumoniae, is the most likely triggering factor involved in the initiation and development of these diseases. Increased starch consumptions by genetically susceptible individuals such as those possessing HLA-B27 allelotypes could trigger the disease in both AS and CD by enhancing the growth and perpetuation of the Klebsiella microbes in the bowel. Exposure to increased levels of these microbes will lead to the production of elevated levels of anti-Klebsiella antibodies as well as autoantibodies against cross-reactive self-antigens with resultant pathological lesions in the bowel and joints. Hence, a decrease of starch-containing products in the daily dietary intake could have a beneficial therapeutic effect on the disease especially when used in conjunction with the currently available medical therapies in the treatment of patients with AS and CD.
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Affiliation(s)
- Taha Rashid
- Analytical Sciences Group, Kings College, 150 Stamford Street, London SE1 9NH, UK
| | - Clyde Wilson
- Department of Pathology and Microbiology, Kings Edward VII Memorial Hospital, 7 Point Finger Road, Paget DV04, Bermuda
| | - Alan Ebringer
- Analytical Sciences Group, Kings College, 150 Stamford Street, London SE1 9NH, UK
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Bogdanos DP, Smyk DS, Invernizzi P, Rigopoulou EI, Blank M, Pouria S, Shoenfeld Y. Infectome: a platform to trace infectious triggers of autoimmunity. Autoimmun Rev 2012; 12:726-40. [PMID: 23266520 PMCID: PMC7105216 DOI: 10.1016/j.autrev.2012.12.005] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2012] [Accepted: 12/12/2012] [Indexed: 02/06/2023]
Abstract
The "exposome" is a term recently used to describe all environmental factors, both exogenous and endogenous, which we are exposed to in a lifetime. It represents an important tool in the study of autoimmunity, complementing classical immunological research tools and cutting-edge genome wide association studies (GWAS). Recently, environmental wide association studies (EWAS) investigated the effect of environment in the development of diseases. Environmental triggers are largely subdivided into infectious and non-infectious agents. In this review, we introduce the concept of the "infectome", which is the part of the exposome referring to the collection of an individual's exposures to infectious agents. The infectome directly relates to geoepidemiological, serological and molecular evidence of the co-occurrence of several infectious agents associated with autoimmune diseases that may provide hints for the triggering factors responsible for the pathogenesis of autoimmunity. We discuss the implications that the investigation of the infectome may have for the understanding of microbial/host interactions in autoimmune diseases with long, pre-clinical phases. It may also contribute to the concept of the human body as a superorganism where the microbiome is part of the whole organism, as can be seen with mitochondria which existed as microbes prior to becoming organelles in eukaryotic cells of multicellular organisms over time. A similar argument can now be made in regard to normal intestinal flora, living in symbiosis within the host. We also provide practical examples as to how we can characterise and measure the totality of a disease-specific infectome, based on the experimental approaches employed from the "immunome" and "microbiome" projects.
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Affiliation(s)
- Dimitrios P Bogdanos
- Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, Denmark Hill Campus, London, UK.
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