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Heiat M, Javanbakht M, Jafari D, Poudineh M, Heydari F, Sharafi H, Alavian SM. Correlation of IL-10 and IL18 with the development of liver cirrhosis associated with hepatitis B virus infection: A systematic review. Cytokine 2025; 186:156818. [PMID: 39671883 DOI: 10.1016/j.cyto.2024.156818] [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: 07/01/2024] [Revised: 10/02/2024] [Accepted: 11/16/2024] [Indexed: 12/15/2024]
Abstract
BACKGROUND Patients who have been infected with the Hepatitis B virus (HBV) are susceptible to developing liver cirrhosis (LC) and hepatocellular carcinoma (HCC). The objective of this systematic review was to comprehensively scrutinize the existing evidence concerning the association between host genetic polymorphisms and HBV-associated LC. METHODS We searched databases of PubMed, Scopus, and Web of Science for relevant articles published from building databases to 25 October 2023. RESULT We detected 104 relevant articles, relating to 84 individuals genes. Nine genes had the strong evidence of correlation, including IL-10, IL-18, IL-1B, TGF- β, TLR3, STAT4, IL-1RN, Tim3, and IFN receptors. A positive correlation was found for 33 genes but this data had not yet been replicated, 11 genes had limited or mixed evidence of a correlation, and 34 genes indicated no correlation. IL-10 and IL-18 had the most evidence of correlation. There was a notable amount of diversity in both the design and method of studies and data quality. CONCLUSION IL-10 and IL-18 had the most evidence of correlation. There was a notable amount of diversity in both the design and method of studies and data quality. It is of necessary to take into account the fundamental mechanism behind these associations and discern those that are confounded by the coexistence of other LC/HCC risk factors and response to therapy. These results are expected to guide future studies on the genetic susceptibility of HBV-related LC/HCC.
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Affiliation(s)
- Mohammad Heiat
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Mohammad Javanbakht
- Nephrology and Urology Research Center, Clinical Science Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Davood Jafari
- Department of Immunology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mohadeseh Poudineh
- Student Research Committee, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Fatemeh Heydari
- Student Research Committee, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | | | - Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
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2
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Khor AHP, Koguchi T, Liu H, Kakuta M, Matsubara D, Wen R, Sagiya Y, Imoto S, Nakagawa H, Matsuda K, Tanikawa C. Regulation of the innate immune response and gut microbiome by p53. Cancer Sci 2024; 115:184-196. [PMID: 38050344 PMCID: PMC10823282 DOI: 10.1111/cas.15991] [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: 01/16/2023] [Revised: 08/25/2023] [Accepted: 09/28/2023] [Indexed: 12/06/2023] Open
Abstract
p53 is a key tumor suppressor mutated in half of human cancers. In recent years, p53 was shown to regulate a wide variety of functions. From the transcriptome analysis of 24 tissues of irradiated mice, we identified 553 genes markedly induced by p53. Gene Ontology (GO) enrichment analysis found that the most associated biological process was innate immunity. 16S rRNA-seq analysis revealed that Akkermansia, which has anti-inflammatory properties and is involved in the regulation of intestinal barrier integrity, was decreased in p53-knockout (p53-/- ) mice after radiation. p53-/- mice were susceptible to radiation-induced GI toxicity and had a significantly shorter survival time than p53-wild-type (p53+/+ ) mice following radiation. However, administration of antibiotics resulted in a significant improvement in survival and protection against GI toxicity. Mbl2 and Lcn2, which have antimicrobial activity, were identified to be directly transactivated by p53 and secreted by liver into the circulatory system. We also found the expression of MBL2 and LCN2 was decreased in liver cancer tissues with p53 mutations compared with those without p53 mutations. These results indicate that p53 is involved in shaping the gut microbiome through its downstream targets related to the innate immune system, thus protecting the intestinal barrier.
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Affiliation(s)
- Amy Hui Ping Khor
- Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier SciencesThe University of TokyoMinato City, TokyoJapan
| | - Tomoyuki Koguchi
- Department of UrologyFukushima Medical University School of MedicineFukushimaJapan
| | - Hao Liu
- Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier SciencesThe University of TokyoMinato City, TokyoJapan
| | - Masanori Kakuta
- Department of Integrated Analytics, M&D Data Science CenterTokyo Medical and Dental UniversityTokyoJapan
| | - Daisuke Matsubara
- Department of Pathology, Faculty of MedicineUniversity of TsukubaIbarakiJapan
| | - Ruimeng Wen
- Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier SciencesThe University of TokyoMinato City, TokyoJapan
| | - Yoji Sagiya
- Laboratory of Genome Technology, Human Genome Center, The Institute of Medical ScienceThe University of TokyoMinato City, TokyoJapan
| | - Seiya Imoto
- Division of Health Medical Intelligence, Human Genome Center, The Institute of Medical ScienceThe University of TokyoMinato City, TokyoJapan
| | - Hidewaki Nakagawa
- Laboratory for Cancer GenomicsRIKEN Center for Integrative Medical SciencesYokohamaJapan
| | - Koichi Matsuda
- Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier SciencesThe University of TokyoMinato City, TokyoJapan
- Laboratory of Genome Technology, Human Genome Center, The Institute of Medical ScienceThe University of TokyoMinato City, TokyoJapan
| | - Chizu Tanikawa
- Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier SciencesThe University of TokyoMinato City, TokyoJapan
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Liao H, Yang J, Xu Y, Xie J, Li K, Chen K, Pei J, Luo Q, Pan M. Mannose-Binding Lectin 2 as a Potential Therapeutic Target for Hepatocellular Carcinoma: Multi-Omics Analysis and Experimental Validation. Cancers (Basel) 2023; 15:4900. [PMID: 37835594 PMCID: PMC10571644 DOI: 10.3390/cancers15194900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 09/28/2023] [Accepted: 10/05/2023] [Indexed: 10/15/2023] Open
Abstract
Mannose-binding lectin 2 (MBL2), a member of the multimeric lectin family, is crucial in immune regulation and tumor development. MBL2 gene polymorphisms are associated with the risk and prognosis of various tumors, including hepatocellular carcinoma (HCC). Its functional role in HCC remains largely unclear. In this study, we aimed to identify whether MBL2 is a key regulator and a potential therapeutic target for HCC. A bioinformatics analysis revealed close relationships among MBL2 downregulation, the tumor-associated proliferation and metastasis pathway, and tumor immunosuppressive microenvironments. Lower expression of MBL2 in HCC patients was linked to an unfavorable prognosis. A cell counting kit-8 assay, colony formation assay, transwell migration assay, and wound healing assay further confirmed that the overexpression of MBL2 could directly inhibit the proliferation and metastasis of HCC. Moreover, MBL2 expression was regulated by miR-34c-3p, as confirmed by the dual-luciferase reporter assay, thereby demonstrating tumor progression in HCC cells. Thus, our study offers the first comprehensive confirmation of the role of MBL2 in the development of HCC through multi-omics analysis and experimental validation. Furthermore, miR-34c-3p was found to be an upstream mechanism of the downregulation of MBL2 expression and could be a promising therapeutic target, expanding treatment options for patients with HCC.
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Affiliation(s)
- Hangyu Liao
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510000, China; (H.L.); (J.Y.); (Y.X.); (J.X.); (K.L.); (K.C.); (J.P.)
| | - Jun Yang
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510000, China; (H.L.); (J.Y.); (Y.X.); (J.X.); (K.L.); (K.C.); (J.P.)
| | - Yuyan Xu
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510000, China; (H.L.); (J.Y.); (Y.X.); (J.X.); (K.L.); (K.C.); (J.P.)
| | - Juncheng Xie
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510000, China; (H.L.); (J.Y.); (Y.X.); (J.X.); (K.L.); (K.C.); (J.P.)
| | - Ke Li
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510000, China; (H.L.); (J.Y.); (Y.X.); (J.X.); (K.L.); (K.C.); (J.P.)
- Department of General Surgery, The First Hospital of Changsha, Changsha 410000, China
| | - Kunling Chen
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510000, China; (H.L.); (J.Y.); (Y.X.); (J.X.); (K.L.); (K.C.); (J.P.)
| | - Jingyuan Pei
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510000, China; (H.L.); (J.Y.); (Y.X.); (J.X.); (K.L.); (K.C.); (J.P.)
| | - Qiong Luo
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510000, China; (H.L.); (J.Y.); (Y.X.); (J.X.); (K.L.); (K.C.); (J.P.)
- Department of General Surgery, Affiliated Hengyang Hospital, Southern Medical University (Hengyang Central Hospital), Hengyang 421000, China
| | - Mingxin Pan
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510000, China; (H.L.); (J.Y.); (Y.X.); (J.X.); (K.L.); (K.C.); (J.P.)
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4
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Tereshchenko SY, Smolnikova MV, Freidin MB. Ficolin-3 and MASP-2 gene variants in Siberian arctic populations: Summarized evidence of selective pressure for the high frequency of lectin complement pathway deficiency. Scand J Immunol 2023; 97:e13249. [PMID: 36574978 DOI: 10.1111/sji.13249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 12/07/2022] [Accepted: 12/19/2022] [Indexed: 12/29/2022]
Abstract
Herewith, we provide novel original data about the prevalence of FCN3 rs532781899 and MASP2 rs72550870 variants among the newborns of aboriginal Siberian Arctic populations (Nenets and Dolgan-Nganasans) and Russians of East Siberia. This novel data has been analysed along with the genetic data about other proteins of the lectin pathway of the complement system (mannose-binding lectin and ficolin-2) obtained earlier. A total of 926 specimens of dried blood spots of the newborns were genotyped. The newborns represented four populations: Nenets, Dolgan-Nganasans, Mixed aboriginal population, and Russians (Caucasians) to study the prevalence of single nucleotide polymorphisms of FCN3 rs532781899 and MASP2 rs72550870. The prevalence of the deletion allele of the rs532781899 variant in the FCN3 gene associated with the decreased production of ficolin-3 was found to be increased in Russians compared to the Nenets aboriginal populations (P = .002). The prevalence of the rs72550870*G allele in the MASP2 gene associated with low serum protease activity was found to be increased in Russians compared with Nenets and Dolgan-Nganasans (P < .001 and P = .03, respectively). The results of the current study and our previous findings corroborate with a hypothesis that human evolution has been directed toward the accumulation of genotypes associated with low activity of the lectin complement activation pathway.
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Affiliation(s)
- Sergey Yu Tereshchenko
- Federal Research Center "Krasnoyarsk Science Center of the Siberian Branch of the Russian Academy of Sciences", Research Institute of Medical Problems of the North, Krasnoyarsk, Russia
| | - Marina V Smolnikova
- Federal Research Center "Krasnoyarsk Science Center of the Siberian Branch of the Russian Academy of Sciences", Research Institute of Medical Problems of the North, Krasnoyarsk, Russia
| | - Maxim B Freidin
- Tomsk National Research Medical Centre, Research Institute of Medical Genetics, Tomsk, Russia.,King's College London, School of Life Course Sciences, Department of Twin Research and Genetic Epidemiology, London, UK
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Chen F, Wang J, Wu Y, Gao Q, Zhang S. Potential Biomarkers for Liver Cancer Diagnosis Based on Multi-Omics Strategy. Front Oncol 2022; 12:822449. [PMID: 35186756 PMCID: PMC8851237 DOI: 10.3389/fonc.2022.822449] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 01/17/2022] [Indexed: 12/11/2022] Open
Abstract
Liver cancer is the fourth leading cause of cancer-related death worldwide. Hepatocellular carcinoma (HCC) accounts for about 85%-90% of all primary liver malignancies. However, only 20-30% of HCC patients are eligible for curative therapy mainly due to the lack of early-detection strategies, highlighting the significance of reliable and accurate biomarkers. The integration of multi-omics became an important tool for biomarker screening and unique alterations in tumor-associated genes, transcripts, proteins, post-translational modifications and metabolites have been observed. We here summarized the novel biomarkers for HCC diagnosis based on multi-omics technology as well as the clinical significance of these potential biomarkers in the early detection of HCC.
