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Kumar NN, Ahmad Dit Al Hakim S, Grygiel-Górniak B. Antinuclear Antibodies in Non-Rheumatic Diseases. Arch Immunol Ther Exp (Warsz) 2025; 73:aite-2025-0004. [PMID: 39827475 DOI: 10.2478/aite-2025-0004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 11/04/2024] [Indexed: 01/22/2025]
Abstract
Antinuclear antibodies (ANAs) are critical immunological markers commonly associated with various connective tissue diseases (CTDs). However, these autoantibodies are also detectable in healthy individuals, patients with non-rheumatic autoimmune diseases, those with viral infections, and subjects using specific medications (such as procainamide, hydralazine, and minocycline) that can lead to drug-induced ANA elevation. The standard method for ANA detection is indirect immunofluorescence, a process that requires precision and thoroughness as it assesses both titer and fluorescence patterns. Additionally, immunoblotting and enzyme-linked immunosorbent assay (ELISA) are recommended to identify specific ANAs precisely, highlighting the importance of precision in ANA detection. This review explores the advantages and limitations of current ANA detection methods. It also describes the clinical implications of ANA presence in non-rheumatic diseases, including autoimmune disorders, infectious conditions, non-autoimmune and non-infectious diseases, and autoimmune cutaneous diseases. The presence of elevated ANA titers in these contexts can complicate clinical decision-making, as the diagnostic value of ANA testing alone is limited in non-rheumatic conditions. However, despite these limitations, ANA remains a key component in diagnosing and prognosis systemic CTDs, as it can indicate disease activity, severity, and response to treatment, which is of utmost importance in rheumatology and internal medicine. This paper provides a comprehensive review of the role of ANA in non-rheumatic diseases. It focuses on ANA diagnostic and prognostic significance and offers valuable insights for clinical practice.
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Affiliation(s)
- Nikita Niranjan Kumar
- Department of Rheumatology, Rehabilitation and Internal Diseases, Poznañ University of Medical Sciences, Poznañ, Poland
| | - Samir Ahmad Dit Al Hakim
- Department of Rheumatology, Rehabilitation and Internal Diseases, Poznañ University of Medical Sciences, Poznañ, Poland
| | - Bogna Grygiel-Górniak
- Department of Rheumatology, Rehabilitation and Internal Diseases, Poznañ University of Medical Sciences, Poznañ, Poland
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2
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Fiorucci S, Urbani G, Di Giorgio C, Biagioli M, Distrutti E. Current Landscape and Evolving Therapies for Primary Biliary Cholangitis. Cells 2024; 13:1580. [PMID: 39329760 PMCID: PMC11429758 DOI: 10.3390/cells13181580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 09/18/2024] [Accepted: 09/19/2024] [Indexed: 09/28/2024] Open
Abstract
Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disorder characterized by progressive cholestatic that, if untreated, can progress to liver fibrosis, cirrhosis and liver decompensation requiring liver transplant. Although the pathogenesis of the disease is multifactorial, there is a consensus that individuals with a genetic predisposition develop the disease in the presence of specific environmental triggers. A dysbiosis of intestinal microbiota is increasingly considered among the potential pathogenic factors. Cholangiocytes, the epithelial cells lining the bile ducts, are the main target of a dysregulated immune response, and cholangiocytes senescence has been recognized as a driving mechanism, leading to impaired bile duct function, in disease progression. Bile acids are also recognized as playing an important role, both in disease development and therapy. Thus, while bile acid-based therapies, specifically ursodeoxycholic acid and obeticholic acid, have been the cornerstone of therapy in PBC, novel therapeutic approaches have been developed in recent years. In this review, we will examine published and ongoing clinical trials in PBC, including the recently approved peroxisome-proliferator-activated receptor (PPAR) agonist, elafibranor and seladelpar. These novel second-line therapies are expected to improve therapy in PBC and the development of personalized approaches.
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Affiliation(s)
- Stefano Fiorucci
- Dipartimento di Medicina e Chirurgia, Università di Perugia, 06123 Perugia, Italy; (G.U.); (C.D.G.); (M.B.)
| | - Ginevra Urbani
- Dipartimento di Medicina e Chirurgia, Università di Perugia, 06123 Perugia, Italy; (G.U.); (C.D.G.); (M.B.)
| | - Cristina Di Giorgio
- Dipartimento di Medicina e Chirurgia, Università di Perugia, 06123 Perugia, Italy; (G.U.); (C.D.G.); (M.B.)
| | - Michele Biagioli
- Dipartimento di Medicina e Chirurgia, Università di Perugia, 06123 Perugia, Italy; (G.U.); (C.D.G.); (M.B.)
| | - Eleonora Distrutti
- SC di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, 06123 Perugia, Italy;
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3
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Fiorucci S, Marchianò S, Urbani G, Di Giorgio C, Distrutti E, Zampella A, Biagioli M. Immunology of bile acids regulated receptors. Prog Lipid Res 2024; 95:101291. [PMID: 39122016 DOI: 10.1016/j.plipres.2024.101291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 07/30/2024] [Accepted: 08/02/2024] [Indexed: 08/12/2024]
Abstract
Bile acids are steroids formed at the interface of host metabolism and intestinal microbiota. While primary bile acids are generated in the liver from cholesterol metabolism, secondary bile acids represent the products of microbial enzymes. Close to 100 different enzymatic modifications of bile acids structures occur in the human intestine and clinically guided metagenomic and metabolomic analyses have led to the identification of an extraordinary number of novel metabolites. These chemical mediators make an essential contribution to the composition and function of the postbiota, participating to the bidirectional communications of the intestinal microbiota with the host and contributing to the architecture of intestinal-liver and -brain and -endocrine axes. Bile acids exert their function by binding to a group of cell membrane and nuclear receptors collectively known as bile acid-regulated receptors (BARRs), expressed in monocytes, tissue-resident macrophages, CD4+ T effector cells, including Th17, T regulatory cells, dendritic cells and type 3 of intestinal lymphoid cells and NKT cells, highlighting their role in immune regulation. In this review we report on how bile acids and their metabolitesmodulate the immune system in inflammations and cancers and could be exploiting for developing novel therapeutic approaches in these disorders.
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Affiliation(s)
- Stefano Fiorucci
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy.
| | - Silvia Marchianò
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
| | - Ginevra Urbani
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
| | | | - Eleonora Distrutti
- SC di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Angela Zampella
- Department of Pharmacy, University of Napoli Federico II, Napoli, Italy
| | - Michele Biagioli
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
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4
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Liang Y, Khandakar B, Hao Y, Xiong Y, Liu BL, Zhang X. Histology and clinical correlations in autoimmune hepatitis, primary biliary cholangitis, and autoimmune hepatitis-primary biliary cholangitis overlap syndrome. Ann Diagn Pathol 2023; 67:152178. [PMID: 37468373 DOI: 10.1016/j.anndiagpath.2023.152178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 07/08/2023] [Accepted: 07/09/2023] [Indexed: 07/21/2023]
Abstract
OBJECTIVES The diagnosis of autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and AIH-PBC overlap syndrome (OS) relies on their histologic features and clinical findings. In this study, we aimed to identify specific morphologic features of these diseases and evaluate their clinical correlation. METHODS We included initial biopsies from untreated patients with AIH (n = 14), PBC (n = 10), and OS (n = 7). Histologic features of the portal tract, portal-lobular interface, and hepatic lobule, fibrosis, as well as clinical data including serology, autoantibodies, treatment, and prognosis were reviewed and analyzed. RESULTS Our results showed that several histologic features differed significantly between AIH and PBC (p < 0.05). Among these features, OS cases were more likely to present with bile duct-centered processes (presence of bile duct damage while absence of inflammation gradient from bile duct to interface, plasma cell cluster and pericentral inflammation) unlike those seen in AIH (p < 0.05), and interface-centered processes (unequivocal interface hepatitis, ductular reaction, and periportal fibrosis) which were not seen in PBC (p < 0.05). We observed a significant correlation between transaminase levels and lobular inflammation, including numbers of lymphocyte, plasma cell and eosinophil. Our study also found that anti-smooth muscle antibody positivity was associated with interface hepatitis (p < 0.01), while antimitochondrial antibody positivity was associated with duct damage (including ductopenia) and granulomas (p < 0.05). CONCLUSION Our results highlight distinctive morphological features between AIH and PBC. The possibility of overlap syndrome should be considered when encountering AIH with bile duct-centered processes or PBC with interface-centered processes in morphology and correlation with autoantibodies.
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Affiliation(s)
- Yuanxin Liang
- Department of Pathology, Yale University School of Medicine, New Haven, CT, United States of America.
| | - Binny Khandakar
- Department of Pathology, Yale University School of Medicine, New Haven, CT, United States of America
| | - Yansheng Hao
- Department of Pathology, University of Rochester Medical Center, Rochester, NY, United States of America
| | - Yiqin Xiong
- Department of Pathology, University of Iowa, Iowa City, IA, United States of America
| | - Bella L Liu
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - Xuchen Zhang
- Department of Pathology, Yale University School of Medicine, New Haven, CT, United States of America
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Favoino E, Grapsi E, Barbuti G, Liakouli V, Ruscitti P, Foti C, Giacomelli R, Perosa F. Systemic sclerosis and primary biliary cholangitis share an antibody population with identical specificity. Clin Exp Immunol 2023; 212:32-38. [PMID: 36715304 PMCID: PMC10081109 DOI: 10.1093/cei/uxad012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/29/2022] [Accepted: 01/27/2023] [Indexed: 01/31/2023] Open
Abstract
Anti-centromere (ACA) and antimitochondrial antibodies (AMA) are specific for limited-cutaneous systemic sclerosis (lcSSc) and primary biliary cholangitis (PBC), respectively, and can coexist in up to 25 and 30% of SSc and PBC patients. Here, we evaluated whether anti-centromeric protein A (CENP-A) antibodies cross-react with mitochondrial antigens. To this end, sera from two lcSSc patients (pt1 and pt4), one of them (pt4) also affected by PBC, were used as the source of ACA, previously shown to recognize different groups of amino acids (motifs) in the CENP-A region spanning amino acids 1-17 (Ap1-17). Pt1 and pt4 Ap1-17-specific IgG were purified by affinity-chromatography on insolubilized Ap1-17-peptide column and tested by western blotting with nuclear and cytoplasmic protein extract from HeLa cells. Immunoreactive proteins were identified by mass spectrometry and validated by immunodot. The results showed that affinity-purified SSc/PBC pt4 anti-Ap1-17 and not SSc pt1 anti-Ap1-17 Ab, specifically cross-reacted with the E2 component of the mitochondrial pyruvate dehydrogenase complex (PDC-E2), the major mitochondrial autoantigen in PBC. Sequence homology analysis indicated that the motif A-x-x-P-x-A-P recognized by pt4 anti-Ap1-17 IgG and shared by CENP-A and PDC-E2, is also expressed by some members of the Human Herpesvirus family, suggesting that they may trigger the production of these cross-reacting antibodies.
