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Gavriilaki E, Tsiftsoglou SA, Touloumenidou T, Farmaki E, Panagopoulou P, Michailidou E, Koravou EE, Mavrikou I, Iosifidis E, Tsiatsiou O, Papadimitriou E, Papadopoulou-Alataki E, Papayanni PG, Varelas C, Kokkoris S, Papalexandri A, Fotoulaki M, Galli-Tsinopoulou A, Zafeiriou D, Roilides E, Sakellari I, Anagnostopoulos A, Tragiannidis A. Targeted Genotyping of MIS-C Patients Reveals a Potential Alternative Pathway Mediated Complement Dysregulation during COVID-19 Infection. Curr Issues Mol Biol 2022; 44:2811-2824. [PMID: 35877417 PMCID: PMC9325260 DOI: 10.3390/cimb44070193] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 06/21/2022] [Accepted: 06/24/2022] [Indexed: 11/24/2022] Open
Abstract
Complement dysregulation has been documented in adults with COVID-19 and implicated in relevant pediatric inflammatory responses against SARS-CoV-2. We propose that signatures of complement missense coding SNPs associated with dysregulation could also be identified in children with multisystem inflammatory syndrome (MIS-C). We investigated 71 pediatric patients with RT-PCR validated SARS-CoV-2 hospitalized in pediatric COVID-19 care units (November 2020-March 2021) in three major groups. Seven (7) patients suffered from MIS-C (MIS-C group), 32 suffered from COVID-19 and were hospitalized (admitted group), whereas 32 suffered from COVID-19, but were sent home. All patients survived and were genotyped for variations in the C3, C5, CFB, CFD, CFH, CFHR1, CFI, CD46, CD55, MASP1, MASP2, MBL2, COLEC11, FCN1, and FCN3 genes. Upon evaluation of the missense coding SNP distribution patterns along the three study groups, we noticed similarities, but also considerably increased frequencies of the alternative pathway (AP) associated with SNPs rs12614 CFB, rs1061170, and rs1065489 CFH in the MIS-C patients. Our analysis suggests that the corresponding substitutions potentially reduce the C3b-inactivation efficiency and promote slower and weaker AP C3bBb pre-convertase assembly on virions. Under these circumstances, the complement AP opsonization capacity may be impaired, leading to compromised immune clearance and systemic inflammation in the MIS-C syndrome.
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Affiliation(s)
- Eleni Gavriilaki
- Hematology Department & BMT Unit, G Papanicolaou Hospital, 57010 Thessaloniki, Greece; (T.T.); (E.-E.K.); (I.M.); (P.G.P.); (C.V.); (A.P.); (I.S.); (A.A.)
| | - Stefanos A. Tsiftsoglou
- Laboratory of Pharmacology, Department of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Tasoula Touloumenidou
- Hematology Department & BMT Unit, G Papanicolaou Hospital, 57010 Thessaloniki, Greece; (T.T.); (E.-E.K.); (I.M.); (P.G.P.); (C.V.); (A.P.); (I.S.); (A.A.)
| | - Evangelia Farmaki
- 1st Pediatric Department, Aristotle University of Thessaloniki, Hipporkation Hospital, 54642 Thessaloniki, Greece; (E.F.); (E.P.); (D.Z.)
| | - Paraskevi Panagopoulou
- 4th Pediatric Department, Aristotle University of Thessaloniki, Papageorgiou Hospital, 56429 Thessaloniki, Greece; (P.P.); (E.P.-A.); (M.F.)
| | - Elissavet Michailidou
- 3rd Pediatric Department, Aristotle University of Thessaloniki, Hippokration Hospital, 54642 Thessaloniki, Greece; (E.M.); (E.I.); (O.T.); (E.R.)
| | - Evaggelia-Evdoxia Koravou
- Hematology Department & BMT Unit, G Papanicolaou Hospital, 57010 Thessaloniki, Greece; (T.T.); (E.-E.K.); (I.M.); (P.G.P.); (C.V.); (A.P.); (I.S.); (A.A.)
| | - Ioulia Mavrikou
- Hematology Department & BMT Unit, G Papanicolaou Hospital, 57010 Thessaloniki, Greece; (T.T.); (E.-E.K.); (I.M.); (P.G.P.); (C.V.); (A.P.); (I.S.); (A.A.)
| | - Elias Iosifidis
- 3rd Pediatric Department, Aristotle University of Thessaloniki, Hippokration Hospital, 54642 Thessaloniki, Greece; (E.M.); (E.I.); (O.T.); (E.R.)
| | - Olga Tsiatsiou
- 3rd Pediatric Department, Aristotle University of Thessaloniki, Hippokration Hospital, 54642 Thessaloniki, Greece; (E.M.); (E.I.); (O.T.); (E.R.)
| | - Eleni Papadimitriou
- 1st Pediatric Department, Aristotle University of Thessaloniki, Hipporkation Hospital, 54642 Thessaloniki, Greece; (E.F.); (E.P.); (D.Z.)