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Affiliation(s)
- Fanghua Chen
- Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Junming Wang
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Yingcheng Wu
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Qiang Gao
- Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Shu Zhang
- Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
- *Correspondence: Shu Zhang,
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6
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Murugaiah V, Varghese PM, Beirag N, DeCordova S, Sim RB, Kishore U. Complement Proteins as Soluble Pattern Recognition Receptors for Pathogenic Viruses. Viruses 2021; 13:v13050824. [PMID: 34063241 PMCID: PMC8147407 DOI: 10.3390/v13050824] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 04/28/2021] [Indexed: 12/11/2022] Open
Abstract
The complement system represents a crucial part of innate immunity. It contains a diverse range of soluble activators, membrane-bound receptors, and regulators. Its principal function is to eliminate pathogens via activation of three distinct pathways: classical, alternative, and lectin. In the case of viruses, the complement activation results in effector functions such as virion opsonisation by complement components, phagocytosis induction, virolysis by the membrane attack complex, and promotion of immune responses through anaphylatoxins and chemotactic factors. Recent studies have shown that the addition of individual complement components can neutralise viruses without requiring the activation of the complement cascade. While the complement-mediated effector functions can neutralise a diverse range of viruses, numerous viruses have evolved mechanisms to subvert complement recognition/activation by encoding several proteins that inhibit the complement system, contributing to viral survival and pathogenesis. This review focuses on these complement-dependent and -independent interactions of complement components (especially C1q, C4b-binding protein, properdin, factor H, Mannose-binding lectin, and Ficolins) with several viruses and their consequences.
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Affiliation(s)
- Valarmathy Murugaiah
- Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK; (V.M.); (P.M.V.); (N.B.); (S.D.)
| | - Praveen M. Varghese
- Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK; (V.M.); (P.M.V.); (N.B.); (S.D.)
| | - Nazar Beirag
- Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK; (V.M.); (P.M.V.); (N.B.); (S.D.)
| | - Syreeta DeCordova
- Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK; (V.M.); (P.M.V.); (N.B.); (S.D.)
| | - Robert B. Sim
- Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK;
| | - Uday Kishore
- Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK; (V.M.); (P.M.V.); (N.B.); (S.D.)
- Correspondence: or
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7
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Malik A, Thanekar U, Amarachintha S, Mourya R, Nalluri S, Bondoc A, Shivakumar P. "Complimenting the Complement": Mechanistic Insights and Opportunities for Therapeutics in Hepatocellular Carcinoma. Front Oncol 2021; 10:627701. [PMID: 33718121 PMCID: PMC7943925 DOI: 10.3389/fonc.2020.627701] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 12/22/2020] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and a leading cause of death in the US and worldwide. HCC remains a global health problem and is highly aggressive with unfavorable prognosis. Even with surgical interventions and newer medical treatment regimens, patients with HCC have poor survival rates. These limited therapeutic strategies and mechanistic understandings of HCC immunopathogenesis urgently warrant non-palliative treatment measures. Irrespective of the multitude etiologies, the liver microenvironment in HCC is intricately associated with chronic necroinflammation, progressive fibrosis, and cirrhosis as precedent events along with dysregulated innate and adaptive immune responses. Central to these immunological networks is the complement cascade (CC), a fundamental defense system inherent to the liver which tightly regulates humoral and cellular responses to noxious stimuli. Importantly, the liver is the primary source for biosynthesis of >80% of complement components and expresses a variety of complement receptors. Recent studies implicate the complement system in liver inflammation, abnormal regenerative responses, fibrosis, carcinogenesis, and development of HCC. Although complement activation differentially promotes immunosuppressive, stimulant, and angiogenic microenvironments conducive to HCC development, it remains under-investigated. Here, we review derangement of specific complement proteins in HCC in the context of altered complement regulatory factors, immune-activating components, and their implications in disease pathogenesis. We also summarize how complement molecules regulate cancer stem cells (CSCs), interact with complement-coagulation cascades, and provide therapeutic opportunities for targeted intervention in HCC.
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Affiliation(s)
- Astha Malik
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Unmesha Thanekar
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Surya Amarachintha
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Reena Mourya
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Shreya Nalluri
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Alexander Bondoc
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Pranavkumar Shivakumar
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
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8
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Kalia N, Singh J, Kaur M. The ambiguous role of mannose-binding lectin (MBL) in human immunity. Open Med (Wars) 2021; 16:299-310. [PMID: 33681468 PMCID: PMC7917369 DOI: 10.1515/med-2021-0239] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 01/22/2021] [Accepted: 01/29/2021] [Indexed: 12/30/2022] Open
Abstract
Mannose-binding lectin (MBL) and lectin complement pathway have become targets of increasing clinical interest. Many aspects of MBL have been recently explored, including the structural properties that allow it to distinguish self from non-self/altered-self structures. Experimental evidences have declared the additional 5′- and 3′-variants that in amalgamation with well-known secretor polymorphisms change MBL function and concentration. Moreover, the current review highlights the differential behavior of MBL on exposure with extra/intracellular pathogens and in autoimmune diseases, stressing the fact that “high MBL levels can increase diseases susceptibility,” a paradox that needs justification. Attributable to these discrepancies, no absolute level of MBL deficiency could be defined so far and thus must be interpreted for specific diseases through case–control population-specific designs. Overall, it is evident that further research is needed about MBL and the lectin pathway of complement. Particularly, the transformative role of MBL over evolution is of interest and its role with regard to pathogenesis of different diseases and potential therapeutic targets within the respective pathways should be further explored. Apart from this, it is necessary to adopt an extensive locus-wide methodology to apprehend the clinical significance of MBL2 polymorphisms in a variety of infectious diseases by the future studies.
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Affiliation(s)
- Namarta Kalia
- Department of Molecular Biology and Biochemistry, Guru Nanak Dev University, Amritsar, India.,Department of Biological Sciences, George Washington University, Washington, DC 20052, USA
| | - Jatinder Singh
- Department of Molecular Biology and Biochemistry, Guru Nanak Dev University, Amritsar, India
| | - Manpreet Kaur
- Department of Human Genetics, Guru Nanak Dev University, Amritsar, India
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9
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Boldt ABW, Oliveira-Toré CDF, Kretzschmar GC, Weinschutz Mendes H, Stinghen ST, Andrade FA, Bumiller-Bini V, Gonçalves LB, Braga ACDM, Stahlke EVRS, Velavan TP, Thiel S, de Messias-Reason IJT. Hepatitis B Virus Infection Among Leprosy Patients: A Case for Polymorphisms Compromising Activation of the Lectin Pathway and Complement Receptors. Front Immunol 2021; 11:574457. [PMID: 33643280 PMCID: PMC7904891 DOI: 10.3389/fimmu.2020.574457] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 12/24/2020] [Indexed: 01/05/2023] Open
Abstract
Thousands of leprosy patients not only suffer from physical deformities, but also either have or have had hepatitis B virus (HBV) coinfection. Polymorphisms of the complement system modulate susceptibility to leprosy, but genetic susceptibility to past or present HBV infection is unknown. We used sequencing and multiplex sequence-specific PCR to genotype 72 polymorphisms of seven genes (MBL2, FCN1, FCN2, FCN3, MASP1, MASP2, C3) encoding components of the lectin pathway, and two genes encoding complement receptors (CR1, VSIG4) in 190 patients, of which 74 were positive for HBsAg and/or anti-HBc (HBV+, 93.2% with a resolved infection) and 116 lepromatous patients, and 408 HBV-blood donors. In addition, we tested for levels of proteins of the lectin pathway. We found no difference between serum concentrations of mannan-binding lectin (MBL), MBL-associated serine proteins (MASP-1, MASP-2, MASP-3, MAp44), ficolin-3 (FCN-3), soluble complement receptor 1 (sCR1) and MBL mediated C4 activation, measured by ELISA or TRIFMA in up to 167 HBV+ and HBV- patients. Haplotypes lowering protein levels or encoding dysfunctional proteins increased susceptibility to HBV infection: MBL2*LYQC (OR = 3.4, p = 0.02), MASP1*AC_CC (OR = 4.0, p = 0.015) and MASP2*1C2-l (OR = 5.4, p = 0.03). Conversely, FCN1*3C2 haplotype, associated with higher gene expression, was protective (OR = 0.56, P = 0.033). Other haplotypes associated with HBV susceptibility were: MASP2*2B1-i (OR = 19.25, P = 0.003), CR1*3A (OR = 2.65, P = 0.011) and VSIG4*TGGRCG (OR = 12.55, P = 0.014). Some polymorphisms in ficolin genes associated with lower protein levels increased susceptibility to leprosy/HBV infection: FCN*1 (OR = 1.66, P = 0.029), FCN2*GGGCAC (OR = 6.73, P = 0.008), and FCN3*del_del_C (OR = 12.54, P = 0.037), and to lepromatous disease/HBV infection: FCN2*TA (OR = 2.5, P = 0.009), whereas FCN2*MAG was associated with increased FCN-2 expression and resistance against coinfection (OR = 0.29, P = 0.026). These associations were independent of demographic factors and did not increase susceptibility to leprosy per se, except MASP2*1C2-l. Associations for FCN2, FCN3, MASP1, MASP2, and VSIG4 variants were also independent of each other. In conclusion, polymorphisms compromising activation of the lectin pathway of complement increase susceptibility to HBV infection, with ficolin polymorphisms playing a major role in modulating the susceptibility among leprosy patients.
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Affiliation(s)
- Angelica Beate Winter Boldt
- Laboratory of Human Molecular Genetics, Postgraduate Program in Genetics, Department of Genetics, Federal University of Paraná, Curitiba, Brazil
- Laboratory of Molecular Immunopathology, Postgraduate Program in Internal Medicine and Health Sciences, Department of Clinical Pathology, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil
| | - Camila de Freitas Oliveira-Toré
- Laboratory of Molecular Immunopathology, Postgraduate Program in Internal Medicine and Health Sciences, Department of Clinical Pathology, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil
| | - Gabriela Canalli Kretzschmar
- Laboratory of Human Molecular Genetics, Postgraduate Program in Genetics, Department of Genetics, Federal University of Paraná, Curitiba, Brazil
| | - Hellen Weinschutz Mendes
- Laboratory of Molecular Immunopathology, Postgraduate Program in Internal Medicine and Health Sciences, Department of Clinical Pathology, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil
| | - Sérvio Túlio Stinghen
- Laboratory of Molecular Immunopathology, Postgraduate Program in Internal Medicine and Health Sciences, Department of Clinical Pathology, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil
| | - Fabiana Antunes Andrade
- Laboratory of Molecular Immunopathology, Postgraduate Program in Internal Medicine and Health Sciences, Department of Clinical Pathology, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil
| | - Valéria Bumiller-Bini
- Laboratory of Human Molecular Genetics, Postgraduate Program in Genetics, Department of Genetics, Federal University of Paraná, Curitiba, Brazil
| | - Letícia Boslooper Gonçalves
- Laboratory of Molecular Immunopathology, Postgraduate Program in Internal Medicine and Health Sciences, Department of Clinical Pathology, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil
| | - Anna Carolina de Moraes Braga
- Laboratory of Molecular Immunopathology, Postgraduate Program in Internal Medicine and Health Sciences, Department of Clinical Pathology, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil
| | | | - Thirumalaisamy P. Velavan
- Institute of Tropical Medicine, Universitätsklinikum Tübingen, Tübingen, Germany
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam
- Faculty of Medicine, Duy Tan University, Da Nang, Vietnam
| | - Steffen Thiel
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Iara José Taborda de Messias-Reason
- Laboratory of Molecular Immunopathology, Postgraduate Program in Internal Medicine and Health Sciences, Department of Clinical Pathology, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil
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Mohamed AA, Abdelhamid M, El-Toukhy N, Sabry A, Khattab RA, El-Damasy DA, Ahmed A, Elkadeem M, Abd-Elsalam S. Predictive and Prognostic Value of Ascitic Fluid Mannose Binding Lectin in Patients with Spontaneous Bacterial Peritonitis. Antiinflamm Antiallergy Agents Med Chem 2021; 20:196-200. [PMID: 32552645 DOI: 10.2174/1871523019666200617132513] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 04/18/2020] [Accepted: 05/07/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Spontaneous bacterial peritonitis is a common bacterial infection of ascitic fluid, mainly in ascites due to liver cirrhosis. Mannose-binding lectin (MBL) can activate phagocytosis and the complement system. Spontaneous bacterial peritonitis was detected to be higher in MBL deficiency. This study aimed to assess ascitic fluid MBL in liver cirrhosis and spontaneous bacterial peritonitis. METHODS Ninety patients with cirrhotic ascites were included. Forty five of them had SBP. Child- Pugh score, Model for End Stage Liver Disease (MELD) and its update (uMELD) scores were used to assess the severity of liver cirrhosis. Ascitic fluid samples were obtained for differentiation of leucocytic count, estimation of albumin, protein, glucose, and serum-ascitic albumin gradient. Ascitic fluid levels of MBL were measured for all patients. SBP was documented if polymorphonuclear leucocytic count ≥250/mm in ascitic fluid. RESULTS Ascitic fluid MBL level was significantly lower in patients with SBP. MBL had a significant negative correlation with ascitic total leukocytic count (TLC), also with serum creatinine, bilirubin, PT, INR and MELD score among SBP patients. However, it had a significant positive correlation with ascitic protein and with platelets. According to multivariate analysis, fever, TLC, platelets, creatinine, MBL, glucose and polymorphs were independent predictors for SBP development. CONCLUSION Ascitic fluid MBL could be a good predictive and prognostic marker in patients with cirrhosis and spontaneous bacterial peritonitis.