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Affiliation(s)
- Elvira Favoino
- Department of Interdisciplinary Medicine, Rheumatic and Systemic Autoimmune Diseases Unit, University of Bari Medical School, Bari, Italy
| | - Ettore Grapsi
- Department of Interdisciplinary Medicine, Rheumatic and Systemic Autoimmune Diseases Unit, University of Bari Medical School, Bari, Italy
| | - Giovanna Barbuti
- Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | - Vasiliki Liakouli
- Department of Precision Medicine, Rheumatology Section, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Piero Ruscitti
- Department of Biotechnological and Applied Clinical Sciences, Rheumatology Unit, University of L’Aquila, L’Aquila, Italy
| | - Caterina Foti
- Department of Biomedical Science and Human Oncology, Unit of Dermatology, University of Bari Medical School, Bari, Italy
| | - Roberto Giacomelli
- Department of Medicine, Rheumatology and Immunology Unit, University of Rome “Campus Biomedico”, Rome, Italy
| | - Federico Perosa
- Department of Interdisciplinary Medicine, Rheumatic and Systemic Autoimmune Diseases Unit, University of Bari Medical School, Bari, Italy
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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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7
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Park JS, Ma H, Roh YS. Ubiquitin pathways regulate the pathogenesis of chronic liver disease. Biochem Pharmacol 2021; 193:114764. [PMID: 34529948 DOI: 10.1016/j.bcp.2021.114764] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 09/05/2021] [Accepted: 09/08/2021] [Indexed: 02/07/2023]
Abstract
Chronic liver disease (CLD) is considered the leading cause of global mortality. In westernized countries, increased consumption of alcohol and overeating foods with high fat/ high glucose promote progression of CLD such as alcoholic liver disease (ALD) and non-alcoholic liver disease (NAFLD). Accumulating evidence and research suggest that ubiquitin, a 75 amino acid protein, plays crucial role in the pathogenesis of CLD through dynamic post-translational modifications (PTMs) exerting diverse cellular outcomes such as protein degradation through ubiquitin-proteasome system (UPS) and autophagy, and regulation of signal transduction. In this review, we present the function of ubiquitination and latest findings on diverse mechanism of PTMs, UPS and autophagy which significantly contribute to the pathogenesis of alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), cirrhosis, and HCC. Despite its high prevalence, morbidity, and mortality, there are only few FDA approved drugs that could be administered to CLD patients. The goal of this review is to present a variety of pathways and therapeutic targets involving ubiquitination in the pathogenesis of CLD. Further, this review summarizes collective views of pharmaceutical inhibition or activation of recent drugs targeting UPS and autophagy system to highlight potential targets and new approaches to treat CLD.
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Affiliation(s)
- Jeong-Su Park
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju 28160, South Korea
| | - Hwan Ma
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju 28160, South Korea
| | - Yoon-Seok Roh
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju 28160, South Korea.
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8
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Zeng X, Li S, Tang S, Li X, Zhang G, Li M, Zeng X, Hu C. Changes of Serum IgG Glycosylation Patterns in Primary Biliary Cholangitis Patients. Front Immunol 2021; 12:669137. [PMID: 34248947 PMCID: PMC8267527 DOI: 10.3389/fimmu.2021.669137] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 06/07/2021] [Indexed: 11/30/2022] Open
Abstract
Objective Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease whose diagnosis is based significantly on autoantibody detection. This study aims to investigate the glycosylation profile of serum IgG in PBC patients using high-throughput lectin microarrays technology. Method Lectin microarray containing 56 lectins was used to detect and analyze the expression of serum IgG glycosylation in 99 PBC patients, 70 disease controls (DCs), and 38 healthy controls (HCs). Significant differences in PBC from control groups as well as across PBC subgroups positive for various autoantibodies were explored and verified by lectin blot technique. Results Lectin microarray detection revealed that compared to DC and HC groups, the specific glycan level of serum IgG sialic acid in PBC patients was increased. For each PBC subgroup, glycan levels of IgG mannose and galactose were decreased in AMA-M2 positive PBC patients compared to the AMA-M2 negative group. IgG N-Acetylgalactosamine (GalNAc) and fucose were decreased in anti-sp100 positive patients. IgG galactose was increased in anti-gp210 positive patients. IgG mannose was decreased in ACA-positive patients. Although the difference in overall sialic acid level was not observed using lectin blot, all results among the above PBC subgroups were consistent with the results of the technique. Conclusion Lectin microarray is an effective and reliable technique for analyzing glycan structure. PBC patients positive for different autoantibody exhibits distinct glycan profile. Altered levels of glycosylation may be related to the occurrence and development of the disease, which could provide a direction for new biomarker identification.
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Affiliation(s)
- Xiaoli Zeng
- Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID) Key Laboratory of Rheumatology & Clinical Immunology, Ministry of Education, Beijing, China.,Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Siting Li
- Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID) Key Laboratory of Rheumatology & Clinical Immunology, Ministry of Education, Beijing, China
| | - Shiyi Tang
- Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID) Key Laboratory of Rheumatology & Clinical Immunology, Ministry of Education, Beijing, China
| | - Xi Li
- Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID) Key Laboratory of Rheumatology & Clinical Immunology, Ministry of Education, Beijing, China.,Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Guoyuan Zhang
- Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, China
| | - Mengtao Li
- Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID) Key Laboratory of Rheumatology & Clinical Immunology, Ministry of Education, Beijing, China
| | - Xiaofeng Zeng
- Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID) Key Laboratory of Rheumatology & Clinical Immunology, Ministry of Education, Beijing, China
| | - Chaojun Hu
- Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID) Key Laboratory of Rheumatology & Clinical Immunology, Ministry of Education, Beijing, China
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9
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An updated advance of autoantibodies in autoimmune diseases. Autoimmun Rev 2020; 20:102743. [PMID: 33333232 DOI: 10.1016/j.autrev.2020.102743] [Citation(s) in RCA: 125] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 08/06/2020] [Indexed: 12/18/2022]
Abstract
Autoantibodies are abnormal antibodies which are generated by pathogenic B cells when targeting an individual's own tissue. Autoantibodies have been identified as a symbol of autoimmune disorders and are frequently considered a clinical marker of these disorders. Autoimmune diseases, including system lupus erythematosus and rheumatoid arthritis, consist of a series of disorders that share some similarities and differences. They are characterized by chronic, systemic, excessive immune activation and inflammation and involve in almost all body tissues. Autoimmune diseases occur more frequently in women than men due to hormonal impacts. In this review we systemically introduce and summarize the latest advances of various autoantibodies in multiple autoimmune diseases.
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10
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Galoosian A, Hanlon C, Zhang J, Holt EW, Yimam KK. Clinical Updates in Primary Biliary Cholangitis: Trends, Epidemiology, Diagnostics, and New Therapeutic Approaches. J Clin Transl Hepatol 2020; 8:49-60. [PMID: 32274345 PMCID: PMC7132015 DOI: 10.14218/jcth.2019.00049] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 12/21/2019] [Accepted: 01/01/2020] [Indexed: 12/12/2022] Open
Abstract
Primary biliary cholangitis, formerly known as primary biliary cirrhosis, is a chronic, autoimmune, and cholestatic disease ameliorating the biliary epithelial system causing fibrosis and end-stage liver disease, over time. Patients range from an asymptomatic phase early in the disease course, to symptoms of decompensated cirrhosis later in its course. This review focuses on the current consensus on the epidemiology, diagnosis, and management of patients with primary biliary cholangitis. We also discuss established medical management as well as novel and investigational therapeutics in the pipeline for management of PBC.
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Affiliation(s)
- Artin Galoosian
- Department of Medicine, California Pacific Medical Center, San Francisco, CA, USA
| | - Courtney Hanlon
- Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
| | - Julia Zhang
- Department of Medicine, California Pacific Medical Center, San Francisco, CA, USA
| | - Edward W. Holt
- Department of Transplant, Division of Hepatology, California Pacific Medical Center, San Francisco, CA, USA
| | - Kidist K. Yimam
- Director of the Autoimmune Liver Disease Program, Department of Transplant, Division of Hepatology, California Pacific Medical Center, San Francisco, CA, USA
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11
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Bombaci M, Pesce E, Torri A, Carpi D, Crosti M, Lanzafame M, Cordiglieri C, Sinisi A, Moro M, Bernuzzi F, Gerussi A, Geginat J, Muratori L, Terracciano LM, Invernizzi P, Abrignani S, Grifantini R. Novel biomarkers for primary biliary cholangitis to improve diagnosis and understand underlying regulatory mechanisms. Liver Int 2019; 39:2124-2135. [PMID: 31033124 DOI: 10.1111/liv.14128] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Revised: 03/15/2019] [Accepted: 04/19/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS Primary biliary cholangitis is an autoimmune biliary disease characterized by injury of bile ducts, eventually leading to cirrhosis and death. In most cases, anti-mitochondrial antibodies and persistently elevated serum alkaline phosphatase are the basis for the serological diagnosis. Anti-nuclear antibodies are also useful and may indicate a more aggressive diseases course. In patients in which anti-mitochondrial antibodies are not detected, an accurate diagnosis requires liver histology. This study aims at identifying specific biomarkers for the serological diagnosis of primary biliary cholangitis. METHODS Sera from patients affected by primary biliary cholangitis, primary sclerosing cholangitis, hepatitis C virus (with and without cryoglobulinemia), hepatocarcinoma and healthy donors were tested on a protein array representing 1658 human proteins. The most reactive autoantigens were confirmed by DELFIA analysis on expanded cohorts of the same mentioned serum classes, and on autoimmune hepatitis sera, using anti-PDC-E2 as reference biomarker. RESULTS Two autoantigens, SPATA31A3 and GARP, showed high reactivity with primary biliary cholangitis sera, containing or not anti-mitochondrial antibodies. Their combination with PDC-E2 allowed to discriminate primary biliary cholangitis from all tested control classes with high sensitivity and specificity. We found that GARP expression is upregulated upon exposure to biliary salts in human cholangiocytes, an event involving EGFR and insulin pathways. GARP expression was also detected in biliary duct cells of PBC patients. CONCLUSIONS This study highlighted SPATA31A3 and GARP as new biomarkers for primary biliary cholangitis and unravelled molecular stimuli underlying GARP expression in human cholangiocytes.