| | - Efimia Papadopoulou-Alataki
- 4th Pediatric Department, Aristotle University of Thessaloniki, Papageorgiou Hospital, 56429 Thessaloniki, Greece; (P.P.); (E.P.-A.); (M.F.)
| | - Penelope Georgia Papayanni
- Hematology Department & BMT Unit, G Papanicolaou Hospital, 57010 Thessaloniki, Greece; (T.T.); (E.-E.K.); (I.M.); (P.G.P.); (C.V.); (A.P.); (I.S.); (A.A.)
| | - Christos Varelas
- Hematology Department & BMT Unit, G Papanicolaou Hospital, 57010 Thessaloniki, Greece; (T.T.); (E.-E.K.); (I.M.); (P.G.P.); (C.V.); (A.P.); (I.S.); (A.A.)
| | - Styliani Kokkoris
- Laboratory of Hematology and Hospital—Blood Transfusion Unit, Medical School, University General Hospital “Attikon”, NKUA, 12462 Athens, Greece;
| | - Apostolia Papalexandri
- Hematology Department & BMT Unit, G Papanicolaou Hospital, 57010 Thessaloniki, Greece; (T.T.); (E.-E.K.); (I.M.); (P.G.P.); (C.V.); (A.P.); (I.S.); (A.A.)
| | - Maria Fotoulaki
- 4th Pediatric Department, Aristotle University of Thessaloniki, Papageorgiou Hospital, 56429 Thessaloniki, Greece; (P.P.); (E.P.-A.); (M.F.)
| | - Assimina Galli-Tsinopoulou
- 2nd Pediatric Department, Aristotle University of Thessaloniki, AHEPA Hospital, 54621 Thessaloniki, Greece; (A.G.-T.); (A.T.)
| | - Dimitrios Zafeiriou
- 1st Pediatric Department, Aristotle University of Thessaloniki, Hipporkation Hospital, 54642 Thessaloniki, Greece; (E.F.); (E.P.); (D.Z.)
| | - Emmanuel Roilides
- 3rd Pediatric Department, Aristotle University of Thessaloniki, Hippokration Hospital, 54642 Thessaloniki, Greece; (E.M.); (E.I.); (O.T.); (E.R.)
| | - Ioanna Sakellari
- Hematology Department & BMT Unit, G Papanicolaou Hospital, 57010 Thessaloniki, Greece; (T.T.); (E.-E.K.); (I.M.); (P.G.P.); (C.V.); (A.P.); (I.S.); (A.A.)
| | - Achilles Anagnostopoulos
- Hematology Department & BMT Unit, G Papanicolaou Hospital, 57010 Thessaloniki, Greece; (T.T.); (E.-E.K.); (I.M.); (P.G.P.); (C.V.); (A.P.); (I.S.); (A.A.)
| | - Athanasios Tragiannidis
- 2nd Pediatric Department, Aristotle University of Thessaloniki, AHEPA Hospital, 54621 Thessaloniki, Greece; (A.G.-T.); (A.T.)
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Gyngell C, Savulescu J. Ethics of genomic passports: should the genetically resistant be exempted from lockdowns and quarantines? JOURNAL OF MEDICAL ETHICS 2021; 48:medethics-2021-107297. [PMID: 34172526 PMCID: PMC9554064 DOI: 10.1136/medethics-2021-107297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 05/23/2021] [Indexed: 06/13/2023]
Abstract
Lockdowns and quarantines have been implemented widely in response to the COVID-19 pandemic. This has been accompanied by a rise in interest in the ethics of 'passport' systems that allow low-risk individuals greater freedoms during lockdowns and exemptions to quarantines. Immunity and vaccination passports have been suggested to facilitate the greater movement of those with acquired immunity and who have been vaccinated. Another group of individuals who pose a low risk to others during pandemics are those with genetically mediated resistances to pathogens. In this paper, we introduce the concept of genomic passports, which so far have not been explored in the bioethics literature. Using COVID-19 as an illustrative example, we explore the ethical issues raised by genomic passports and highlight differences and similarities to immunity passports. We conclude that, although there remain significant practical and ethical challenges to the implementation of genomic passports, there will be ways to ethically use them in the future.