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Affiliation(s)
- Amal A Mohamed
- Department of Biochemistry, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| | - Mohamed Abdelhamid
- Department of Hepatology & Gastroenterology and Infectious Diseases, Faculty of Medicine, Benha University, Benha, Egypt
| | - Naglaa El-Toukhy
- Department of Hepatology & Gastroenterology and Infectious Diseases, Faculty of Medicine, Benha University, Benha, Egypt
| | - Ahmed Sabry
- Department of Hepatology & Gastroenterology and Infectious Diseases, Faculty of Medicine, Benha University, Benha, Egypt
| | - Rania A Khattab
- Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Dalia Ali El-Damasy
- Department of Microbiology, Faculty of Pharmacy, Egyptian Russian University, Badr City, Egypt
| | - Abeer Ahmed
- Department of Microbiology, Faculty of Medicine, Beni Suef University, Beni Suef, Egypt
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11
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Murugaiah V, Tsolaki AG, Kishore U. Collectins: Innate Immune Pattern Recognition Molecules. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1204:75-127. [PMID: 32152944 PMCID: PMC7120701 DOI: 10.1007/978-981-15-1580-4_4] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Collectins are collagen-containing C-type (calcium-dependent) lectins which are important pathogen pattern recognising innate immune molecules. Their primary structure is characterised by an N-terminal, triple-helical collagenous region made up of Gly-X-Y repeats, an a-helical coiled-coil trimerising neck region, and a C-terminal C-type lectin or carbohydrate recognition domain (CRD). Further oligomerisation of this primary structure can give rise to more complex and multimeric structures that can be seen under electron microscope. Collectins can be found in serum as well as in a range of tissues at the mucosal surfaces. Mannanbinding lectin can activate the complement system while other members of the collectin family are extremely versatile in recognising a diverse range of pathogens via their CRDs and bring about effector functions designed at the clearance of invading pathogens. These mechanisms include opsonisation, enhancement of phagocytosis, triggering superoxidative burst and nitric oxide production. Collectins can also potentiate the adaptive immune response via antigen presenting cells such as macrophages and dendritic cells through modulation of cytokines and chemokines, thus they can act as a link between innate and adaptive immunity. This chapter describes the structure-function relationships of collectins, their diverse functions, and their interaction with viruses, bacteria, fungi and parasites.
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Affiliation(s)
- Valarmathy Murugaiah
- College of Health and Life Sciences, Brunel University London, London, UB8 3PH, UK
| | - Anthony G Tsolaki
- College of Health and Life Sciences, Brunel University London, London, UB8 3PH, UK
| | - Uday Kishore
- College of Health and Life Sciences, Brunel University London, London, UB8 3PH, UK.
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12
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Nosratabadi R, Alavian SM, Zare-Bidaki M, Shahrokhi VM, Arababadi MK. Innate immunity related pathogen recognition receptors and chronic hepatitis B infection. Mol Immunol 2017; 90:64-73. [PMID: 28704708 DOI: 10.1016/j.molimm.2017.07.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Revised: 06/07/2017] [Accepted: 07/01/2017] [Indexed: 01/30/2023]
Abstract
Innate immunity consists of several kinds of pathogen recognition receptors (PRRs), which participate in the recognition of pathogens and consequently activation of innate immune system against pathogens. Recently, several investigations reported that PRRs may also play key roles in the induction/stimulation of immune system related complications in microbial infections. Hepatitis B virus (HBV), as the main cause of viral hepatitis in human, can induce several clinical forms of hepatitis B and also might be associated with hepatic complications such as cirrhosis and hepatocellular carcinoma (HCC). Based on the important roles of PRRs in the eradication of microbial infections including viral infections and their related complications, it appears that the molecules may be a main part of immune responses against viral infections including HBV and participate in the HBV related complications. Thus, this review article has brought together information regarding the roles of PRRs in immunity against HBV and its complications.
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Affiliation(s)
- Reza Nosratabadi
- Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Dept. of Immunology, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Disease, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mohammad Zare-Bidaki
- Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Dept. of Microbiology, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Vahid Mohammadi Shahrokhi
- Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Dept. of Immunology, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Mohammad Kazemi Arababadi
- Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Dept. of Immunology, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
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13
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HBV Viral Load and Liver Enzyme Levels May Be Associated with the Wild MBL2 AA Genotype. Mediators Inflamm 2017; 2017:3718451. [PMID: 28408790 PMCID: PMC5376955 DOI: 10.1155/2017/3718451] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Revised: 01/24/2017] [Accepted: 02/06/2017] [Indexed: 01/26/2023] Open
Abstract
The present study investigated the frequencies of rs1800450 (MBL ⁎B, G>A), rs1800451 (MBL ⁎C, G>A), and rs5030737 (MBL ⁎D, C>T) polymorphisms in exon 1 of the MBL2 gene among patients with chronic viral hepatitis. Blood samples from patients infected with hepatitis B virus (HBV; n = 65), hepatitis C virus (HCV; n = 92), and a noninfected control group (n = 300) were investigated. The presence of polymorphisms was detected using a real-time polymerase chain reaction to correlate with liver disease pathogenesis and fibrosis staging according to the Metavir classification. The genotypic and allelic frequencies showed no significant differences between the groups, but patients with active HBV and the wild AA genotype presented a positive correlation between increased transaminase and HBV DNA levels and the presence of mild to moderate fibrosis. Patients with HCV and the wild AA genotype presented mild inflammation and higher HCV RNA levels, although the same association was not observed for the fibrosis scores. The results suggest that the mutations in exon 1 of the MBL2 gene do not contribute directly to the clinical and laboratory features of HCV and HBV infections, but further studies should be performed to confirm whether the wild AA genotype has indirect effect on disease progression.
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Gu X, Ji Q, Wang H, Jiang M, Yang J, Fang M, Wang M, Gao C. Genetic variants of mannose-binding lectin 2 gene influence progression and prognosis of patients with hepatitis B virus infection in China. Clin Res Hepatol Gastroenterol 2016; 40:614-621. [PMID: 26857650 DOI: 10.1016/j.clinre.2015.12.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Accepted: 12/21/2015] [Indexed: 02/04/2023]
Abstract
AIM Mannose-binding lectin (MBL) is a member of the calcium-dependent collectin family involved in the innate immune system that mediates phagocytosis and activates complement by binding to carbohydrate motifs. We studied allele and haplotype frequencies of -221C/G and codon 54G/A in MBL2 gene to reveal their relationship with the developing and progression of hepatitis B virus (HBV)-related liver diseases. METHODS This study was performed in 171 healthy controls, 133 chronic hepatitis B (CHB) patients, 97 patients with HBV-related liver cirrhosis (LC) and 334 HBV-related hepatocellular carcinoma (HCC) patients. The genotypes of these two polymorphisms in these subjects were detected using polymerase chain reaction-ligation detection reaction (PCR-LDR) method. Stratification analyses by clinical characteristics and survival analysis of HCC patients were also performed according to their genotypes. RESULTS The genotype and allele frequencies at codon 54 manifested a significant difference between healthy controls and patients with progressive HBV-related liver diseases, especially liver cirrhosis. Allele A appeared to have protective effect from developing LC and HCC compared with G allele. The percentages of the patients with G allele at -221C/G increased in HBV-related disease groups. When combined together as a haplotype, lower haplotype AC frequency was associated with a decreased risk for the progression of HBV-related liver diseases and HCC developing. Furthermore, HCC patients with G allele at codon 54 showed to have better survival than those with A allele. CONCLUSION These results indicated that polymorphisms in MBL2 gene may influence susceptibility, progression and prognosis of HBV-related liver diseases.
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Affiliation(s)
- Xing Gu
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, PR China
| | - Qiang Ji
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, PR China
| | - Hao Wang
- Department of Laboratory Medicine, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, PR China
| | - Mingming Jiang
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, PR China
| | - Juan Yang
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, PR China
| | - Meng Fang
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, PR China
| | - Mengmeng Wang
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, PR China
| | - Chunfang Gao
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, PR China.
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Laursen TL, Sandahl TD, Støy S, Schiødt FV, Lee WM, Vilstrup H, Thiel S, Grønbæk H, U.S. Acute Liver Failure Study Group. Circulating mannan-binding lectin, M-, L-, H-ficolin and collectin-liver-1 levels in patients with acute liver failure. Liver Int 2015; 35:756-63. [PMID: 25203057 PMCID: PMC4329085 DOI: 10.1111/liv.12682] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Accepted: 08/26/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS The complement system is activated in liver diseases including acute liver failure (ALF); however, the role of the lectin pathway of complement has scarcely been investigated in ALF. The pathway is initiated by soluble pattern recognition molecules: mannan-binding lectin (MBL), M-, L-, and H-ficolin and collectin-liver-1 (CL-L1), which are predominantly synthesized in the liver. We aimed to study lectin levels in ALF patients and associations with clinical outcome. METHODS Serum samples from 75 patients enrolled by the US ALF Study Group were collected on days 1 and 3. We included 75 healthy blood donors and 20 cirrhosis patients as controls. Analyses were performed using sandwich-type immunoassays (ELISA, TRIFMA). RESULTS At day 1, the MBL level in ALF patients was 40% lower compared with healthy controls {[median (interquartile range) 0.72 μg/ml(0.91) vs. 1.15 (1.92)(P = 0.02]}, and increased significantly by day 3 [0.83 μg/ml(0.94)(P = 0.01)]. The M-ficolin level was 60% lower [0.54 μg/ml(0.50) vs. 1.48(1.01)(P < 0.0001)]. The CL-L1 level at day 1 was slightly higher compared with healthy controls [3.20 μg/ml(2.37) vs. 2.64(0.72)(P = 0.11)]; this was significant at day 3 [3.35(1.84)(P = 0.006)]. H- and L-ficolin levels were similar to healthy controls. Spontaneous ALF survivors had higher levels of MBL at day 1 [0.96 μg/ml(1.15) vs. 0.60(0.60)(P = 0.02)] and lower levels of L-ficolin by day 3 compared with patients who died or were transplanted [1.61 μg/ml(1.19) vs. 2.17(2.19)(P = 0.02)]. CONCLUSION We observed significant dynamics in lectin levels in ALF patients, which may suggest they play a role in ALF pathogenesis. High MBL and low L-ficolin levels are associated with survival.