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Affiliation(s)
- Mauro Bombaci
- Istituto Nazionale Genetica Molecolare, Padiglione Romeo ed Enrica Invernizzi, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - Elisa Pesce
- Istituto Nazionale Genetica Molecolare, Padiglione Romeo ed Enrica Invernizzi, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - Anna Torri
- Istituto Nazionale Genetica Molecolare, Padiglione Romeo ed Enrica Invernizzi, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - Donatella Carpi
- Istituto Nazionale Genetica Molecolare, Padiglione Romeo ed Enrica Invernizzi, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - Mariacristina Crosti
- Istituto Nazionale Genetica Molecolare, Padiglione Romeo ed Enrica Invernizzi, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - Manuela Lanzafame
- Institute of Pathology, University Hospital Basel, Basel, Switzerland
| | - Chiara Cordiglieri
- Istituto Nazionale Genetica Molecolare, Padiglione Romeo ed Enrica Invernizzi, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - Antonia Sinisi
- Istituto Nazionale Genetica Molecolare, Padiglione Romeo ed Enrica Invernizzi, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - Monica Moro
- Istituto Nazionale Genetica Molecolare, Padiglione Romeo ed Enrica Invernizzi, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - Francesca Bernuzzi
- Division Gastroenterology and Center for Autoimmune Liver Diseases, University of Milan, Bicocca School of Medicine, Monza, Italy
| | - Alessio Gerussi
- Division Gastroenterology and Center for Autoimmune Liver Diseases, University of Milan, Bicocca School of Medicine, Monza, Italy
| | - Jens Geginat
- Istituto Nazionale Genetica Molecolare, Padiglione Romeo ed Enrica Invernizzi, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - Luigi Muratori
- Department of Medical and Surgical Sciences, University of Bologna, Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | | | - Pietro Invernizzi
- Division Gastroenterology and Center for Autoimmune Liver Diseases, University of Milan, Bicocca School of Medicine, Monza, Italy
| | - Sergio Abrignani
- Istituto Nazionale Genetica Molecolare, Padiglione Romeo ed Enrica Invernizzi, IRCCS Ospedale Maggiore Policlinico, Milan, Italy.,Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy
| | - Renata Grifantini
- Istituto Nazionale Genetica Molecolare, Padiglione Romeo ed Enrica Invernizzi, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
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12
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Wang C, Zheng X, Jiang P, Tang R, Gong Y, Dai Y, Wang L, Xu P, Sun W, Wang L, Han C, Jiang Y, Wei Y, Zhang K, Wu J, Shao Y, Gao Y, Yu J, Hu Z, Zang Z, Zhao Y, Wu X, Dai N, Liu L, Nie J, Jiang B, Lin M, Li L, Li Y, Chen S, Shu L, Qiu F, Wu Q, Zhang M, Chen R, Jawed R, Zhang Y, Shi X, Zhu Z, Pei H, Huang L, Zhao W, Tian Y, Zhu X, Qiu H, Gershwin ME, Chen W, Seldin MF, Liu X, Sun L, Ma X. Genome-wide Association Studies of Specific Antinuclear Autoantibody Subphenotypes in Primary Biliary Cholangitis. Hepatology 2019; 70:294-307. [PMID: 30854688 PMCID: PMC6618054 DOI: 10.1002/hep.30604] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Accepted: 03/03/2019] [Indexed: 02/05/2023]
Abstract
Anti-nuclear antibodies to speckled 100 kDa (sp100) and glycoprotein 210 (gp210) are specific serologic markers of primary biliary cholangitis (PBC) of uncertain/controversial clinical or prognostic significance. To study the genetic determinants associated with sp100 and gp210 autoantibody subphenotypes, we performed a genome-wide association analysis of 930 PBC cases based on their autoantibody status, followed by a replication study in 1,252 PBC cases. We confirmed single-nucleotide polymorphisms rs492899 (P = 3.27 × 10-22 ; odds ratio [OR], 2.90; 95% confidence interval [CI], 2.34-3.66) and rs1794280 (P = 5.78 × 10-28 ; OR, 3.89; 95% CI, 3.05-4.96) in the human major histocompatibility complex (MHC) region associated with the sp100 autoantibody. However, no genetic variant was identified as being associated with the gp210 autoantibody. To further define specific classical human leukocyte antigen (HLA) alleles or amino acids associated with the sp100 autoantibody, we imputed 922 PBC cases (211 anti-sp100-positive versus 711 negative cases) using a Han Chinese MHC reference database. Conditional analysis identified that HLA-DRβ1-Asn77/Arg74, DRβ1-Ser37, and DPβ1-Lys65 were major determinants for sp100 production. For the classical HLA alleles, the strongest association was with DRB1*03:01 (P = 1.51 × 10-9 ; OR, 2.97; 95% CI, 2.06-4.29). Regression analysis with classical HLA alleles identified DRB1*03:01, DRB1*15:01, DRB1*01, and DPB1*03:01 alleles can explain most of the HLA association with sp100 autoantibody. Conclusion: This study indicated significant genetic predisposition to the sp100 autoantibody, but not the gp210 autoantibody, subphenotype in PBC patients. Additional studies will be necessary to determine if these findings have clinical significance to PBC pathogenesis and/or therapeutics.
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Affiliation(s)
- Chan Wang
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life SciencesSoutheast UniversityNanjingJiangsuChina
| | - Xiaodong Zheng
- Department of DermatologyThe First Affiliated Hospital of Anhui Medical University, and Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China & Key Laboratory of Major Autoimmune Diseases, Anhui ProvinceHefeiChina
| | - Peng Jiang
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life SciencesSoutheast UniversityNanjingJiangsuChina
| | - Ruqi Tang
- Department of Gastroenterology and HepatologyShanghai Institute of Digestive Diseases, Shanghai Jiao Tong University School of Medicine Affiliated Renji HospitalShanghaiChina
| | - Yuhua Gong
- Department of Laboratory MedicineThe Third People's Hospital of ZhenjiangZhenjiangJiangsuChina
| | - Yaping Dai
- Department of Laboratory MedicineThe Fifth People's Hospital of WuxiWuxiJiangsuChina
| | - Lan Wang
- Department of Laboratory MedicineThe 81st Hospital of PLANanjingJiangsuChina
| | - Ping Xu
- Department of Laboratory MedicineThe Fifth People's Hospital of Suzhou, Soochow UniversitySuzhouJiangsuChina
| | - Wenjuan Sun
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life SciencesSoutheast UniversityNanjingJiangsuChina
| | - Lu Wang
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life SciencesSoutheast UniversityNanjingJiangsuChina
| | - Chongxu Han
- Department of Laboratory MedicineSubei People's Hospital, Clinical Medical College, Yangzhou UniversityYangzhouJiangsuChina
| | - Yuzhang Jiang
- Department of Laboratory MedicineHuai'an First People's Hospital, Nanjing Medical UniversityHuai'anJiangsuChina
| | - Yiran Wei
- Department of Gastroenterology and HepatologyShanghai Institute of Digestive Diseases, Shanghai Jiao Tong University School of Medicine Affiliated Renji HospitalShanghaiChina
| | - Kui Zhang
- Department of Laboratory MedicineNanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical SchoolNanjingJiangsuChina
| | - Jian Wu
- Department of RheumatologyFirst Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Youlin Shao
- Department of HepatologyThe Third People's Hospital of ChangzhouChangzhouJiangsuChina
| | - Yueqiu Gao
- Department of Liver DiseasesShuguang Hospital, Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Jianjiang Yu
- Department of Laboratory MedicineJiangyin People's Hospital, Southeast UniversityJiangyinJiangsuChina
| | - Zhigang Hu
- Department of Laboratory MedicineAffiliated Wuxi People's Hospital of Nanjing Medical UniversityWuxiJiangsuChina
| | - Zhidong Zang
- Department of HepatologyThe Second Hospital of Nanjing, Southeast UniversityNanjingJiangsuChina
| | - Yi Zhao
- Department of Gastrointestinal EndoscopyEastern Hepatobiliary Surgery HospitalShanghaiChina
| | - Xudong Wu
- Department of GastroenterologyYancheng First People's HospitalYanchengJiangsuChina
| | - Na Dai
- Department of GastroenterologyJiangsu University Affiliated Kunshan HospitalKunshanJiangsuChina
| | - Lei Liu
- Department of GastroenterologyYixing People's HospitalYixinJiangsuChina
| | - Jinshan Nie
- Department of GastroenterologyTaicang First People's Hospital, Soochow UniversityTaicangJiangsuChina
| | - Bo Jiang
- Department of HepatologyJingjiang Second People's HospitalJingjiangJiangsuChina
| | - Maosong Lin
- Department of GastroenterologyTaizhou People's HospitalTaizhouJiangsuChina
| | - Li Li
- Department of Laboratory MedicineZhongda Hospital, Southeast UniversityNanjingJiangsuChina
| | - You Li
- Department of Gastroenterology and HepatologyShanghai Institute of Digestive Diseases, Shanghai Jiao Tong University School of Medicine Affiliated Renji HospitalShanghaiChina
| | - Sufang Chen
- Department of Laboratory MedicineThe Fifth People's Hospital of Suzhou, Soochow UniversitySuzhouJiangsuChina
| | - Lixin Shu
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life SciencesSoutheast UniversityNanjingJiangsuChina
| | - Fang Qiu
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life SciencesSoutheast UniversityNanjingJiangsuChina
| | - Qiuyuan Wu
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life SciencesSoutheast UniversityNanjingJiangsuChina
| | - Mingming Zhang
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life SciencesSoutheast UniversityNanjingJiangsuChina
| | - Ru Chen
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life SciencesSoutheast UniversityNanjingJiangsuChina
| | - Rohil Jawed
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life SciencesSoutheast UniversityNanjingJiangsuChina
| | - Yu Zhang
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life SciencesSoutheast UniversityNanjingJiangsuChina
| | - Xingjuan Shi
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life SciencesSoutheast UniversityNanjingJiangsuChina
| | - Zhen Zhu
- Department of HepatologyThe Third People's Hospital of ChangzhouChangzhouJiangsuChina
| | - Hao Pei
- Department of Laboratory MedicineThe Fifth People's Hospital of WuxiWuxiJiangsuChina
| | - Lihua Huang
- Department of Laboratory MedicineThe Fifth People's Hospital of WuxiWuxiJiangsuChina
| | - Weifeng Zhao
- Department of GastroenterologyFirst Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Ye Tian
- Department of RadiologyThe Second Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Xiang Zhu
- Department of Laboratory MedicineThe Fifth People's Hospital of Suzhou, Soochow UniversitySuzhouJiangsuChina
| | - Hong Qiu
- Department of Laboratory MedicineThe 81st Hospital of PLANanjingJiangsuChina
| | - M. Eric Gershwin
- Division of Rheumatology, Allergy and Clinical ImmunologyUniversity of California at Davis School of MedicineDavisCA
| | - Weichang Chen
- Department of GastroenterologyFirst Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Michael F. Seldin
- Department of Biochemistry and Molecular MedicineUniversity of California at Davis School of MedicineDavisCA
| | - Xiangdong Liu
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life SciencesSoutheast UniversityNanjingJiangsuChina
| | - Liangdan Sun
- Department of DermatologyThe First Affiliated Hospital of Anhui Medical University, and Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China & Key Laboratory of Major Autoimmune Diseases, Anhui ProvinceHefeiChina
| | - Xiong Ma
- Department of Gastroenterology and HepatologyShanghai Institute of Digestive Diseases, Shanghai Jiao Tong University School of Medicine Affiliated Renji HospitalShanghaiChina
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Abstract
Primary biliary cholangitis and autoimmune hepatitis are common autoimmune diseases of the liver. Both have typical clinical presentations, including certain autoantibodies on serologic testing. Histologic features are also often typical: primary biliary cholangitis shows bile duct destruction (sometimes with granulomas), and autoimmune hepatitis shows prominent portal and lobular lymphoplasmacytic inflammation. Both have a wide differential diagnosis, including one another; they may also simultaneously occur within the same patient. Careful use of clinical and histologic criteria may be necessary for diagnosis. First-line therapy is immunosuppression for autoimmune hepatitis and ursodeoxycholic acid for primary biliary cholangitis. Both diseases may progress to cirrhosis.