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Affiliation(s)
- Tea Lund Laursen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Denmark
| | | | - Sidsel Støy
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Denmark
| | - Frank Vinholt Schiødt
- Department of Gastroenterology and Hepatology, Bispebjerg Hospital, 2400 Copenhagen NV, Denmark
| | - William M. Lee
- Division of Digestive and Liver Diseases, University of Texas, Southwestern Medical Center, Dallas, TX, USA
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Denmark
| | - Steffen Thiel
- Department of Biomedicine - Medical Microbiology and Immunology, Aarhus University, Denmark
| | - Henning Grønbæk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Denmark
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16
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Human lectins and their roles in viral infections. Molecules 2015; 20:2229-71. [PMID: 25642836 PMCID: PMC6272597 DOI: 10.3390/molecules20022229] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Revised: 01/21/2015] [Accepted: 01/23/2015] [Indexed: 12/20/2022] Open
Abstract
Innate recognition of virus proteins is an important component of the immune response to viral pathogens. A component of this immune recognition is the family of lectins; pattern recognition receptors (PRRs) that recognise viral pathogen-associated molecular patterns (PAMPs) including viral glycoproteins. In this review we discuss the contribution of soluble and membrane-associated PRRs to immunity against virus pathogens, and the potential role of these molecules in facilitating virus replication. These processes are illustrated with examples of viruses including human immunodeficiency virus (HIV), hepatitis C virus (HCV) and Ebola virus (EBOV). We focus on the structure, function and genetics of the well-characterised C-type lectin mannose-binding lectin, the ficolins, and the membrane-bound CD209 proteins expressed on dendritic cells. The potential for lectin-based antiviral therapies is also discussed.
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17
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Erdemir G, Ozkan TB, Ozgur T, Budak F, Kilic SS, Onay H. Mannose-binding lectin gene polymorphism and chronic hepatitis B infection in children. Saudi J Gastroenterol 2015; 21:84-9. [PMID: 25843194 PMCID: PMC4392580 DOI: 10.4103/1319-3767.153825] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND/AIMS Mannose-binding lectin (MBL) is a member of innate immune system that activates complement system through lectin pathway. MBL deficiency is associated with susceptibility to infectious diseases. In this study, the relation between MBL gene polymorphism and chronic hepatitis B infection in children is evaluated. PATIENTS AND METHODS The study included 67 children with chronic hepatitis B and 99 healthy controls. The hepatitis B patients were divided into immuntolerant, chronic inactive, and treatment groups according to their laboratory findings. MBL gene codon 52, 54, and 57 polymorphisms were studied with polymerase chain reaction in all patients and controls. The associations of MBL gene polymorphism with clinical, laboratory, and histopathologic findings were evaluated. RESULTS Homozygous codon 54 polymorphism of MBL was found significantly higher in chronic hepatitis B patients than controls. Rate of the polymorphism was similar in all groups and, responsive and nonresponsive patients in the treatment group. CONCLUSIONS The hepatitis B patients who are homozygous for codon 54 of MBL are prone to develop chronic infection. Longitudinal studies with larger groups are needed.
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Affiliation(s)
- Gulin Erdemir
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Uludag University Medical Faculty, Bursa, Turkey,Address for correspondence: Dr. Gulin Erdemir, Uludag University Medical Faculty, Department of Pediatric Gastroenterology, Hepatology and Nutrition, Bursa, Turkey. E-mail:
| | - Tanju B. Ozkan
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Uludag University Medical Faculty, Bursa, Turkey
| | - Taner Ozgur
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Uludag University Medical Faculty, Bursa, Turkey
| | - Ferah Budak
- Department of Microbiology, Uludag University Medical Faculty, Bursa, Turkey
| | - Sara S. Kilic
- Department of Pediatric Immunology, Uludag University Medical Faculty, Bursa, Turkey
| | - Huseyin Onay
- Department of Genetics, Ege University Medical Faculty, Izmir, Turkey
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18
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Bai X, Tian T, Wang P, Yang X, Wang Z, Dong M. Potential roles of placental human beta-defensin-3 and apolipoprotein B mRNA-editing enzyme catalytic polypeptide 3G in prevention of intrauterine transmission of hepatitis B virus. J Med Virol 2014; 87:375-9. [PMID: 25196417 DOI: 10.1002/jmv.24072] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/13/2014] [Indexed: 01/20/2023]
Abstract
Approximately 5% of newborns were infected by hepatitis B virus (HBV) via intrauterine transmission and this is the main reason for high prevalence of HBV in endemic regions. However, the mechanisms by which intrauterine transmission is avoided in most cases remain elusive and placental natural anti-microbial factors may play a role in the prevention of HBV intrauterine transmission. The expression levels of human β-defensin-3 (HBD-3), apolipoprotein B mRNA-editing enzyme catalytic polypeptide 3G (A3G) and mannose binding lectin (MBL) were determined in the placenta of 30 HBV-seronegative pregnant women (controls), 7 HBV-seropositive pregnant women with infants infected via intrauterine transmission (infected group) and 30 HBV-seropositive pregnant women with non-infected infants (non-infected group). The expression of HBD-3, A3G, and MBL of placental trophoblast cell line Swan71 was determined after exposed to HBV. There were significant differences in placental HBD-3 and A3G levels among three groups, but the expression of MBL did not significantly differ. The expressions of HBD-3 and A3G were higher in non-infected group than controls and infected group, but not significantly different between infected group and controls. The exposure to HBV increased significantly the expression of HBD-3, A3G, and MBL by Swan 71. It may be concluded HBV up-regulates HBD-3 and A3G expression in vivo and in vitro in placental trophoblast and lack of this up-regulation is possibly associated with intrauterine transmission of HBV.
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Affiliation(s)
- Xiaoxia Bai
- Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
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19
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Osthoff M, Irungu E, Ngure K, Mugo N, Thomas KK, Baeten JM, Eisen DP. Mannose-binding lectin and ficolin-2 do not influence humoral immune response to hepatitis B vaccine. Vaccine 2014; 32:4772-7. [PMID: 25024112 PMCID: PMC4374143 DOI: 10.1016/j.vaccine.2014.06.023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Revised: 04/17/2014] [Accepted: 06/06/2014] [Indexed: 01/05/2023]
Abstract
BACKGROUND Host genetics appear to be an important factor in the failure to generate a protective immune response after hepatitis B (HBV) vaccination. Mannose-binding lectin (MBL) and ficolin-2 (FCN2), two pattern recognition receptors of the lectin pathway of complement, influence the clinical outcome of HBV, and MBL deficiency has been shown to augment the humoral response to HBV vaccination in several experimental models. Here, we investigated the association of MBL and FCN2 with the humoral response to HBV vaccination in a candidate gene and functional study. PATIENTS AND METHODS A post hoc analysis of a prospective, interventional HBV vaccination study among human immunodeficiency virus type 1 (HIV-1) uninfected individuals in Kenya was conducted. Serum levels and polymorphisms of MBL and FCN2 were analysed in relation to the immune response to HBV vaccination. RESULTS Protective hepatitis B surface antibody levels (≥ 10 mI U/mL) were evident in 251/293 (85.7%) individuals. Median MBL and FCN2 levels were similar in responders vs. non-responders with a weak trend towards lower median MBL levels in non-responders (1.0 vs. 1.6μg/mL, p=0.1). Similarly, there was no difference in four MBL and six FCN2 polymorphisms analysed in the two groups with the exception of an increased frequency of a homozygous MBL codon 57 mutation in non-responders (4 (9.5%) vs. 8 (3.2%), p=0.05) corresponding to lower MBL levels. Results were similar after adjusting for age and sex. CONCLUSIONS Our study does not support a prominent role of the lectin pathway of complement in general and MBL and FCN2 in particular in the humoral immune response to HBV vaccination in African adults.
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Affiliation(s)
- Michael Osthoff
- Victorian Infectious Diseases Service, Royal Melbourne Hospital, Parkville, VIC, Australia; Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia
| | | | - Kenneth Ngure
- Jomo Kenyatta University of Agriculture and Technology, Nairobi, Kenya; Department of Global Health, University of Washington, Seattle, WA, USA
| | - Nelly Mugo
- Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya
| | | | - Jared M Baeten
- Department of Epidemiology, University of Washington, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA; Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya
| | - Damon P Eisen
- Victorian Infectious Diseases Service, Royal Melbourne Hospital, Parkville, VIC, Australia; Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia.
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Keizer MP, Wouters D, Schlapbach LJ, Kuijpers TW. Restoration of MBL-deficiency: redefining the safety, efficacy and viability of MBL-substitution therapy. Mol Immunol 2014; 61:174-84. [PMID: 25044097 DOI: 10.1016/j.molimm.2014.06.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Revised: 05/30/2014] [Accepted: 06/03/2014] [Indexed: 12/28/2022]
Abstract
MBL-deficiency is a commonly occurring deficiency of the innate immune system, affecting a substantial part of the population and has been extensively studied. MBL appears to function as a disease modifier. The role of MBL in different conditions is context-dependent. Many clinical studies show conflicting results, which can be partially explained by different definitions of MBL-deficiency, including phenotype- and genotype-based approaches. In this review we give an overview of literature of MBL, its role in different pathologies, diseases and patient populations. We review MBL replacement studies, and discuss the potential of MBL substitution therapy. We finally suggest that new MBL substitution trials should be conducted within a predefined patient population. MBL-deficiency should be based on serum levels and confirmed by genotyping.
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Affiliation(s)
- M P Keizer
- Department of Immunopathology, Sanquin Blood Supply, Division Research and Landsteiner Laboratory of the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Pediatric Hematology, Immunology & Infectious Diseases, Emma Children's Hospital, AMC, University of Amsterdam, Amsterdam, The Netherlands.
| | - D Wouters
- Department of Immunopathology, Sanquin Blood Supply, Division Research and Landsteiner Laboratory of the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - L J Schlapbach
- Paediatric Critical Care Research Group, Mater Research, University of Queensland, Brisbane, Australia
| | - T W Kuijpers
- Department of Pediatric Hematology, Immunology & Infectious Diseases, Emma Children's Hospital, AMC, University of Amsterdam, Amsterdam, The Netherlands; Department of Blood Cell Research, Sanquin Blood Supply, Division Research and Landsteiner Laboratory of the AMC, University of Amsterdam, Amsterdam, The Netherlands
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Zeng Z. Human genes involved in hepatitis B virus infection. World J Gastroenterol 2014; 20:7696-7706. [PMID: 24976707 PMCID: PMC4069298 DOI: 10.3748/wjg.v20.i24.7696] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 01/10/2014] [Accepted: 03/07/2014] [Indexed: 02/06/2023] Open
Abstract
Persistent hepatitis B virus (HBV) infection is a significant public health problem because it is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). Roughly one-third of the world population has been infected with HBV and there are about 350 million (5%-6%) persistent carriers. HBV causes 80% of all liver cancer cases and is the second most important carcinogen, after smoking tobacco. There is an approximate 90% risk of becoming a persistent carrier following perinatal infection in infants born to e antigen positive carrier mothers and a 30% risk in pre-school children. Only 5%-10% of adults become persistent carriers following infection. Of individuals persistently infected with HBV, 10%-30% will develop liver cirrhosis and HCC. These highly variable outcomes in both clearance rates and disease outcomes in persistently infected individuals cannot be fully explained by differences in immunological, viral or environmental factors. Thus, differences in host genetic factors may affect the natural history of hepatitis B.
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Ballegaard V, Haugaard AK, Garred P, Nielsen SD, Munthe-Fog L. The lectin pathway of complement: advantage or disadvantage in HIV pathogenesis? Clin Immunol 2014; 154:13-25. [PMID: 24928325 DOI: 10.1016/j.clim.2014.06.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Revised: 06/01/2014] [Accepted: 06/02/2014] [Indexed: 02/02/2023]
Abstract
The pattern recognition molecules of the lectin complement pathway are important components of the innate immune system with known functions in host-virus interactions. This paper summarizes current knowledge of how these intriguing molecules, including mannose-binding lectin (MBL), Ficolin-1, -2 and -3, and collectin-11 (CL-11) may influence HIV-pathogenesis. It has been demonstrated that MBL is capable of binding and neutralizing HIV and may affect host susceptibility to HIV infection and disease progression. In addition, MBL may cause variations in the host immune response against HIV. Ficolin-1, -2 and -3 and CL-11 could have similar functions in HIV infection as the ficolins have been shown to play a role in other viral infections, and CL-11 resembles MBL and the ficolins in structure and binding capacity.
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Affiliation(s)
- V Ballegaard
- Viro-Immunology, Department of Infectious Diseases, Rigshospitalet (Copenhagen University Hospital), Denmark
| | - A K Haugaard
- Viro-Immunology, Department of Infectious Diseases, Rigshospitalet (Copenhagen University Hospital), Denmark
| | - P Garred
- Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Rigshospitalet (Copenhagen University Hospital), Denmark
| | - S D Nielsen
- Viro-Immunology, Department of Infectious Diseases, Rigshospitalet (Copenhagen University Hospital), Denmark.
| | - L Munthe-Fog
- Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Rigshospitalet (Copenhagen University Hospital), Denmark
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Association between Mannose-binding lectin gene polymorphisms and hepatitis B virus infection: a meta-analysis. PLoS One 2013; 8:e75371. [PMID: 24116040 PMCID: PMC3792921 DOI: 10.1371/journal.pone.0075371] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2013] [Accepted: 08/11/2013] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE The results of studies on the relation between Mannose-binding lectin gene (mbl2) polymorphism and HBV infection were contradictory and inconclusive. In order to shed a light on these inconsistent findings and to clarify the role of mbl2 polymorphisms in susceptibility or progression of chronic hepatitis B (CHB), a meta-analysis was performed. METHODS PubMed and Embase were searched for available articles. A meta-analysis was performed to examine the association between mbl2 polymorphisms and chronicity or progression of hepatitis B infection. Odds ratio (OR) and its 95% confidence interval (CI) served as indexes. RESULTS A total of 17 eligible studies were involved, including 2151 healthy controls (HC), 1293 spontaneous recovered (SR) patients with acute infection, 2337 cases with chronic hepatitis B (CHB) and 554 cases with progressive hepatitis B. There was no evidence of significant association between mbl2 exon1 polymorphisms and CHB risk in any genetic model or pairwise comparisons when compared with HC group or SR group. In the stratified analysis of ethnic groups, also no obvious relation between mbl2 polymorphism and CHB risk was identified. There was still no significant association between the complete mbl2 genotypic profile (including both the exon1 and the promoter gene) polymorphisms and CHB risk, as compared with SR group. However, it was found that there was an association between the mbl2 AO/OO genotype and severe hepatitis B (SHB) or liver cirrhosis (LC) (LC vs. HC:OR=3.66, 95%CI, 2.38-5.63; SHB vs. HC, OR=3.88, 95%CI, 2.26-6.64), but there was no relationship between the mbl2 AO/OO genotype and hepatocellular carcinoma (HCC) (OR=1.26, 95%CI, 0.82-1.94). CONCLUSION The present meta-analysis indicated that mbl2 exon1 polymorphisms might not significantly associate with chronicity of HBV infection, but might be significantly related to the progressive HBV such as SHB and LC.
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Zhang TC, Liu W, Liu XQ, Pan FM, Gao YF, Yan F, Li X. Single nucleotide polymorphisms rs2120131, rs4935047, and rs7095891 in the MBL2 gene show no association with susceptibility to chronic hepatitis B in a Chinese Han population. J Med Virol 2013; 85:602-7. [PMID: 23417614 DOI: 10.1002/jmv.23514] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/05/2012] [Indexed: 11/12/2022]
Abstract
Thus far, many studies have evaluated the correlation between MBL2 gene polymorphisms and hepatitis B infection. Tag single nucleotide polymorphisms (SNPs) were used to investigate the relationship between MBL2 gene polymorphisms and susceptibility to chronic hepatitis B virus (HBV) infection by comparing 996 chronic HBV infection cases to 301 acute infection controls. There was no significant correlation between rs2120131, rs4935047, and rs7095891 and chronic HBV infection. This suggested that the new SNPs within MBL2 were not associated with susceptibility to chronic hepatitis B in a Chinese Han population.
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Affiliation(s)
- Tian-Chen Zhang
- Jiangxi Center for Disease Control and Prevention, 555 Beijing East Road, Nanchang, Jiangxi 330000, China
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Serum Mannan-Binding Lectin in Egyptian Patients With Chronic Hepatitis C: Its Relation to Disease Progression and Response to Treatment. HEPATITIS MONTHLY 2012. [DOI: 10.5812/hepatmon.5861] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
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Esmat S, Omran D, Sleem GA, Rashed L. Serum mannan-binding lectin in egyptian patients with chronic hepatitis C: its relation to disease progression and response to treatment. HEPATITIS MONTHLY 2012; 12:259-264. [PMID: 22690233 PMCID: PMC3360935 DOI: 10.5812/hepatmon.704] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/13/2011] [Revised: 04/30/2011] [Accepted: 05/10/2011] [Indexed: 12/11/2022]
Abstract
BACKGROUND Chronic hepatitis C virus (HCV) infection is a major worldwide public health problem. Egypt has the highest prevalence of adult HCV infection in the world, averaging 15%-25% in rural communities. Mannan-binding lectin (MBL) is a liver-derived pluripotent serum lectin that plays a role in the innate immune system of the host. It is an acute-phase protein that is involved in the activation of the classical complement pathway. MBL may play a defensive role in HCV infection. OBJECTIVES To investigate the relationship between MBL concentration and HCV infection in Egyptian patients suffering chronic hepatitis C. PATIENTS AND METHODS Serum samples obtained from 35 Egyptian hepatitis C patients and 30 normal controls were assayed for MBL. MBL concentrations were correlated to disease characteristics and treatment response. RESULTS Serum MBL was significantly higher in HCV patients than in controls, but no relationship was found between MBL concentration and disease progression in terms of hepatic fibrosis and inflammation. Responders to interferon (INF)-based therapy had significantly higher serum MBL than non-responders. CONCLUSIONS We found no association between serum MBL concentration and progression of HCV related liver disease. Responders to INF-based therapy had significantly higher serum MBL than non-responders.
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Affiliation(s)
- Serag Esmat
- Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Dalia Omran
- Department of Tropical Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Gihan A. Sleem
- Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Laila Rashed
- Department of Biochemistry, Faculty of Medicine, Cairo University, Cairo, Egypt
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Prevalence, virology and antiviral drugs susceptibility of hepatitis B virus rtN238H polymerase mutation from 1865 Chinese patients with chronic hepatitis B. Antiviral Res 2012; 93:185-90. [DOI: 10.1016/j.antiviral.2011.11.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2011] [Revised: 11/01/2011] [Accepted: 11/18/2011] [Indexed: 02/07/2023]
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Zhang G, Li Z, Han Q, Li N, Zhu Q, Li F, Lv Y, Chen J, Lou S, Liu Z. Altered TNF-α and IFN-γ levels associated with PD1 but not TNFA polymorphisms in patients with chronic HBV infection. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2011; 11:1624-1630. [PMID: 21712100 DOI: 10.1016/j.meegid.2011.06.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/24/2011] [Revised: 05/31/2011] [Accepted: 06/07/2011] [Indexed: 02/06/2023]
Abstract
Production of tumor necrosis factor (TNF)-α and interferon (IFN)-γ, two important cytokines involved in the immune responses to hepatitis B virus (HBV) infection, may be influenced by gene polymorphisms of TNFA and PD1. This study determined the associations of serum TNF-α and IFN-γ levels with TNFA promoter -308 G/A and -238 G/A and PD1 -606 G/A and +8669 G/A polymorphisms in chronic HBV patients and healthy controls. The results showed that TNFA polymorphisms had no association with TNF-α and IFN-γ levels. However, patients with PD1 -606 AA genotype had lower TNF-α and IFN-γ levels. HBV infection in patients with PD1 +8669 GG genotype altered TNF-α to higher levels compared with controls. HBV patients with PD1 -606A/+8669A or -606G/+8669A haplotype tended to have significantly lower or higher TNF-α and IFN-γ levels, respectively. Combined with the lower frequency of PD1 +8669 GG genotype in HBV patients and the minor contribution of PD1 -606 G allele to the protective role of PD1 +8669 G allele, it is indicated that PD1 -606 G allele in a haplotype with PD1 +8669 G allele may have strong inhibitory effect on programmed cell death-1 (PD-1) function and thus reduce its negative impact on T-cell activation and function, leading to higher cytokines secretion and exhibiting a protective role, while the minor predisposing role of PD1 -606 AA genotype to chronic HBV infection may be incurred by decreasing the inhibitory effect on PD-1 function.
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Affiliation(s)
- Guoyu Zhang
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, People's Republic of China
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Hu Y, Wu D, Tao R, Shang S. Association between mannose-binding lectin gene polymorphism and pediatric cytomegalovirus infection. Viral Immunol 2011; 23:443-7. [PMID: 20712489 DOI: 10.1089/vim.2009.0109] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Mannose-binding lectin (MBL) is an important constituent of the human innate immune system, and can bind to a wide range of pathogens, including viruses such as influenza A, HIV, herpes simplex 2, and SARS-CoV. MBL deficiency results from single nucleotide polymorphisms (SNPs) in exon 1, and the promoter region of the human MBL2 gene has been found to be associated with susceptibility to a number of infections. However, studies on the interactions between MBL and CMV infection are limited. In this study, we investigated 104 children suffering from HCMV infection, in an effort to find any association between MBL and HCMV infection of children in China. We analyzed the genotypes of 104 HCMV patients and 105 healthy controls, and investigated the distributions of polymorphisms at -550(H/L), -221(Y/X), and +4(P/Q), together with their structural variants. Although there was no significant difference in the distribution of B alleles between HCMV patients and healthy controls, the frequencies of the high-MBL-level related genotype of YA type in HCMV patients were significantly lower than those seen in healthy controls, while low-level related genotypes of XB type were more common in HCMV patients. In addition, CMV-DNA quantification revealed higher viral loads of the XB type in HCMV patients. Thus we can speculate that as an acute response protein and a pattern-recognition molecule of the innate immune system, MBL may play a role in protecting against HCMV infection in children, and MBL gene mutations may be a significant risk factor for the development of infantile HCMV infection.