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Affiliation(s)
- Raul S Gonzalez
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Box 626, Rochester, NY 14642, USA.
| | - Kay Washington
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, 1161 21st Avenue South, C-3316 MCN, Nashville, TN 37232-2561, USA
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Christen U, Hintermann E. Autoantibodies in Autoimmune Hepatitis: Can Epitopes Tell Us about the Etiology of the Disease? Front Immunol 2018; 9:163. [PMID: 29503645 PMCID: PMC5820307 DOI: 10.3389/fimmu.2018.00163] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 01/18/2018] [Indexed: 12/12/2022] Open
Abstract
Autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) are serious autoimmune liver diseases that are characterized by a progressive destruction of the liver parenchyma and/or the hepatic bile ducts and the development of chronic fibrosis. Left untreated autoimmune liver diseases are often life-threatening, and patients require a liver transplantation to survive. Thus, an early and reliable diagnosis is paramount for the initiation of a proper therapy with immunosuppressive and/or anticholelithic drugs. Besides the analysis of liver biopsies and serum markers indicating liver damage, the screening for specific autoantibodies is an indispensable tool for the diagnosis of autoimmune liver diseases. Such liver autoantigen-specific antibodies might be involved in the disease pathogenesis, and their epitope specificity may give some insight into the etiology of the disease. Here, we will mainly focus on the generation and specificity of autoantibodies in AIH patients. In addition, we will review data from animal models that aim toward a better understanding of the origins and pathogenicity of such autoantibodies.
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Affiliation(s)
- Urs Christen
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Frankfurt am Main, Germany
| | - Edith Hintermann
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Frankfurt am Main, Germany
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15
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Selmi C, Generali E, Gershwin ME. Rheumatic Manifestations in Autoimmune Liver Disease. Rheum Dis Clin North Am 2018; 44:65-87. [PMID: 29149928 DOI: 10.1016/j.rdc.2017.09.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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16
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Ma WT, Chang C, Gershwin ME, Lian ZX. Development of autoantibodies precedes clinical manifestations of autoimmune diseases: A comprehensive review. J Autoimmun 2017; 83:95-112. [PMID: 28739356 DOI: 10.1016/j.jaut.2017.07.003] [Citation(s) in RCA: 92] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 06/30/2017] [Accepted: 07/01/2017] [Indexed: 12/21/2022]
Abstract
The etiology of autoimmune diseases is due to a combination of genetic predisposition and environmental factors that alter the expression of immune regulatory genes through various mechanisms including epigenetics. Both humoral and cellular elements of the adaptive immune system play a role in the pathogenesis of autoimmune diseases and the presence of autoantibodies have been detected in most but not all autoimmune diseases before the appearance of clinical symptoms. In some cases, the presence or levels of these autoantibodies portends not only the risk of developing a corresponding autoimmune disease, but occasionally the severity as well. This observation is intriguing because it suggests that we can, to some degree, predict who may or may not develop autoimmune diseases. However, the role of autoantibodies in the pathogenesis of autoimmune diseases, whether they actually affect disease progression or are merely an epiphenomenon is still not completely clear in many autoimmune diseases. Because of these gaps in our knowledge, the ability to accurately predict a future autoimmune disease can only be considered a relative risk factor. Importantly, it raises the critical question of defining other events that may drive a patient from a preclinical to a clinical phase of disease.
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Affiliation(s)
- Wen-Tao Ma
- Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou 510006, China; Liver Immunology Laboratory, School of Life Sciences, University of Science and Technology of China, Hefei 230027, China; College of Veterinary Medicine, Northwest Agriculture and Forestry University, Yangling 712100, China
| | - Christopher Chang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA.
| | - Zhe-Xiong Lian
- Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou 510006, China; Liver Immunology Laboratory, School of Life Sciences, University of Science and Technology of China, Hefei 230027, China; Innovation Center for Cell Signaling Network, Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China.
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17
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Diagnostic autoantibodies for autoimmune liver diseases. Clin Transl Immunology 2017; 6:e139. [PMID: 28690845 PMCID: PMC5493583 DOI: 10.1038/cti.2017.14] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 03/22/2017] [Accepted: 03/22/2017] [Indexed: 12/17/2022] Open
Abstract
Autoimmune liver diseases are conditions of low prevalence that comprise the triad of autoimmune hepatitis, primary biliary cholangitis (cirrhosis) and primary sclerosing cholangitis and their poorly characterised overlapping syndromes. Diagnostic autoantibodies are associated with autoimmune hepatitis and primary biliary cholangitis but not with primary sclerosing cholangitis. Autoantibodies are useful disease markers that facilitate early diagnosis of autoimmune hepatitis and primary biliary cholangitis and allow for therapeutic intervention to prevent progression to liver cirrhosis and associated complications. Adult onset type 1 autoimmune hepatitis is associated with F-actin reactive smooth muscle autoantibody, antinuclear autoantibody in 60% of patients, and autoantibody to SLA/LP in 15–20%. Juvenile onset type 2 autoimmune hepatitis is associated with LKM-1 and LC-1 autoantibodies. Primary biliary cholangitis is associated with a mitochondria-associated autoantibody designated M2 in >90% of patients and with disease-specific antinuclear autoantibodies in 50% that bind to antigens in the nuclear core complex and in multiple nuclear dots. Autoantibodies to the nuclear core complex target gp210, nucleoporin p62 and nuclear lamin B receptor. Autoantibodies to multiple nuclear dots target Sp100 and PML antigens. Liver autoantibodies in asymptomatic patients with normal liver function may precede the subsequent development of overt autoimmune liver disease. For routine diagnostic immunology laboratories, initial screening for liver autoantibodies by immunofluorescence remains the method of choice with confirmation for reactivity with their target antigen by enzyme-linked immunosorbent assay (ELISA) or line blot when required.
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18
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Han E, Jo SJ, Lee H, Choi AR, Lim J, Jung ES, Oh EJ. Clinical relevance of combined anti-mitochondrial M2 detection assays for primary biliary cirrhosis. Clin Chim Acta 2017; 464:113-117. [PMID: 27864100 DOI: 10.1016/j.cca.2016.11.021] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Revised: 10/25/2016] [Accepted: 11/14/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND Antimitochondrial antibody (AMA) is a specific serologic marker in primary biliary cirrhosis (PBC). The aim of this study was to evaluate the clinical relevance of combined AMA assays. METHODS Sera were obtained from 79 patients with PBC and 108 patients with other liver disease. They were tested by indirect immunofluorescence (IIF) using rat kidney/stomach tissue and HEp2 cells as substrate, 4 AMA-M2 assays, anti-sp100, and anti-gp210 assays. RESULTS Using IIF-AMA with cut-off titer of 1:40, the sensitivity and specificity for PBC were 88.6% and 87.0%, respectively. A cut-off titer of 1:80 improved the specificity to 93.5%. The 4 commercial assay kits using AMA-M2 autoantibodies showed sensitivity of 55.7-79.7% and specificity of 91.7-95.4% with moderate to good agreement. AMA-M2 assays using both native and recombinant E2 antigens had higher sensitivity. ANAs on HEp2 cells, anti-sp100, and anti-gp210 were detected in 67.1%, 13.9-15.2%, and 22.8-27.8% of PBC patients, respectively. Additional AMA-M2 specific assays in IIF-AMA negative and low titer positive (1:40) sera increased the sensitivity and specificity to 88.6% and 90.7%, respectively. CONCLUSIONS Serological diagnosis for PBC using IIF with high titer cut-off and additional AMA-M2 specific tests by ELISA or LIA in IIF-negative sera should be used.
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Affiliation(s)
- Eunhee Han
- Departments of Laboratory Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sung Jin Jo
- Departments of Laboratory Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hyeyoung Lee
- Departments of Laboratory Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ae-Ran Choi
- Departments of Laboratory Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jihyang Lim
- Departments of Laboratory Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Eun-Sun Jung
- Departments of Pathology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Eun-Jee Oh
- Departments of Laboratory Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
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Naughton BJ, Duncan FJ, Murrey DA, Meadows AS, Newsom DE, Stoicea N, White P, Scharre DW, Mccarty DM, Fu H. Blood genome-wide transcriptional profiles reflect broad molecular impairments and strong blood-brain links in Alzheimer's disease. J Alzheimers Dis 2016; 43:93-108. [PMID: 25079797 DOI: 10.3233/jad-140606] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
To date, little is known regarding the etiology and disease mechanisms of Alzheimer's disease (AD). There is a general urgency for novel approaches to advance AD research. In this study, we analyzed blood RNA from female patients with advanced AD and matched healthy controls using genome-wide gene expression microarrays. Our data showed significant alterations in 3,944 genes (≥2-fold, FDR ≤1%) in AD whole blood, including 2,932 genes that are involved in broad biological functions. Importantly, we observed abnormal transcripts of numerous tissue-specific genes in AD blood involving virtually all tissues, especially the brain. Of altered genes, 157 are known to be essential in neurological functions, such as neuronal plasticity, synaptic transmission and neurogenesis. More importantly, 205 dysregulated genes in AD blood have been linked to neurological disease, including AD/dementia and Parkinson's disease, and 43 are known to be the causative genes of 42 inherited mental retardation and neurodegenerative diseases. The detected transcriptional abnormalities also support robust inflammation, profound extracellular matrix impairments, broad metabolic dysfunction, aberrant oxidative stress, DNA damage, and cell death. While the mechanisms are currently unclear, this study demonstrates strong blood-brain correlations in AD. The blood transcriptional profiles reflect the complex neuropathological status in AD, including neuropathological changes and broad somatic impairments. The majority of genes altered in AD blood have not previously been linked to AD. We believe that blood genome-wide transcriptional profiling may provide a powerful and minimally invasive tool for the identification of novel targets beyond Aβ and tauopathy for AD research.