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Affiliation(s)
- Yingzi Hu
- Laboratory Center, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
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Engin A, Ugurlu S, Caglar E, Oztop AY, Inan D, Elaldi N, Dokmetas I, Bakir M. Serum Levels of Mannan-Binding Lectin in Patients with Crimean-Congo Hemorrhagic Fever. Vector Borne Zoonotic Dis 2010; 10:1037-41. [DOI: 10.1089/vbz.2009.0060] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Aynur Engin
- Department of Infectious Diseases and Clinical Microbiology, Cumhuriyet University School of Medicine, Sivas, Turkey
| | - Serdal Ugurlu
- Department of Internal Medicine, Cumhuriyet University School of Medicine, Sivas, Turkey
| | - Erkan Caglar
- Department of Internal Medicine, Istanbul University Cerrahpasa School of Medicine, Istanbul, Turkey
| | - Atifet Yasemin Oztop
- Department of Microbiology and Clinical Microbiology, Cumhuriyet University School of Medicine, Sivas, Turkey
| | - Dursun Inan
- Department of Internal Medicine, Cumhuriyet University School of Medicine, Sivas, Turkey
| | - Nazif Elaldi
- Department of Infectious Diseases and Clinical Microbiology, Cumhuriyet University School of Medicine, Sivas, Turkey
| | - Ilyas Dokmetas
- Department of Infectious Diseases and Clinical Microbiology, Cumhuriyet University School of Medicine, Sivas, Turkey
| | - Mehmet Bakir
- Department of Infectious Diseases and Clinical Microbiology, Cumhuriyet University School of Medicine, Sivas, Turkey
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Recombinant form of human wild type mannan-binding lectin (MBL/A) but not its structural variant (MBL/C) promotes phagocytosis of zymosan by activating complement. Mol Immunol 2010; 47:2505-14. [PMID: 20579738 DOI: 10.1016/j.molimm.2010.05.292] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2010] [Accepted: 05/27/2010] [Indexed: 01/22/2023]
Abstract
Mannan-binding lectin (MBL) mediates innate immune responses, such as activation of the complement lectin pathway and phagocytosis, to help fight infections. In the present study, employing recombinant forms of human MBL (rMBL), the role of wild type MBL (rMBL/A) and its structural variant rMBL/C in mediating THP-1 phagocytosis of fluorescent-labeled zymosan was examined and compared to MBL purified from human plasma (pMBL/A). Flow cytometric analyses revealed that opsonization of zymosan with rMBL/A and pMBL/A (0.5-30microg/ml) resulted in a 1.9- and 2.7-fold enhancement in its uptake by THP-1 cells in the presence of serum that was depleted of both MBL and the classical pathway component, C1q (MBL/C1q Dpl serum). In contrast, no enhancement in phagocytosis was observed when zymosan was opsonized with rMBL/C. Addition of MBL monoclonal antibody, EDTA, or mannan to the opsonization reaction mixture inhibited THP-1 phagocytosis of pMBL/A opsonized zymosan. Heat inactivation of MBL/C1q Dpl serum abolished the 2-fold increase in phagocytosis and in the absence of serum the direct opsonic activity of MBL did not contribute significantly to the uptake of zymosan into THP-1 cells. Activation products of complement components C3 and C4 were deposited on zymosan opsonized with pMBL/A and rMBL/A but not rMBL/C indicating that MBL-mediated phagocytosis of zymosan requires activation of the complement lectin pathway. The findings imply that impaired MBL-mediated phagocytosis may put individuals homozygous for the mutant allele MBL/C but not wild type MBL/A at increased risk to infections such as yeast.
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Mannose-binding lectin gene polymorphisms are not associated with susceptibility to hepatitis C virus infection in the Brazilian Amazon region. Hum Immunol 2009; 70:754-7. [PMID: 19540295 DOI: 10.1016/j.humimm.2009.06.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2009] [Revised: 06/10/2009] [Accepted: 06/15/2009] [Indexed: 11/21/2022]
Abstract
The present study compares the genotype frequencies between two population groups composed by 73 hepatitis C virus (HCV)-infected patients and 92 seronegative controls and investigates the role of allele variants as a possible factor in the susceptibility to HCV infection and the influence on disease progression. The identification of MBL*B and MBL*C alleles was performed by restriction fragment length polymorphism analysis of the 349-bp product using BanI and MboII restriction enzymes, respectively, and a polymerase chain reaction-sequence-specific polymorphism for discrimination of MBL*D. The analysis of allele and genotype frequencies between an HCV-infected group and seronegative controls did not indicate significant differences. The comparison of chronically infected subjects with and without liver cirrhosis was also not statistically significant. The odds ratio estimations were not significant, and the values obtained cannot suggest that the presence of allele variant MBL*B could have some influence in the risk of HCV infection progression to liver cirrhosis and that the presence of allele MBL*D could confer some protection against disease progression, but a larger sample size is necessary to confirm the present results.
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Tsai CC, Lin TM, You HL, Eng HL. Mannose-binding lectin in high-risk human papillomavirus infection. Am J Obstet Gynecol 2009; 200:618.e1-6. [PMID: 19371855 DOI: 10.1016/j.ajog.2009.02.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2008] [Revised: 08/28/2008] [Accepted: 02/11/2009] [Indexed: 11/26/2022]
Abstract
OBJECTIVE Mannose-binding lectin (MBL) is a serum lectin that mediates phagocytosis and activates complement. We investigated the association of mbl-2 functional polymorphisms with human papillomavirus (HPV) infection, which is a primary etiologic factor for cervical cancer. STUDY DESIGN The frequencies of haplotypes and genotypes of mbl-2 exon1 and promoter region variants were analyzed in 150 patients with HPV and 277 control subjects with no HPV. Unconditional logistic regression analysis was performed to evaluate an association between specific mbl-2 alleles and susceptibility to HPV infection. RESULTS The frequency of high-producer mbl-2 genotypes was higher in patients with HPV than in control subjects with no HPV (P = .001). The genotype of the mbl-2 gene polymorphisms represented the least significant risk for the group with HPV. CONCLUSION Certain polymorphisms in the MBL promoter region are increased among cervical samples that demonstrate HPV infection. This finding suggests a potential link between MBL and high-risk HPV infection.
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Sun W, Zhong F, Zhi L, Zhou G, He F. Systematic -omics analysis of HBV-associated liver diseases. Cancer Lett 2009; 286:89-95. [PMID: 19144459 DOI: 10.1016/j.canlet.2008.12.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2008] [Revised: 11/25/2008] [Accepted: 12/02/2008] [Indexed: 12/23/2022]
Abstract
Hepatitis B virus (HBV) infection causes acute and chronic liver diseases and increases the risk of developing hepatocellular carcinoma (HCC). However, the pathogenesis of HBV infection and carcinogenesis of HBV-associated HCC are still elusive. In this review, systematic -omics studies made in the scales of genomics, transcriptomics and proteomics were discussed. The susceptibility to HBV infection and the course of disease progress are greatly different among individuals. Using population- or/and family-based approaches, relevant genes have been mapped or identified to be associated with host immune responses to HBV antigens and susceptibility to HCC. Comprehensive transcriptomic analyses have shown that the HBV-induced hepatocarcinogenesis may involve the whole course from signal transduction, transcription, translation to protein degradation, which differs in some measure from HCV-induced hepatocarcinogenesis, and that exogenous transcription factor HBX and endogenous NF-kappaB are likely two key points of the course. By the means of proteomics, dozens of important dysregulated proteins (including isoforms or fragments) were identified from carcinogenesis mechanism analysis and biomarker validation. Of them, the alteration of heat shock proteins and impairment of methylation cycle were found to be associated with clinical HBV-associated HCC. As a whole, the systematic -omics analysis of HBV-associated liver diseases has offered multi-scale pathological information in the process from HBV infection to HCC onset.
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Affiliation(s)
- Wei Sun
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, 33 Life Science Park, Beijing 102206, China
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Litzman J, Freiberger T, Grimbacher B, Gathmann B, Salzer U, Pavlík T, Vlcek J, Postránecká V, Trávnícková Z, Thon V. Mannose-binding lectin gene polymorphic variants predispose to the development of bronchopulmonary complications but have no influence on other clinical and laboratory symptoms or signs of common variable immunodeficiency. Clin Exp Immunol 2008; 153:324-30. [PMID: 18637104 DOI: 10.1111/j.1365-2249.2008.03700.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Mannose-binding lectin (MBL), activating protein of the lectin pathway of the complement system, is an important component of the non-specific immune response. MBL2 gene polymorphisms, both in the coding and promoter regions, lead to low or deficient serum MBL levels. Low serum MBL levels were shown to be associated with serious infectious complications, mainly in patients in whom other non-specific immune system barriers were disturbed (granulocytopenia, cystic fibrosis). We have analysed two promoter (-550 and -221) and three exon (codons 52, 54 and 57) MBL2 polymorphisms in a total of 94 patients with common variable immunodeficiency (CVID) from two immunodeficiency centres. Low-producing genotypes were associated with the presence of bronchiectasis (P = 0.009), lung fibrosis (P = 0.037) and also with respiratory insufficiency (P = 0.029). We could not demonstrate any association of MBL deficiency with age at onset of clinical symptoms, age at diagnosis, the number of pneumonias before diagnosis or serum immunoglobulin (Ig)G, IgA and IgM levels before initiation of Ig treatment. No association with emphysema development was observed, such as with lung function test abnormalities. No effect of MBL2 genotypes on the presence of diarrhoea, granuloma formation, lymphadenopathy, splenomegaly, frequency of respiratory tract infection or the number of antibiotic courses of the patients was observed. Our study suggests that low MBL-producing genotypes predispose to bronchiectasis formation, and also fibrosis and respiratory insufficiency development, but have no effect on other complications in CVID patients.
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Affiliation(s)
- J Litzman
- Department of Clinical Immunology and Allergology, Faculty of Medicine, Masaryk University, St Anne's Faculty Hospital, Pekarska, Czech Republic.
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Koutsounaki E, Goulielmos GN, Koulentaki M, Choulaki C, Kouroumalis E, Galanakis E. Mannose-binding lectin MBL2 gene polymorphisms and outcome of hepatitis C virus-infected patients. J Clin Immunol 2008; 28:495-500. [PMID: 18592362 DOI: 10.1007/s10875-008-9201-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2008] [Accepted: 03/26/2008] [Indexed: 01/27/2023]
Abstract
INTRODUCTION Mannose-binding lectin (MBL) is involved in host's response to several infections including hepatitis B but little is known about MBL and hepatitis C virus (HCV) infection. The present study attempts to investigate whether MBL2 genotype and serum MBL levels affect the course of HCV infection. RESULTS AND DISCUSSIONS We investigated the variant alleles in MBL2 gene promoter and exon-1 regions in 80 Caucasian HCV-infected patients. Mutations in MBL2 were determined by polymerase chain reaction and restriction fragment length polymorphisms analysis. Serum MBL levels were measured by ELISA. Polymorphism homozygosity in exon-1 region was significantly related to lower serum MBL levels (p < 0.001), to liver inflammation (p = 0.034, OR = 11.7) and, in a lesser degree, to fibrosis. Polymorphisms in promoter sites -221nt and -550nt were not shown to be related with serum MBL levels or progress to liver inflammation and fibrosis. Serum MBL levels were adversely associated with progression to fibrosis (p = 0.037). Response to antiviral treatment was related to hepatitis C virus genotype (p < 0.001, OR = 10.9), but not to MBL2 genotype or serum MBL levels. CONCLUSION These findings suggest that polymorphisms in MBL2 gene exon-1 region are related to low serum MBL levels and progression of HCV infection to liver inflammation and fibrosis.
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Affiliation(s)
- Eirini Koutsounaki
- Laboratory of Internal Medicine, Faculty of Medicine, University of Crete, P.O. Box 2208, Heraklion 710 03, Greece.
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Zeng Z, Guan L, An P, Sun S, O'Brien SJ, Winkler CA, the HBV study consortium. A population-based study to investigate host genetic factors associated with hepatitis B infection and pathogenesis in the Chinese population. BMC Infect Dis 2008; 8:1. [PMID: 18171470 PMCID: PMC2238742 DOI: 10.1186/1471-2334-8-1] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2007] [Accepted: 01/02/2008] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is a significant public health problem that may lead to chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). Approximately 30% of the world's population has been infected with HBV and approximately 350 million (5-6%) are persistent carriers. More than 120 million Chinese are infected with HBV. The role of host genetic factors and their interactions with environmental factors leading to chronic HBV infection and its complications are not well understood. We believe that a better understanding of these factors and interactions will lead to more effective diagnostic and therapeutic options. METHODS/DESIGN This is a population-based, case-control study protocol to enroll 2200 Han Chinese from medical centers in northern and western China. Adult subjects in the following groups are being enrolled: healthy donors (n = 200), HBV infected persons achieving virus clearance (n = 400), asymptomatic HBV persistent carriers (n = 400), chronic hepatitis B cases (n = 400), decompensated liver cirrhosis with HBV infection cases (n = 400), and hepatocellular carcinoma with HBV infection cases (n = 400). In addition, for haplotype inference and quality control of sample handling and genotyping results, children of 1000 cases will be asked to provide a buccal sample for DNA extraction. With the exception of adult patients presenting with liver cirrhosis or HCC, all other cases and controls will be 40 years or older at enrollment. A questionnaire is being administered to capture dietary and environmental risk factors. Both candidate-gene and genome-wide association approaches will be used to assess the role of single genetic factors and higher order interactions with other genetic or environmental factors in HBV diseases. CONCLUSION This study is designed and powered to detect single gene effects as well as gene-gene and environmental-gene interactions. The identification of allelic polymorphisms in genes involved in the pathway leading to chronic viral infection, liver cirrhosis and, ultimately, hepatocellular carcinoma would provide insights to those factors leading to HBV replication, liver inflammation, fibrosis, and the carcinogenic process. An understanding of the contribution of host genetic factors and their interactions may inform public health policy, improve diagnostics and clinical management, and provide targets for drug development.