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Affiliation(s)
- Bartholomew J Naughton
- Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
| | - F Jason Duncan
- Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
| | - Darren A Murrey
- Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
| | - Aaron S Meadows
- Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
| | - David E Newsom
- Biomedical Genomics Core, Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
| | - Nicoleta Stoicea
- Division of Cognitive Neurology, Forest Hills Center for Alzheimer's Disease, College of Medicine and Public Health, The Ohio State University, Columbus, OH, USA Department of Neurology, College of Medicine and Public Health, The Ohio State University, Columbus, OH, USA
| | - Peter White
- Biomedical Genomics Core, Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, OH, USA
| | - Douglas W Scharre
- Division of Cognitive Neurology, Forest Hills Center for Alzheimer's Disease, College of Medicine and Public Health, The Ohio State University, Columbus, OH, USA Department of Neurology, College of Medicine and Public Health, The Ohio State University, Columbus, OH, USA
| | - Douglas M Mccarty
- Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, OH, USA
| | - Haiyan Fu
- Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, OH, USA
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20
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The coexistence of Sjögren's syndrome and primary biliary cirrhosis: a comprehensive review. Clin Rev Allergy Immunol 2016; 48:301-15. [PMID: 25682089 DOI: 10.1007/s12016-015-8471-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Organ-specific and systemic autoimmune diseases share numerous features and often coexist in the same patient. Autoimmune cholangitis/primary biliary cirrhosis and Sjogren syndrome represent paradigmatic examples of the common grounds of different autoimmunity phenotypes based on similarities in clinical manifestations and immunopathogenesis. In fact, primary biliary cirrhosis and Sjogren's syndrome have both been coined as an autoimmune epithelitis in which apoptosis may be in both cases the key element to explain the organ-specific immune-mediated injury against the biliary and exocrine gland epithelia, respectively. Further, growing evidence supports in both diseases the view that B cells, T cytotoxic cells, and T helper cells are involved in chronic inflammation, likely via the altered expression of pro-inflammatory cytokines. The presence of estrogen receptors on the biliary and exocrine gland epithelia has been advocated as a key to the female predominance encountered in primary biliary cirrhosis and Sjogren's syndrome. Sadly, despite available data, therapeutic approaches remain largely unsatisfactory and recent studies with mechanistic approaches (as in the case of B cell depletion with rituximab) have been of partial benefit only. Future studies should focus on new molecular tools (single-cell transcriptomics, microRNA, epigenetics) to provide unique insights into common mechanisms.
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21
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SP140L, an Evolutionarily Recent Member of the SP100 Family, Is an Autoantigen in Primary Biliary Cirrhosis. J Immunol Res 2015; 2015:526518. [PMID: 26347895 PMCID: PMC4548144 DOI: 10.1155/2015/526518] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Accepted: 07/07/2015] [Indexed: 12/21/2022] Open
Abstract
The SP100 family members comprise a set of closely related genes on chromosome 2q37.1. The widely expressed SP100 and the leukocyte-specific proteins SP110 and SP140 have been associated with transcriptional regulation and various human diseases. Here, we have characterized the SP100 family member SP140L. The genome sequence analysis showed the formation of SP140L gene through rearrangements of the two neighboring genes, SP100 and SP140, during the evolution of higher primates. The SP140L expression is interferon-inducible with high transcript levels in B cells and other peripheral blood mononuclear cells. Subcellularly, SP140L colocalizes with SP100 and SP140 in nuclear structures that are devoid of SP110, PML, or p300 proteins. Similarly to SP100 and SP140 protein, we detected serum autoantibodies to SP140L in patients with primary biliary cirrhosis using luciferase immunoprecipitation system and immunoblotting assays. In conclusion, our results show that SP140L is phylogenetically recent member of SP100 proteins and acts as an autoantigen in primary biliary cirrhosis patients.
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22
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Reshetnyak VI. Primary biliary cirrhosis: Clinical and laboratory criteria for its diagnosis. World J Gastroenterol 2015; 21:7683-7708. [PMID: 26167070 PMCID: PMC4491957 DOI: 10.3748/wjg.v21.i25.7683] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Revised: 04/07/2015] [Accepted: 06/10/2015] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic granulomatous, and destructive inflammatory lesion of small intralobular and septal bile ducts, which is likely to be caused by an autoimmune mechanism with a the presence of serum antimitochondrial antibodies and a potential tendency to progress to cirrhosis. Despite the fact that the etiology of this disease has been unknown so far, there has been a considerable body of scientific evidence that can reveal the clinical and laboratory signs of PBC and the individual components of its pathogenesis and elaborate diagnostic criteria for the disease and its symptomatic therapy. Deficiencies in autoimmune tolerance are critical factors for the initiation and perpetuation of the disease. The purpose of this review is to summarize the data available in the literature and the author's findings on clinical and laboratory criteria for the diagnosis of PBC. This review describes the major clinical manifestations of the disease and the mechanisms of its development. It presents the immunological, biochemical, and morphological signs of PBC and their significance for its diagnosis. A great deal of novel scientific evidence for the problem of PBC has been accumulated. However, the inadequate efficiency of therapy for the disease lends impetus to the quest for its etiological factors and to further investigations of its pathogenetic mechanisms and, on this basis, to searches for new methods for its early diagnosis.
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Staining pattern classification of antinuclear autoantibodies based on block segmentation in indirect immunofluorescence images. PLoS One 2014; 9:e113132. [PMID: 25474260 PMCID: PMC4256175 DOI: 10.1371/journal.pone.0113132] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Accepted: 10/20/2014] [Indexed: 12/02/2022] Open
Abstract
Indirect immunofluorescence based on HEp-2 cell substrate is the most commonly used
staining method for antinuclear autoantibodies associated with different types of
autoimmune pathologies. The aim of this paper is to design an automatic system to identify
the staining patterns based on block segmentation compared to the cell segmentation most
used in previous research. Various feature descriptors and classifiers are tested and
compared in the classification of the staining pattern of blocks and it is found that the
technique of the combination of the local binary pattern and the k-nearest neighbor
algorithm achieve the best performance. Relying on the results of block pattern
classification, experiments on the whole images show that classifier fusion rules are able
to identify the staining patterns of the whole well (specimen image) with a total accuracy
of about 94.62%.
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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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Hu SL, Zhao FR, Hu Q, Chen WX. Meta-analysis assessment of GP210 and SP100 for the diagnosis of primary biliary cirrhosis. PLoS One 2014; 9:e101916. [PMID: 25010534 PMCID: PMC4092088 DOI: 10.1371/journal.pone.0101916] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Accepted: 06/10/2014] [Indexed: 01/26/2023] Open
Abstract
PURPOSE To conduct a systematic review of included studies assessing the association of GP210 and SP100 with the risk of primary biliary cirrhosis (PBC) using meta-analysis. METHODS Five databases, the Cochrane Library, MEDLINE, VIP, CNKI, WANFANG were used to detect the role of GP210 and SP100 in diagnosis of PBC. Approximately 13,000 participants from several countries were included in this analysis. Meta-DiSc statistical software was used for analysis. RESULTS 25 studies on GP210 and 21 studies on SP100 were included in the meta-analysis. The DOR, sensitivity, specificity of GP210 in diagnosis of PBC were 24.854 (11.957-51.660), 0.272 (0.257-0.288), 0.985 (0.982-0.988), respectively, and they were 9.133 (4.739-17.600), 0.231 (0.213-0.249), 0.977 (0.973-0.981) for SP100. CONCLUSION Our meta-analysis indicated both GP210 and SP100 had high specificity but low sensitivity in diagnosis of PBC.
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Affiliation(s)
- Shi-Ling Hu
- The Department of Laboratory Medicine, the Second Hospital Affiliated to Chongqing Medical University, Chongqing, China
| | - Feng-Rong Zhao
- The Department of Gynecology and obstetrics, Youyang People’s Hospital, Chongqing, China
| | - Qin Hu
- The Department of Laboratory Medicine, the Second Hospital Affiliated to Chongqing Medical University, Chongqing, China
| | - Wei-Xian Chen
- The Department of Laboratory Medicine, the Second Hospital Affiliated to Chongqing Medical University, Chongqing, China
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Dyson J, Jones D. Diagnosis and management of patients with primary biliary cirrhosis. Clin Liver Dis (Hoboken) 2014; 3:52-55. [PMID: 30992885 PMCID: PMC6448699 DOI: 10.1002/cld.320] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Affiliation(s)
| | - David Jones
- Liver Research GroupInstitute of Cellular MedicineUniversity of Newcastle, Newcastle upon TyneUnited Kingdom
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Yamagiwa S, Kamimura H, Takamura M, Aoyagi Y. Autoantibodies in primary biliary cirrhosis: recent progress in research on the pathogenetic and clinical significance. World J Gastroenterol 2014; 20:2606-2612. [PMID: 24627596 PMCID: PMC3949269 DOI: 10.3748/wjg.v20.i10.2606] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2013] [Revised: 11/22/2013] [Accepted: 01/08/2014] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic liver disease characterized by immune-mediated destruction of the small- and medium-sized intrahepatic bile ducts and the presence of antimitochondrial antibodies (AMA) in the serum. AMA are detected in over 90% of patients with PBC, whereas their prevalence in the general population is extremely low, varying from 0.16% to 1%. Previous studies have shown that the unique characteristics of biliary epithelial cells undergoing apoptosis may result in a highly direct and very specific immune response to mitochondrial autoantigens. Moreover, recent studies have demonstrated that serum from AMA-positive PBC patients is reactive with a number of xenobiotic modified E2 subunits of the pyruvate dehydrogenase complex, which is not observed in the serum of normal individuals. These findings indicate that chemicals originating from the environment may be associated with a breakdown in the tolerance to mitochondrial autoantigens. While it is currently generally accepted that AMA are the most specific serological markers of PBC, more than 60 autoantibodies have been investigated in patients with PBC, and some have previously been considered specific to other autoimmune diseases. This review covers the recent progress in research on the pathogenetic and clinical significance of important autoantibodies in PBC. Determining the pathogenic role of those autoantibodies in PBC remains a priority of basic and clinical research.
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Ohishi Y, Nakamuta M, Ishikawa N, Saitoh O, Nakamura H, Aiba Y, Komori A, Migita K, Yatsuhashi H, Fukushima N, Kohjima M, Yoshimoto T, Fukuizumi K, Ishibashi M, Nishino T, Shirabe K, Taketomi A, Maehara Y, Ishibashi H, Nakamura M. Genetic polymorphisms of OCT-1 confer susceptibility to severe progression of primary biliary cirrhosis in Japanese patients. J Gastroenterol 2014; 49:332-42. [PMID: 23612856 DOI: 10.1007/s00535-013-0795-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2012] [Accepted: 03/14/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND To identify the genetic factors involved in the pathogenesis of primary biliary cirrhosis (PBC), we focused on the organic cation transporter 1 (OCT1/SLC22A1), which is closely associated with phosphatidylcholine synthesis in hepatocytes. METHODS We selected four (rs683369, rs2282143, rs622342 and rs1443844) OCT-1 single nucleotide polymorphisms (SNPs), and genotyped these SNPs using the TaqMan probe method in 275 Japanese PBC patients and 194 gender-matched, healthy volunteers as controls. RESULTS The Chi-square test revealed that the rs683369 variant allele (G) was associated with insusceptibility to PBC development [P = 0.009, odds ratio (OR) 0.60, 95 % confidence interval (CI) 0.40-0.88] in an allele model, and that the rs683369 variant allele (G) was associated with jaundice-type progression in a minor allele dominant genotype model (P = 0.032, OR 3.10, 95 % CI 1.05-9.14). The OCT-1 rs2282143 variant (T) and rs622342 variant (C) were also associated with jaundice-type progression in a minor allele recessive genotype model (P = 0.0002, OR 10.58, 95 % CI 2.36-47.54, and P = 0.006, OR 7.84, 95 % CI 1.39-44.36, respectively). Furthermore, the association of OCT-1 rs683369 and rs622342 with susceptibility to jaundice-type progression was confirmed by a replication study with a distinct set of PBC patients who underwent liver transplantation. CONCLUSIONS The present study is the first report on the association of OCT-1 genetic polymorphisms with the overall development and jaundice-type progression of PBC.
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Affiliation(s)
- Yuki Ohishi
- Department of Pharmacy, Clinical Research Institute, National Hospital Organization (NHO) Kyushu Medical Center, 1-8-1 Jigyouhama, Fukuoka, 810-8563, Japan
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Zafrir Y, Gilburd B, Carrasco MG, Kivity S, Sánchez-Castañón M, López-Hoyos M, Mandel M, Szmyrka M, Shoenfeld Y, Agmon-Levin N. Evaluation of an automated chemiluminescent immunoassay kit for antinuclear antibodies in autoimmune diseases. Immunol Res 2014; 56:451-6. [PMID: 23579775 DOI: 10.1007/s12026-013-8416-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The identification of antinuclear antibodies (ANA) is an essential step in the diagnosis of different autoimmune diseases. The gold standard method for their detection is immunofluorescence assay. However, this is a subjective and laborious method, thus a need for simplified objective methods has aroused. In the current work, we evaluated such automated method, the LIAISON(®) (DiaSorin, Italy) for the detection of ANA. A total of 242 sera were analyzed including 67 from healthy subjects, 107 from primary biliary cirrhosis (PBC) patients, 20 from scleroderma patients and 48 from patients with Sjögren's syndrome. All sera were analyzed using the automated chemiluminescent immunoassays, LIAISON(®) for the presence of ANA (kit No. 310300). Positive samples were further analyzed for the presence of antidouble-stranded DNA (dsDNA) and autoantibodies to 6 extractable nuclear antigens (ENA) of the LIAISON(®) (kits No. 310330 and 310331). Negative samples were further analyzed by Blueblot ANA assay (D-TEK, Belgium) or BlueDot Liver (D-TEK, Belgium) as appropriate. The LIAISON(®) specificity for ANA screening was 97%. ANA positivity was determined in 80% of all patients. The sensitivity was 95.5% in scleroderma, 83% in PBC and 72.9% in Sjogren's syndrome. ENA was positive in all ANA-positive scleroderma and Sjögren's sera and in 27% of ANA-positive PBC sera. Among scleroderma or Sjögren patients that were ANA negative, 4 samples were positive for anti-SSA and 2 for RNP-68 utilizing Blueblot assays. M2 protein was found in 1 out of the ANA-negative PBC patients. The LIAISON(®) ANA screen is specific and sensitive for the evaluation of ANA in patients with primary biliary cirrhosis, scleroderma and Sjögren's syndrome.
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Affiliation(s)
- Yaron Zafrir
- Sheba Medical Center (affiliated to Sackler Faculty of Medicine, Tel-Aviv University), 52621, Tel-Hashomer, Israel
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Saito H, Takahashi A, Abe K, Okai K, Katsushima F, Monoe K, Kanno Y, Ohira H. Autoantibodies by line immunoassay in patients with primary biliary cirrhosis. Fukushima J Med Sci 2013; 58:107-16. [PMID: 23237866 DOI: 10.5387/fms.58.107] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES We attempted to measure multiple autoantibodies simultaneously using line immunoassay (LIA) in patients with primary biliary cirrhosis (PBC) with or without anti-mitochondrial antibody (AMA) and patients with PBC-autoimmune hepatitis (AIH) overlap, and we examined the clinical significance of measuring these autoantibodies. METHODS The study population consisted of 80 patients with PBC (including 12 AMA-negative patients), 16 patients with PBC-AIH overlap and 40 patients with AIH as controls. Nine antibodies (AMA-M2, M2-3E, Sp100, PML, gp210, Ro-52, LKM-1, LC-1 and SLA/LP) were detected by LIA, and AMA-M2 and anti-centromere antibody (ACA) were detected by ELISA. We examined the relationship between these autoantibodies and clinical findings. RESULTS The positive prevalence of each autoantibody and ACA in the PBC group, as determined by LIA, was as follows: 13.8% for anti-Sp100, 8.7% for anti-PML, 40% for anti-gp210 and 27.5% for anti-Ro-52 antibodies and 32.5% for ACA. In the PBC-AIH overlap group, the prevalence of anti-gp210 antibody (68.7%) and that of anti-Ro-52 antibody (81.2%) were significantly higher than those in the PBC and AIH groups. Only a few patients were positive for 2 or more autoantibodies. Nine patients were determined to be negative for all autoantibodies by LIA, of whom 7 were positive for ACA. Patients positive for anti-gp210 antibody included more patients classified as stage 4 on histology than did the negative group. Those positive for ACA included more patents with varices than did the negative group. CONCLUSION LIA can measure multiple autoantibodies simultaneously and thus is considered useful in diagnosing PBC and PBC-AIH overlap. In addition, ACA is a useful marker for identifying AMA-negative PBC.
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Affiliation(s)
- Hironobu Saito
- Department of Gastroenterology and Rheumatology, Fukushima Medical University
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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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Abstract
BACKGROUND Primary biliary cirrhosis (PBC) is an autoimmune liver disease of unknown etiology characterized by the presence of antimitochondrial antibodies (AMA) in 90 - 95% of patients. AMA are directed against members of 2-oxo-acid dehydrogenase complex, including mainly the E2 subunit of pyruvate dehydrogenase, the E2 subunit of branched chain 2-oxo-acid dehydrogenase complex and the E2 subunit of the oxoglutarate dehydrogenase complex. Apart from AMA, PBC is characterized by the presence of PBC-specific antinuclear antibodies (ANA). The molecular targets of these PBC-specific ANA have been characterized as gp210, lamin B receptor, nucleoporin 62, sp100 and promyelocytic leukemia proteins. OBJECTIVE To discuss the molecular diagnostics of PBC in the context of AMA and PBC-specific ANA detection by the use of conventional and 'new' novel technologies. METHODS Critical analysis of all published data regarding PBC serology between 1985 and 2007 was performed in order to suggest a diagnostic algorithm for the serological diagnosis of PBC. RESULTS/CONCLUSIONS AMA are first detected by indirect immunofluorescence (IIF) on frozen sections of rat liver, kidney and stomach substrates. However, because IIF is time-consuming, labor-intensive and observer-dependent, molecular-based assays such as immunoblot and enzyme-linked immunosorbent assays have been developed with high sensitivity and specificity. Similarly, molecular-based assays have also been developed for the detection of PBC-specific ANA. The latter investigation seems to be of outmost importance because these autoantibodies can be used as a positive tool in the diagnosis of AMA-negative PBC while at the same time identifying a subgroup of PBC patients with more advanced disease. New test systems for the detection of PBC-specific antibodies based on the xMultiple Analyte Profiling Luminex methodology seems to be the future in molecular diagnostics of PBC as it was expected first to decrease the cost and second to speed up an accurate serological profile, although they may decrease further the proportion of AMA-negative PBC cases.
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Affiliation(s)
- Eirini I Rigopoulou
- University of Thessaly, Department of Medicine, Academic Liver Unit and Research Lab of Internal Medicine, Medical School, Papakiriazi 22 Street, 41222 Larissa, Greece +30 2410 565251 ; +30 2410 565250 ;
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Bauer A, Habior A, Kraszewska E. Detection of anti-SP100 antibodies in primary biliary cirrhosis. Comparison of ELISA and immunofluorescence. J Immunoassay Immunochem 2013; 34:346-55. [PMID: 23859785 DOI: 10.1080/15321819.2012.741088] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Primary biliary cirrhosis (PBC) is, which a chronic, autoimmune liver disease. Some patients have antinuclear antibodies anti-Sp100, which are considered to be disease-specific. We compared an enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence (IIF) for detection of anti-Sp100. The sensitivity of anti-Sp100 determined by ELISA and IIF was 44% and 34%, respectively. Specificity was 99% for ELISA and 98% for IIF, respectively. The positive and negative predictive value (PPV, NPV) for anti-Sp100 determined by ELISA were 98%, 60% and 95%, 56% for IIF respectively. IIF required substantial experience in interpreting subjective patterns, whereas ELISA was more sensitive, cheaper, less time consuming, and produced clear-cut quantitative results.
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Affiliation(s)
- Alicja Bauer
- Department of Biochemistry and Molecular Biology, Medical Centre of Postgraduate Education, Warsaw, Poland.
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Oliveira EMG, Oliveira PM, Becker V, Dellavance A, Andrade LEC, Lanzoni V, Silva AEB, Ferraz MLG. Overlapping of primary biliary cirrhosis and small duct primary sclerosing cholangitis: first case report. J Clin Med Res 2012; 4:429-33. [PMID: 23226177 PMCID: PMC3513426 DOI: 10.4021/jocmr1060w] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/20/2012] [Indexed: 12/27/2022] Open
Abstract
Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are both autoimmune cholestatic liver disease and the association of these two conditions in the same patient is very rare. We report the case of a female patient presenting with a cholestatic liver disease and a panel of autoantibodies specific for PBC, including antibodies to mitochondrial E2-pyruvate dehydrogenase, gp-210 and Sp-100. Beside these findings, the liver biopsy revealed concentric fibrosis of small biliary ducts and the magnetic resonance cholangiography presented no abnormal findings. Diagnosis of small duct PSC/PBC overlapping was done. No description of this association was found in the literature. Clinical and serological features of this unusual finding are discussed.
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Imura-Kumada S, Hasegawa M, Matsushita T, Hamaguchi Y, Encabo S, Shums Z, Norman GL, Takehara K, Fujimoto M. High prevalence of primary biliary cirrhosis and disease-associated autoantibodies in Japanese patients with systemic sclerosis. Mod Rheumatol 2012; 22:892-8. [PMID: 22327744 DOI: 10.1007/s10165-012-0607-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2011] [Accepted: 01/25/2012] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To investigate the prevalence of primary biliary cirrhosis (PBC) and PBC-associated autoantibodies in Japanese systemic sclerosis (SSc) patients. METHODS Clinical data from 225 Japanese SSc patients were retrospectively obtained. Serum samples from these patients were examined for PBC-associated autoantibodies, anti-mitochondrial M2 antibodies (AMA), anti-sp100 antibodies (anti-sp100), and anti-gp210 antibodies (anti-gp210) by enzyme-linked immunosorbent assay. RESULTS Of 225 patients, 37 (16.4%) had AMA, 13 (5.8%) had anti-sp100, and 3 (1.3%) had anti-gp210. Three patients were positive for both AMA and anti-sp100, and 2 were positive for both AMA and anti-gp210. PBC was found in 22 (9.8%) patients positive for AMA with or without anti-sp100 or anti-gp210, but not in those with anti-sp100 or anti-gp210 without AMA. Furthermore, 13 patients lacking these three antibodies were diagnosed with or suspected of PBC by liver biopsy and/or their clinical manifestation. Multivariable analysis revealed that AMA and anti-centromere antibodies were independently associated with PBC in SSc patients, while anti-sp100 and anti-gp210 were not. CONCLUSIONS This study has demonstrated even higher prevalence of both PBC-associated autoantibodies and PBC in the Japanese SSc population than in the Caucasian SSc population. AMA and anti-centromere antibodies are likely to indicate increasing risk of PBC in SSc patients.