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Affiliation(s)
- Zheng Zeng
- Department of Infectious Diseases, Peking University First Hospital, Beijing, P.R.China
| | - Li Guan
- SAIC/Laboratory of Genomic Diversity, National Cancer Institute-Frederick, National Institutes of Health, Frederick, USA
| | - Ping An
- SAIC/Laboratory of Genomic Diversity, National Cancer Institute-Frederick, National Institutes of Health, Frederick, USA
| | - Shan Sun
- Conservation International (CI) China program, Beijing, P.R.China
| | - Stephen J O'Brien
- Laboratory of Genomic Diversity, National Cancer Institute-Frederick, National Institutes of Health, Frederick, USA
| | - Cheryl A Winkler
- SAIC/Laboratory of Genomic Diversity, National Cancer Institute-Frederick, National Institutes of Health, Frederick, USA
| | - the HBV study consortium
- HBV study consortium: Department of Infectious Diseases, Peking University First Hospital, Beijing, P.R.China (Zheng Zeng, Yanyan Yu, Xiaoyuan Xu, Haiying Lu); Institute of Liver Diseases Research, Beijing Military General Hospital, Beijing, P.R.China (Darong Hu); Beijing Ditan Hospital (Rongbing Wang, Yifan Chen); Department of Surgery, Beijing Institute of Tumor Prevention and Therapy, Beijing, P.R.China (Cunyi Hao); Department of Infectious Diseases, Shanxi Medical University, Taiyuan, P.R.China (Heping Zhou); Department of Infectious Diseases, Qinhuangdao No. 3 Hospital, Qinhuangdao, P.R.China (Zhonghou Han); Department of Surgery, Inner Mongolia Medical College, Hohhot, P.R.China (Lidao Bao, Xiping Zhang); Department of Infectious Diseases, Xuzhou No. 3 Hospital, Xuzhou, P.R.China (Dasi Guo); Department of Infectious Diseases, Xinjian Medical University, Urumoqi, P.R.China (Yaoxin Zhang); Department of Infectious Diseases, the Second Affiliate Hospital of China Medical University, Shenyang, P.R.China (Xiaoguang Dou); Institute of Liver Diseases Research, Peking University Second Hospital, Beijing, P.R.China (Lai Wei); Department of Surgery, Peking Union Medical College, Beijing, P.R.China (Jingan Rui, Qiang Qu)
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Takahashi K, Ezekowitz RAB. The role of the mannose-binding lectin in innate immunity. Clin Infect Dis 2007; 41 Suppl 7:S440-4. [PMID: 16237644 DOI: 10.1086/431987] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
The innate immune system, which includes mannose-binding lectin (MBL), recognizes a broad range of molecular patterns on a broad range of infectious agents and is able to distinguish them from self. MBL is a liver-derived serum protein and is secreted into the serum, where it can activate an immune response before the induction of antigen-specific immunity. Circumstantial evidence in human populations suggests that low serum levels of MBL predispose to infection. To analyze the role of MBL in vivo, we created MBL-null mice and challenged these mice with infection under various conditions. Our results suggest that MBL plays an important role as a first-line host defense against certain infectious agents. In addition, it is likely that MBL is a key regulator of inflammation beyond expected roles in the infection.
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Affiliation(s)
- Kazue Takahashi
- Department of Pediatrics, Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114, USA.
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39
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Association of polymorphisms in the first exon of mannose binding lectin gene (MBL2) in Brazilian patients with HCV infection. Clin Immunol 2007; 124:13-7. [PMID: 17513174 DOI: 10.1016/j.clim.2007.04.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2007] [Revised: 04/16/2007] [Accepted: 04/16/2007] [Indexed: 10/23/2022]
Abstract
In our study we investigated the role of the polymorphisms in the first exon of MBL2 gene in the susceptibility to HCV infection and disease progression in a Northeastern Brazilian population. One hundred and eleven patients seen at the Gastroenterology Service of the Oswaldo Cruz Hospital of the University of Pernambuco were included in this study. A total of 165 unexposed, uninfected individuals matched for place of origin were employed as healthy controls. MBL2 genotyping was performed by using a melting temperature assay. The 0 allele was significantly more frequent in the HCV positive group than the healthy controls (34% vs. 20%, p<0.01, respectively) and was associated to an increased risk of HCV-1 infection (O.R.=2.1; C.I. 1.41-3.19). Also genotypes frequencies were significantly different in HCV positive subjects when compared to healthy controls with the 00 and A0 genotypes being significantly overrepresented in HCV infected subject (15% and 37%, respectively) as compared to healthy subjects (6% and 27%, respectively, p<0.01 ) Allele and genotypes frequencies were also evaluated in HCV infected subjects according to their response to pegylated-INFalpha/riboviron therapy. There was a trend for HCV positive responders vs. non-responders to be 0 allele positive and a similar trend was observed for the MBL2 A0 and 00 genotypes, but neither of these reached statistical significance. Our findings indicate that MBL might represent an important antiviral molecule having a protective role in the first stages of HCV infection, as shown by the increased frequency of wild-type alleles in control population as compared to the infected group.
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40
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Brown KS, Ryder SD, Irving WL, Sim RB, Hickling TP. Mannan binding lectin and viral hepatitis. Immunol Lett 2006; 108:34-44. [PMID: 17157924 DOI: 10.1016/j.imlet.2006.10.006] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2006] [Revised: 10/29/2006] [Accepted: 10/29/2006] [Indexed: 01/04/2023]
Abstract
Mannan binding lectin (MBL) is a pattern recognition molecule of the innate immune system that binds to sugars on the surface of invading micro-organisms. Target binding, complement activation and other functions of MBL are dependent on the presence of multiple carbohydrate recognition domains. Several polymorphisms in the promoter and structural regions of MBL2 adversely affect the plasma concentration and oligomeric state of MBL. The possession of mutant alleles has been linked to disease outcome for a variety of bacterial and viral infections. Viral hepatitis is caused by unrelated viruses referred to as hepatitis virus A-E. The disease usually has both acute and chronic phases, the latter leading to cirrhosis and hepatocellular carcinoma. Hepatitis viruses B and C (HBV and HCV, respectively) are a significant cause of morbidity worldwide. HBV encodes envelope glycoproteins termed large, middle, and small that may exist in glycosylated or unglycosylated forms on the virion. An interaction between HBV glycoproteins and MBL has been demonstrated in vitro. Significant associations between MBL levels, determined by MBL2 haplotypes, and HBV persistence and disease progression have been described. HCV encodes two highly glycosylated envelope proteins, E1 and E2, which are potential targets for interaction with MBL. Mutant MBL2 haplotypes have been linked to disease progression and response to therapy in HCV infection. Here we summarise the effect of MBL2 polymorphisms on MBL function and how this may relate to disease outcome in HBV and HCV infection.
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Affiliation(s)
- Kristelle S Brown
- Institute of Infection, Immunity and Inflammation, School of Molecular Medical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
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41
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Abstract
The human collectin, mannose‐binding lectin (MBL), is an important protein of the humoral innate immune system. With multiple carbohydrate‐recognition domains, it is able to bind to sugar groups displayed on the surfaces of a wide range of microorganisms and thereby provide first‐line defence. Importantly, it also activates the complement system through a distinctive third pathway, independent of both antibody and the C1 complex. Three single point mutations in exon 1 of the expressed human MBL‐2 gene appear to impair the generation of functional oligomers. Such deficiencies of functional protein are common in certain populations, e.g. in sub‐Saharan Africa, but virtually absent in others, e.g. indigenous Australians. MBL disease association studies have been a fruitful area of research and implicate a role for MBL in infective, inflammatory and autoimmune disease processes. Overall, there appears to be a genetic balance in which individuals generally benefit from high levels of the protein. However, in certain situations, reduced levels of circulating MBL may be beneficial to the host and this may explain the persistence of the deleterious gene polymorphisms in many population groups.
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Affiliation(s)
- R M Dommett
- Infectious Diseases and Microbiology Unit, Institute of Child Health, UCL, 30 Guilford Street, London WC1N 1EH, UK
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42
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Abstract
Mannose-binding lectin (MBL) is a pattern-recognition molecule that binds to characteristic carbohydrate motifs present on the surface of many different pathogens. MBL binding stimulates the immune system via the lectin pathway of complement activation. In certain clinical situations, often characterized by pre-existing immune compromise, MBL deficiency increases the risk of infectious and other disease-specific complications. Many of the key pathogenic processes inherent to common gastroenterological diseases, such as infection, immunological damage, and carcinogenesis, have been linked to MBL. This editorial reviews the biology of MBL, outlines key disease associations to document the breadth of influence of MBL, and finally, highlights the relevance of MBL to both gastroenterological health and disease.
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Affiliation(s)
- Daniel-L Worthley
- Department of Gastroenterology and Hepatology, Flinders Medical Centre, Room 3D230, Bedford Park, SA, 5042, Australia.
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43
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Bouwman LH, Roep BO, Roos A. Mannose-Binding Lectin: Clinical Implications for Infection, Transplantation, and Autoimmunity. Hum Immunol 2006; 67:247-56. [PMID: 16720204 DOI: 10.1016/j.humimm.2006.02.030] [Citation(s) in RCA: 124] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2005] [Indexed: 01/24/2023]
Abstract
Mannose-binding lectin (MBL) is a recognition molecule of the lectin pathway of complement and a key component of innate immunity. MBL variant alleles have been described in the coding region of the MBL gene, which are associated with low MBL serum concentration and impaired MBL structure and function. Both high and low serum levels of functional MBL have been associated with a variety of diseases and disease complications. Functioning as double-edged sword, low MBL serum levels have been shown to enhance the risk for infections. On the other hand, high MBL serum levels and high MBL activity have been associated with inflammatory diseases, transplant rejection, and diabetic nephropathy. Underscoring the Jekyll-and-Hyde character of MBL, both high and low serum MBL levels are associated with several aspects of autoimmune diseases. This review provides a general outline of the genetic and molecular characteristics of MBL and discusses MBL-disease association and its consequence in infection, transplantation, and autoimmunity.
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Affiliation(s)
- Lee H Bouwman
- Department of Surgery, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
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44
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Abstract
The innate host defence molecule mannose-binding lectin (MBL) has attracted great interest as a potential candidate for passive immunotherapy to prevent infection. MBL is a multimeric lectin that recognizes a wide array of pathogens independently of specific antibody, and initiates the lectin pathway of complement activation. The basic structural unit is a triple helix of MBL peptides, which aggregate into complement-fixing higher-order structures (tetramers, pentamers and hexamers). The gene encoding MBL, MBL2, contains several common polymorphisms that influence transcription and assembly of the molecule into multimers. MBL2 coding alleles associated with low blood levels are present in up to 40% of Caucasoids, with up to 8% having genotypes associated with profound reduction in circulating MBL levels. Low-producing MBL2 variants and low MBL levels are associated with increased susceptibility to and severity of a variety of infective illnesses, particularly when immunity is already compromised--for example, in infants and young children, patients with cystic fibrosis, and after chemotherapy and transplantation. These observations suggest that administration of recombinant or purified MBL may be of benefit in clinical settings where MBL deficiency is associated with a high burden of infection. This review provides a background to MBL biology and disease associations, and identifies the exciting therapeutic possibilities of MBL replacement.