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Affiliation(s)
- Sayako Imura-Kumada
- Department of Dermatology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan
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Zografos TA, Gatselis N, Zachou K, Liaskos C, Gabeta S, Koukoulis GK, Dalekos GN. Primary biliary cirrhosis-specific autoantibodies in first degree relatives of Greek primary biliary cirrhosis patients. World J Gastroenterol 2012; 18:4721-8. [PMID: 23002341 PMCID: PMC3442210 DOI: 10.3748/wjg.v18.i34.4721] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2012] [Revised: 03/31/2012] [Accepted: 04/09/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the prevalence and significance of primary biliary cirrhosis (PBC)-specific autoantibodies in first-degree relatives (FDRs) of Greek PBC patients.
METHODS: The presence of antimitochondrial antibodies (AMA) and PBC-specific antinuclear antibodies (ANA) were determined using indirect immunofluorescence assays, dot-blot assays, and molecularly based enzyme-linked immunosorbent assays in 101 asymptomatic for liver-related symptoms FDRs of 44 PBC patients. In order to specify our results, the same investigation was performed in 40 healthy controls and in a disease control group consisting of 40 asymptomatic for liver-related symptoms FDRs of patients with other autoimmune liver diseases namely, autoimmune hepatitis-1 or primary sclerosing cholangitis (AIH-1/PSC).
RESULTS: AMA positivity was observed in 19 (only 4 with abnormal liver function tests) FDRs of PBC patients and none of the healthy controls. The prevalence of AMA was significantly higher in FDRs of PBC patients than in AIH-1/PSC FDRs and healthy controls [18.8%, 95% confidence interval (CI): 12%-28.1% vs 2.5%, 95% CI: 0.1%-14.7%, P = 0.01; 18.8%, 95% CI: 12%-28.1% vs 0%, 95% CI: 0%-10.9%, P = 0.003, respectively]. PBC-specific ANA positivity was observed in only one FDR from a PSC patient. Multivariate analysis showed that having a proband with PBC independently associated with AMA positivity (odds ratio: 11.24, 95% CI: 1.27-25.34, P = 0.03) whereas among the investigated comorbidities and risk factors, a positive past history for urinary tract infections (UTI) was also independently associated with AMA detection in FDRs of PBC patients (odds ratio: 3.92, 95% CI: 1.25-12.35, P = 0.02).
CONCLUSION: In FDRs of Greek PBC patients, AMA prevalence is significantly increased and independently associated with past UTI. PBC-specific ANA were not detected in anyone of PBC FDRs.
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Krzyczmonik K, Świtnicki M, Kaczanowski S. Analysis of immunogenicity of different protein groups from malaria parasite Plasmodium falciparum. INFECTION GENETICS AND EVOLUTION 2012; 12:1911-6. [PMID: 22986003 DOI: 10.1016/j.meegid.2012.07.023] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2012] [Revised: 07/24/2012] [Accepted: 07/29/2012] [Indexed: 11/18/2022]
Abstract
It was observed that pressure of host immune system leads to diversifying selection (which can be measured in terms of pN/pS ratio). In this research we checked whether Plasmodium falciparum proteins containing experimentally evident epitopes from the IEDB database are subject to diversifying selection. We also investigated which life stage of this parasite and which proteins are subject to the strongest immune pressure. To answer these questions we used information about experimentally evident epitopes from P. falciparum, that interact with human immune system and sequences of different isolates of P. falciparum obtained from PlasmoDB. We confirmed the expectations that proteins containing IEDB epitopes are subject to stronger diversifying selection which is evidenced by higher pN/pS ratio. A stage characterized by the highest average pN/pS ratio is that of the sporozoite. The greatest fraction of putative antigens is also present at this stage. We also found that the sporozoite stage is particularly interesting for further analysis as it potentially contains the highest number of unidentified epitopes.
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Affiliation(s)
- Katarzyna Krzyczmonik
- Bioinformatics Department, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, ul Pawinskiego 5a, 02-106 Warszawa, Poland.
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Mytilinaiou MG, Meyer W, Scheper T, Rigopoulou EI, Probst C, Koutsoumpas AL, Abeles D, Burroughs AK, Komorowski L, Vergani D, Bogdanos DP. Diagnostic and clinical utility of antibodies against the nuclear body promyelocytic leukaemia and Sp100 antigens in patients with primary biliary cirrhosis. Clin Chim Acta 2012; 413:1211-6. [PMID: 22503841 DOI: 10.1016/j.cca.2012.03.020] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2012] [Revised: 03/24/2012] [Accepted: 03/25/2012] [Indexed: 12/16/2022]
Abstract
BACKGROUND The lack of an immunoassay that detects antibodies to promyelocytic leukaemia (PML) protein, the primary biliary cirrhosis (PBC)-specific multiple nuclear dot (MND) antigen, has prompted us to develop a line immunoassay (LIA) for the simultaneous detection of PML and Sp100 MND-specific autoantibodies. METHODS PML and Sp100 were expressed in Escherichia coli, and analysed by SDS-PAGE and immunoblotting using a monoclonal antibody and MALDI-ToF fingerprinting. A quantitative PML and Sp100 LIA were developed and testing was performed in 150 anti-mitochondrial antibody (AMA) positive, 20 AMA-PBCs and 130 controls. RESULTS Thirty-five (23%) of 150 AMA+ PBCs (18 anti-MND+) were anti-PML+ (12%) or anti-Sp100+ (20%), 10 being anti-PML+/Sp100+, 5 single anti-PML+ and 20 single anti-Sp100+. Six (30%, 5 anti-MND+) AMA-PBCs were anti-PML+ or Sp100+. Only 2 (1.7%) pathological controls were anti-PML+ and/or anti-Sp100+. Levels of anti-PML correlated with those of anti-Sp100 (R=0.64, p<0.0001). The autoantibody profile largely remained unchanged over a 10year-follow up (52 patients, 352 samples). Anti-PML, Sp100 or MND-reactive PBCs were younger and had longer disease duration than the seronegative (p=0.06, for both). Anti-Sp100 levels correlated with the Mayo risk score (r=0.63, p=0.01). Anti-PML+/Sp100+ patients had more advanced disease compared to patients negative for anti-PML/Sp100 (p=0.04). CONCLUSION The new line immunoassay offers a robust and accurate method for the detection of clinically-relevant PBC-specific anti-MND antibodies.
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MESH Headings
- Adult
- Amino Acid Sequence
- Antibody Specificity
- Antigens, Nuclear/analysis
- Antigens, Nuclear/blood
- Antigens, Nuclear/genetics
- Antigens, Nuclear/immunology
- Autoantibodies/analysis
- Autoantibodies/blood
- Autoantibodies/immunology
- Autoantigens/analysis
- Autoantigens/blood
- Autoantigens/genetics
- Autoantigens/immunology
- Case-Control Studies
- Escherichia coli/genetics
- Follow-Up Studies
- Humans
- Immunoassay/methods
- Leukemia, Promyelocytic, Acute/diagnosis
- Leukemia, Promyelocytic, Acute/immunology
- Liver Cirrhosis, Biliary/diagnosis
- Liver Cirrhosis, Biliary/immunology
- Middle Aged
- Molecular Sequence Data
- Time Factors
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Affiliation(s)
- Maria G Mytilinaiou
- Liver Immunopathology, Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, UK
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Yang CY, Leung PSC, Yang GX, Kenny TP, Zhang W, Coppel R, Norman GL, Ansari AA, Mackay IR, Worman HJ, Gershwin ME. Epitope-specific anti-nuclear antibodies are expressed in a mouse model of primary biliary cirrhosis and are cytokine-dependent. Clin Exp Immunol 2012; 168:261-7. [PMID: 22519587 PMCID: PMC3390476 DOI: 10.1111/j.1365-2249.2012.04577.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/08/2012] [Indexed: 01/29/2023] Open
Abstract
Although the hallmark of primary biliary cirrhosis (PBC) is the presence of anti-mitochondrial antibodies (AMA), a significant number of patients have anti-nuclear antibodies (ANA) directed primarily against two nuclear proteins, gp210 and sp100. In PBC, there are considerable data on the specificity of these anti-nuclear antibodies as well as suggestive evidence that antibodies to gp210 predict a poor outcome. However, a further understanding of the significance of these autoantibodies has been hampered by limitations in accessing human subjects in a preclinical or early asymptomatic stage. To overcome this limitation, we have taken advantage of transgenic mice with abrogated transforming growth factor-β signalling in T cells (dnTGF-βRII) that develop histological features of PBC as well as the same AMA specificity. We studied these mice for serum ANA, including specific autoantibodies against gp210 and sp100. We further examined sera from dnTGF-βRII mice with concurrent deletions of the genes encoding interleukin (IL)-12p35, IL-12p40, IL-23p19, IL-17, IL-6, interferon (IFN)-γ or tumour necrosis factor (TNF)-α. Sera from all the dnTGF-βRII mouse lines contained antibodies against gp210 and sp100. Of significance, mice with germline deletions of the genes encoding IL-12p40, IL-23p19, IL-17, IL-6 and TNF-α had significantly lower titres of anti-gp210 antibodies. These results provide a platform to dissect the mechanisms of gp210 and sp100 autoantibody production in dnTGF-βRII mice as well as to study the possible role of ANA in the pathophysiology of PBC.
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Affiliation(s)
- C-Y Yang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, USA
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40
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Hu CJ, Song G, Huang W, Liu GZ, Deng CW, Zeng HP, Wang L, Zhang FC, Zhang X, Jeong JS, Blackshaw S, Jiang LZ, Zhu H, Wu L, Li YZ. Identification of new autoantigens for primary biliary cirrhosis using human proteome microarrays. Mol Cell Proteomics 2012; 11:669-80. [PMID: 22647870 DOI: 10.1074/mcp.m111.015529] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of unknown etiology and is considered to be an autoimmune disease. Autoantibodies are important tools for accurate diagnosis of PBC. Here, we employed serum profiling analysis using a human proteome microarray composed of about 17,000 full-length unique proteins and identified 23 proteins that correlated with PBC. To validate these results, we fabricated a PBC-focused microarray with 21 of these newly identified candidates and nine additional known PBC antigens. By screening the PBC microarrays with additional cohorts of 191 PBC patients and 321 controls (43 autoimmune hepatitis, 55 hepatitis B virus, 31 hepatitis C virus, 48 rheumatoid arthritis, 45 systematic lupus erythematosus, 49 systemic sclerosis, and 50 healthy), six proteins were confirmed as novel PBC autoantigens with high sensitivities and specificities, including hexokinase-1 (isoforms I and II), Kelch-like protein 7, Kelch-like protein 12, zinc finger and BTB domain-containing protein 2, and eukaryotic translation initiation factor 2C, subunit 1. To facilitate clinical diagnosis, we developed ELISA for Kelch-like protein 12 and zinc finger and BTB domain-containing protein 2 and tested large cohorts (297 PBC and 637 control sera) to confirm the sensitivities and specificities observed in the microarray-based assays. In conclusion, our research showed that a strategy using high content protein microarray combined with a smaller but more focused protein microarray can effectively identify and validate novel PBC-specific autoantigens and has the capacity to be translated to clinical diagnosis by means of an ELISA-based method.
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Affiliation(s)
- Chao-Jun Hu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100032, China
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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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Imura-Kumada S, Hasegawa M, Matsushita T, Hamaguchi Y, Encabo S, Shums Z, Norman GL, Takehara K, Fujimoto M. High prevalence of primary biliary cirrhosis and disease-associated autoantibodies in Japanese patients with systemic sclerosis. Mod Rheumatol 2012. [PMID: 22327744 DOI: 10.3109/s10165-012-0607-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To investigate the prevalence of primary biliary cirrhosis (PBC) and PBC-associated autoantibodies in Japanese systemic sclerosis (SSc) patients. METHODS Clinical data from 225 Japanese SSc patients were retrospectively obtained. Serum samples from these patients were examined for PBC-associated autoantibodies, anti-mitochondrial M2 antibodies (AMA), anti-sp100 antibodies (anti-sp100), and anti-gp210 antibodies (anti-gp210) by enzyme-linked immunosorbent assay. RESULTS Of 225 patients, 37 (16.4%) had AMA, 13 (5.8%) had anti-sp100, and 3 (1.3%) had anti-gp210. Three patients were positive for both AMA and anti-sp100, and 2 were positive for both AMA and anti-gp210. PBC was found in 22 (9.8%) patients positive for AMA with or without anti-sp100 or anti-gp210, but not in those with anti-sp100 or anti-gp210 without AMA. Furthermore, 13 patients lacking these three antibodies were diagnosed with or suspected of PBC by liver biopsy and/or their clinical manifestation. Multivariable analysis revealed that AMA and anti-centromere antibodies were independently associated with PBC in SSc patients, while anti-sp100 and anti-gp210 were not. CONCLUSIONS This study has demonstrated even higher prevalence of both PBC-associated autoantibodies and PBC in the Japanese SSc population than in the Caucasian SSc population. AMA and anti-centromere antibodies are likely to indicate increasing risk of PBC in SSc patients.
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Affiliation(s)
- Sayako Imura-Kumada
- Department of Dermatology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan
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Granito A, Muratori P, Quarneti C, Pappas G, Cicola R, Muratori L. Antinuclear antibodies as ancillary markers in primary biliary cirrhosis. Expert Rev Mol Diagn 2012; 12:65-74. [PMID: 22133120 DOI: 10.1586/erm.11.82] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Antimitochondrial antibodies are the serological hallmark of primary biliary cirrhosis (PBC). Besides antimitochondrial antibodies, the autoantibody profile of PBC includes antinuclear antibodies (ANA) which are detectable by indirect immunofluorescence in up to 50% of PBC patients. Two immunofluorescence patterns are considered 'PBC-specific': the multiple nuclear dots and rim-like/membranous patterns. The target antigens of the multiple nuclear dots pattern have been identified as Sp100 and promyelocytic leukemia protein, whereas the rim-like/membranous pattern is given by autoantibodies recognizing multiple proteins such as gp210, nucleoporin p62 and the lamin B receptor. Other ANA, especially those already known in the rheumatological setting, such as anticentromere, anti-SSA/Ro and anti-dsDNA antibodies, can be frequently found in PBC, often coexisting in the same patient. In this article, we will report on recent progress in the antigenic characterization of ANA in PBC, their detection with both traditional assays and Western blot/ELISA with molecularly defined nuclear antigens, and we will discuss their clinical significance.
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Affiliation(s)
- Alessandro Granito
- Department of Clinical Medicine, Alma Mater Studiorum-University of Bologna, S.Orsola-Malpighi Hospital, Italy.
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45
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A novel automated indirect immunofluorescence autoantibody evaluation. Clin Rheumatol 2011; 31:503-9. [DOI: 10.1007/s10067-011-1884-1] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2011] [Revised: 09/24/2011] [Accepted: 10/15/2011] [Indexed: 12/20/2022]
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Novel opportunities in automated classification of antinuclear antibodies on HEp-2 cells. Autoimmun Rev 2011; 10:647-52. [DOI: 10.1016/j.autrev.2011.04.022] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Daniilidou M, Tsolaki M, Giannakouros T, Nikolakaki E. Detection of elevated antibodies against SR protein kinase 1 in the serum of Alzheimer's disease patients. J Neuroimmunol 2011; 238:67-72. [PMID: 21794928 DOI: 10.1016/j.jneuroim.2011.06.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2011] [Revised: 05/23/2011] [Accepted: 06/24/2011] [Indexed: 10/17/2022]
Abstract
Autoantibodies targeting specific cellular antigens are often present in sera and cerebrospinal fluids (CSFs) of patients with Alzheimer's disease (AD) and could play a role in the onset and/or progression of the disease. In this study we identified SR Protein Kinase 1 (SRPK1) as a new autoantigen elevated in AD. SRPK1, the prototype of the serine/arginine family of kinases, has been implicated in the regulation of multiple cellular processes such as pre-mRNA splicing, cell proliferation, chromatin structure, nuclear import and germ cell development. Using an ELISA assay, anti-SRPK1 antibodies, targeting mainly the first catalytic domain of the kinase, were detected in sera of patients with AD, at significantly elevated levels as compared to control subjects. The findings of this study document for the first time the existence of antibodies targeting SRPK1 in human sera and are indicative of a correlation between the levels of a-SRPK1 antibodies and the incidence of AD.
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Affiliation(s)
- Makrina Daniilidou
- Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece
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Medina JF. Role of the anion exchanger 2 in the pathogenesis and treatment of primary biliary cirrhosis. Dig Dis 2011; 29:103-12. [PMID: 21691115 DOI: 10.1159/000324144] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The essential anion exchanger (AE) involved in biliary bicarbonate secretion is AE2/SLC4A2, a membrane protein which has also been recognized to be relevant for the regulation of the intracellular pH (pH(i)) in several cell types. Previously, we reported that the expression of AE2 mRNA is diminished in liver biopsies and peripheral blood mononuclear cells from patients with primary biliary cirrhosis (PBC). Immunohistochemical studies indicated that the expression of the AE2 protein is decreased in the bile ducts and hepatocytes in PBC livers. Moreover, we found that bile duct cells isolated from PBC patients and cultured for a few passages exhibit defective Na(+)-independent Cl(-)/HCO(3)(-) exchange. Interestingly, positron emission tomography studies have shown that PBC patients, even at early stages of the disease, fail to secrete bicarbonate to bile in response to secretin, a defect that can be partially reversed after several months of treatment with ursodeoxycholic acid. Altogether, these findings sustain our hypothesis that dysfunctions related to AE2 might have a role in the pathogenesis of PBC. Inadequate AE2 function in lymphocytes may disturb pH(i) regulation in these cells and alter immune homeostasis leading to autoimmunity. On the other hand, reduced AE2 in cholangiocytes could cause cholestasis and oxidative stress of bile duct cells. Cholangiocyte changes, together with altered immune homeostasis, could favor the development of antimitochondrial antibodies and the autoimmune attack on biliary ducts. Our recent findings that Ae2(a,b)-deficient mice indeed display most of these features strongly support the notion that AE2 abnormalities may be involved in the pathogenesis of PBC.
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Affiliation(s)
- Juan F Medina
- Division of Gene Therapy and Hepatology - Liver Unit, School of Medicine, Clinic and CIMA University of Navarra, and Ciberehd, Pamplona, Spain.
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Stinton LM, Swain M, Myers RP, Shaheen AA, Fritzler MJ. Autoantibodies to GW bodies and other autoantigens in primary biliary cirrhosis. Clin Exp Immunol 2011; 163:147-56. [PMID: 21091667 PMCID: PMC3043305 DOI: 10.1111/j.1365-2249.2010.04288.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/11/2010] [Indexed: 12/13/2022] Open
Abstract
Autoantibodies to intracellular targets in mitochondria and nuclei are serological hallmarks of primary biliary cirrhosis (PBC). One of the most recently identified cellular targets of PBC autoantibodies is a novel cytoplasmic structure referred to as GW bodies [GWB, G (glycine) W (tryptophan)-containing bodies (GWB)]. GWB are indentified as discrete cytoplasmic domains that are involved in mRNA processing via the RNA interference (RNAi) pathway. Key components of GWB include the proteins GW182, Ago2, RNA-associated protein 55 (RAP55) and Ge-1/Hedls. The primary objective was to study the frequency and clinical association of antibodies directed to GWB components, in 109 PBC patients. Autoantibodies to mitochondrial antigen-pyruvate dehydrogenase complex (M2), branched-chain 2-oxo-acid dehydrogenase complex and 2-oxo glutarate dehydrogenase complex (3E-BPO), gp210, sp100, promyelocytic leukaemia cell antigen (PML) and liver kidney microsomal-1 antigen (LKM-1) were detected by a line immunoassay and antibodies to GWB (GW182, RAP55, Ge-1, GW2, GW3) and glutamate receptor interacting protein (GRIP)-associated protein-1 (GRASP-1), by an addressable laser bead immunoassay (ALBIA). The most common GWB autoantigen targets were: RAP55-28%, GW182-12%, GW2-2% and antibodies to GRASP-1-17%. By comparison, the frequency of reactivity to established PBC autoantigens was: gp210, 27%; sp100, 27% and PML, 17%. None of the autoantibodies were associated with differences in Mayo risk score or liver decompensation. This study is the first study to show that antibodies to RAP55, GW182 and GRASP-1 are the most common GWB targets in PBC.
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Affiliation(s)
- L M Stinton
- Department of Medicine, University of Calgary, AB, Canada
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Wiik AS, Høier-Madsen M, Forslid J, Charles P, Meyrowitsch J. Antinuclear antibodies: A contemporary nomenclature using HEp-2 cells. J Autoimmun 2010; 35:276-90. [DOI: 10.1016/j.jaut.2010.06.019] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
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