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Affiliation(s)
- D L Worthley
- Department of Gastroenterology, Flinders Medical Centre, South Australia, Australia
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45
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Chong WP, To YF, Ip WK, Yuen MF, Poon TP, Wong WHS, Lai CL, Lau YL. Mannose-binding lectin in chronic hepatitis B virus infection. Hepatology 2005; 42:1037-45. [PMID: 16231358 DOI: 10.1002/hep.20891] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Mannose binding lectin (MBL) is a pattern-recognition molecule of the innate immune system. The roles of MBL and its gene (mbl2) polymorphisms, -221X/Y and codon 54A/B, in hepatitis B virus (HBV) infection were investigated in this study. We recruited 320 nonprogressed hepatitis B surface antigen (HBsAg) carriers; 199 progressed HBsAg carriers with hepatocellular carcinoma or cirrhosis; 87 spontaneously recovered individuals who were HBsAg negative and anti-HBs and anti HBc positive; and 484 controls who were naïve to HBV. There was no significant difference between nonprogressed carriers, spontaneously recovered individuals, and controls in terms of serum MBL levels and mbl2 polymorphisms distributions. However, the low MBL genotypes had a dose-dependent correlation with the cirrhosis and hepatocellular carcinoma in progressed carriers with odds ratios of 1.36 and 3.21 for the low and extremely low MBL genotypes, respectively (P = .01). The low-expression promoter haplotype XA (OR = 1.97) and the mutant haplotype YB (OR = 1.90) were also associated with the cirrhosis and hepatocellular carcinoma (P = .002). As expected, the lower serum MBL levels in progressed carriers as compared with nonprogressed carriers were due to an overrepresentation of low and extremely low MBL genotypes. Moreover, MBL could bind HBsAg in a dose- and calcium-dependent and mannan-inhibitable manner in vitro, suggesting that binding occurs via the carbohydrate recognition domains. This binding also enhanced C4 deposition. In conclusion, these results suggest that low MBL genotypes associate with the occurrence of cirrhosis and hepatocellular carcinoma in progressed HBsAg carriers, and MBL can bind HBsAg.
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Affiliation(s)
- Wai Po Chong
- Department of Paediatrics and Adolescent Medicine, Hong Kong Jockey Club Clinical Research Centre, Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
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46
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Kravitz MS, Pitashny M, Shoenfeld Y. Protective Molecules–C-Reactive Protein (CRP), Serum Amyloid P (SAP), Pentraxin3 (PTX3), Mannose-Binding Lectin (MBL), and Apolipoprotein A1 (Apo A1), and Their Autoantibodies: Prevalence and Clinical Significance in Autoimmunity. J Clin Immunol 2005; 25:582-91. [PMID: 16380821 DOI: 10.1007/s10875-005-7828-2] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2005] [Accepted: 08/08/2005] [Indexed: 12/21/2022]
Abstract
Apoptotic defects and impaired clearance of cellular debris are considered key events in the development of autoimmunity, as they can contribute to autoantigen overload, and may initiate an autoimmune response. The pentraxins are a group of highly conserved proteins including the short pentraxins, C-reactive protein (CRP) and serum amyloid-P (SAP), and the long pentraxin-3 (PTX3), which are all involved in innate immunity and in acute-phase responses. Mannan-binding lectin (MBL) is an activator of the complement system, and Apolipoprotein A-1 (Apo A-1) is pivotal in the cholesterol homeostasis and has anti-inflammatory properties. In addition to their role in innate immunity and inflammation, each of these five proteins participates in the removal of damaged and apoptotic cells. In this review, we discuss the clinical significance of different levels of these proteins, their role in the induction or protection from autoimmunity, and the presence of specific autoantibodies against them in the different autoimmune diseases.
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Affiliation(s)
- Martine Szyper Kravitz
- Center for Autoimmune Diseases and Department of Medicine B, Chaim Sheba Medical Center Tel-Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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47
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Lam MF, Leung JCK, Tang CCS, Lo WK, Tse KC, Yip TP, Lui SL, Chan TM, Lai KN. Mannose binding lectin level and polymorphism in patients on long-term peritoneal dialysis. Nephrol Dial Transplant 2005; 20:2489-96. [PMID: 16115848 DOI: 10.1093/ndt/gfi089] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Infection is a leading cause of mortality and morbidity in patients with end-stage renal disease. The increased susceptibility to infection is probably secondary to the impaired immune defence in uraemia and other co-morbid factors such as diabetes mellitus. Peritonitis remains the most common and major complication in the treatment modality of peritoneal dialysis (PD) for uraemic patients. Mannose binding lectin (MBL) is a calcium dependent C-type lectin that acts as an important first line defence mechanism against infection by its capability to activate the complement system and enhance phagocytosis. METHODS We examined whether serum concentration of MBL and the point mutation of MBL may act as a risk factor in PD-related peritonitis. We studied four groups of dialysis patients: PD patients with two or more episodes of peritonitis, peritonitis-free PD patients, haemodialysis (HD) patients not previously on PD, and HD patients who were converted from PD due to technique failure following peritonitis-related abdominal adhesion. Results. Both homozygous and heterozygous patients had profoundly reduced serum level of MBL. The codon 54 point mutation rate amongst our dialysis patients was comparable with that of healthy subjects. Dialysis patients had a significantly lower serum level of MBL than healthy controls independent of the MBL gene mutation or the mode of dialysis treatment. Patients on PD with codon 54 point mutation were found to have a lower serum MBL level compared with HD patients with similar MBL gene mutation. However, we found no difference in the serum MBL level or frequency of codon 54 point mutation between four groups of dialysis patients. CONCLUSIONS Dialysis patients have lower MBL levels that may increase the susceptibility of infection. However, the existence of other risk factors such as connection technique, nasal bacterial carriers, bowel pathology and personal hygiene precludes the MBL level as the sole primary factor for peritonitis in patients on maintenance PD treatment.
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Affiliation(s)
- Man Fai Lam
- Nephrology Division, Department of Medicine, University of Hong Kong, Hong Kong
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48
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Bonnevie-Nielsen V, Field LL, Lu S, Zheng DJ, Li M, Martensen PM, Nielsen TB, Beck-Nielsen H, Lau YL, Pociot F. Variation in antiviral 2',5'-oligoadenylate synthetase (2'5'AS) enzyme activity is controlled by a single-nucleotide polymorphism at a splice-acceptor site in the OAS1 gene. Am J Hum Genet 2005; 76:623-33. [PMID: 15732009 PMCID: PMC1199299 DOI: 10.1086/429391] [Citation(s) in RCA: 119] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2004] [Accepted: 02/02/2005] [Indexed: 11/03/2022] Open
Abstract
It is likely that human genetic differences mediate susceptibility to viral infection and virus-triggered disorders. OAS genes encoding the antiviral enzyme 2',5'-oligoadenylate synthetase (2'5'AS) are critical components of the innate immune response to viruses. This enzyme uses adenosine triphosphate in 2'-specific nucleotidyl transfer reactions to synthesize 2',5'-oligoadenylates, which activate latent ribonuclease, resulting in degradation of viral RNA and inhibition of virus replication. We showed elsewhere that constitutive (basal) activity of 2'5'AS is correlated with virus-stimulated activity. In the present study, we asked whether constitutive activity is genetically determined and, if so, by which variants. Analysis of 83 families containing two parents and two children demonstrated significant correlations between basal activity in parent-child pairs (P<.0001) and sibling pairs (P=.0044), but not spousal pairs, suggesting strong genetic control of basal activity. We next analyzed association between basal activity and 15 markers across the OAS gene cluster. Significant association was detected at multiple markers, the strongest being at an A/G single-nucleotide polymorphism at the exon 7 splice-acceptor site (AG or AA) of the OAS1 gene. At this unusual polymorphism, allele G had a higher gene frequency in persons with high enzyme activity than in those with low enzyme activity (0.44 vs. 0.20; P=3 x 10(-11)). Enzyme activity varied in a dose-dependent manner across the GG, GA, and AA genotypes (tested by analysis of variance; P=1 x 10(-14)). Allele G generates the previously described p46 enzyme isoform, whereas allele A ablates the splice site and generates a dual-function antiviral/proapoptotic p48 isoform and a novel p52 isoform. This genetic polymorphism makes OAS1 an excellent candidate for a human gene that influences host susceptibility to viral infection.
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Affiliation(s)
- Vagn Bonnevie-Nielsen
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
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Cheong JY, Cho SW, Lim SK, Shin DH, Yoon SK, Lee JE, Hahm KB, Kim JH. Lack of association between hepatitis B virus infection and polymorphism of mannose-binding lectin gene in Korean population. J Korean Med Sci 2005; 20:65-9. [PMID: 15716605 PMCID: PMC2808578 DOI: 10.3346/jkms.2005.20.1.65] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Mannose-binding lectin (MBL) plays an important role in immune defense. This study was undertaken to investigate the association between hepatitis B virus infection and polymorphisms of MBL gene. We assessed the single nucleotide polymorphism at codon 54 in exon 1 of MBL in patients with hepatitis B virus infection and HBsAg negative controls in Korean population. A total of 498 enrolled subjects was classified into four groups. Group 1; Clearance, Group 2; Inactive healthy carrier, Group 3; Chronic hepatitis, Group 4; Liver cirrhosis. MBL gene polymorphisms at codon 54 led to three genotypes (G/G, G/A, A/A). When we divided subjects into clearance group (group 1) and persistence group (group 2-4), G/G genotype and A-allele carrier were observed in 55.6% and 44.4% in clearance group, 64.8% and 35.2% in persistence group (p=0.081), respectively. When hepatitis B virus persistent cases were divided into inactive healthy carrier (group 2) and disease progression group (group 3 and 4), MBL gene polymorphisms at codon 54 were not related to disease progression (p=0.166). MBL gene polymorphism at codon 54 was not associated with the clearance of hepatitis B virus infection nor progression of disease in chronic hepatitis B virus infection.
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Affiliation(s)
- Jae Youn Cheong
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Sung Won Cho
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Sun Kyo Lim
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Do Hyun Shin
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Seung Kew Yoon
- Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea
| | | | - Ki Baik Hahm
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Jin Hong Kim
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
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Dahl M, Tybjaerg-Hansen A, Schnohr P, Nordestgaard BG. A population-based study of morbidity and mortality in mannose-binding lectin deficiency. ACTA ACUST UNITED AC 2004; 199:1391-9. [PMID: 15148337 PMCID: PMC2211811 DOI: 10.1084/jem.20040111] [Citation(s) in RCA: 117] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Reduced levels of wild-type mannose-binding lectin (MBL) may increase susceptibility for infection, other common diseases, and death. We investigated associations between MBL deficiency and risk of infection, other common diseases, and death during 24, 24, and 8 yr of follow-up, respectively. We genotyped 9,245 individuals from the adult Danish population for three MBL deficiency alleles, B, C, and D, as opposed to the normal noncarrier A allele. Hospitalization incidence per 10,000 person · yr was 644 in noncarriers compared with 631 in heterozygotes (log-rank: P = 0.39) and 658 in deficiency homozygotes (P = 0.53). Death incidence per 10,000 person · yr was 235 in noncarriers compared with 244 in heterozygotes (P = 0.44) and 274 in deficiency homozygotes (P = 0.12). After stratification by specific cause of hospitalization or death, only hospitalization from cardiovascular disorders was increased in deficiency homozygotes versus noncarriers (P = 0.02). When retested in two case control studies, this association could not be confirmed. Incidence of hospitalization or death from infections or other serious common disorders did not differ between deficiency homozygotes and noncarriers. In conclusion, in this large study in an ethnically homogenous Caucasian population, there was no evidence for significant differences in infectious disease or mortality in MBL-deficient individuals versus controls. Our results suggest that MBL deficiency is not a major risk factor for morbidity or death in the adult Caucasian population.
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Affiliation(s)
- Morten Dahl
- Department of Clinical Biochemistry 54M1, Herlev Ringvej 75, Herlev University Hospital, DK-2730 Herlev, Denmark
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