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Affiliation(s)
- Christopher Gyngell
- Biomedical Ethics Research Group, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
- Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, Australia
| | - Julian Savulescu
- Biomedical Ethics Research Group, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
- Faculty of Philosophy, University of Oxford, Oxford, UK
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3
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Benetti E, Giliberti A, Emiliozzi A, Valentino F, Bergantini L, Fallerini C, Anedda F, Amitrano S, Conticini E, Tita R, d’Alessandro M, Fava F, Marcantonio S, Baldassarri M, Bruttini M, Mazzei MA, Montagnani F, Mandalà M, Bargagli E, Furini S, GEN-COVID Multicenter Study, Renieri A, Mari F. Clinical and molecular characterization of COVID-19 hospitalized patients. PLoS One 2020; 15:e0242534. [PMID: 33206719 PMCID: PMC7673557 DOI: 10.1371/journal.pone.0242534] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 11/05/2020] [Indexed: 01/08/2023] Open
Abstract
Clinical and molecular characterization by Whole Exome Sequencing (WES) is reported in 35 COVID-19 patients attending the University Hospital in Siena, Italy, from April 7 to May 7, 2020. Eighty percent of patients required respiratory assistance, half of them being on mechanical ventilation. Fiftyone percent had hepatic involvement and hyposmia was ascertained in 3 patients. Searching for common genes by collapsing methods against 150 WES of controls of the Italian population failed to give straightforward statistically significant results with the exception of two genes. This result is not unexpected since we are facing the most challenging common disorder triggered by environmental factors with a strong underlying heritability (50%). The lesson learned from Autism-Spectrum-Disorders prompted us to re-analyse the cohort treating each patient as an independent case, following a Mendelian-like model. We identified for each patient an average of 2.5 pathogenic mutations involved in virus infection susceptibility and pinpointing to one or more rare disorder(s). To our knowledge, this is the first report on WES and COVID-19. Our results suggest a combined model for COVID-19 susceptibility with a number of common susceptibility genes which represent the favorite background in which additional host private mutations may determine disease progression.
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Affiliation(s)
- Elisa Benetti
- Department of Medical Biotechnologies, University of Siena, Siena, Italy
| | | | - Arianna Emiliozzi
- Department of Medical Biotechnologies, University of Siena, Siena, Italy
- Department of Specialized and Internal Medicine, Tropical and Infectious Diseases Unit, Azienda Ospedaliera Universitaria Senese, Senese, Italy
| | | | - Laura Bergantini
- Unit of Respiratory Diseases and Lung Transplantation, Department of Internal and Specialist Medicine, University of Siena, Siena, Italy
| | | | - Federico Anedda
- Department of Emergency and Urgency, Medicine, Surgery and Neurosciences, Unit of Intensive Care Medicine, Siena University Hospital, Siena, Italy
| | - Sara Amitrano
- Genetica Medica, Azienda Ospedaliera Universitaria Senese, Senese, Italy
| | - Edoardo Conticini
- Rheumatology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Policlinico Le Scotte, Siena, Italy
| | - Rossella Tita
- Genetica Medica, Azienda Ospedaliera Universitaria Senese, Senese, Italy
| | - Miriana d’Alessandro
- Unit of Respiratory Diseases and Lung Transplantation, Department of Internal and Specialist Medicine, University of Siena, Siena, Italy
| | - Francesca Fava
- Medical Genetics, University of Siena, Siena, Italy
- Genetica Medica, Azienda Ospedaliera Universitaria Senese, Senese, Italy
| | - Simona Marcantonio
- Department of Emergency and Urgency, Medicine, Surgery and Neurosciences, Unit of Intensive Care Medicine, Siena University Hospital, Siena, Italy
| | | | - Mirella Bruttini
- Medical Genetics, University of Siena, Siena, Italy
- Genetica Medica, Azienda Ospedaliera Universitaria Senese, Senese, Italy
| | - Maria Antonietta Mazzei
- Department of Medical, Surgical and Neuro Sciences and Radiological Sciences, Unit of Diagnostic Imaging, University of Siena, Azienda Ospedaliera Universitaria Senese, Senese, Italy
| | - Francesca Montagnani
- Department of Medical Biotechnologies, University of Siena, Siena, Italy
- Department of Specialized and Internal Medicine, Tropical and Infectious Diseases Unit, Azienda Ospedaliera Universitaria Senese, Senese, Italy
| | - Marco Mandalà
- Otolaryngology Unit, University of Siena, Siena, Italy
| | - Elena Bargagli
- Unit of Respiratory Diseases and Lung Transplantation, Department of Internal and Specialist Medicine, University of Siena, Siena, Italy
| | - Simone Furini
- Department of Medical Biotechnologies, University of Siena, Siena, Italy
| | | | - Alessandra Renieri
- Medical Genetics, University of Siena, Siena, Italy
- Genetica Medica, Azienda Ospedaliera Universitaria Senese, Senese, Italy
| | - Francesca Mari
- Medical Genetics, University of Siena, Siena, Italy
- Genetica Medica, Azienda Ospedaliera Universitaria Senese, Senese, Italy
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Jalal PJ, King BJ, Saeed A, Adedeji Y, Mason CP, Ball JK, Irving WL, McClure CP, Tarr AW. Elevated serum activity of MBL and ficolin-2 as biomarkers for progression to hepatocellular carcinoma in chronic HCV infection. Virology 2019; 530:99-106. [PMID: 30798068 DOI: 10.1016/j.virol.2019.02.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 02/04/2019] [Accepted: 02/04/2019] [Indexed: 11/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is an uncommon but significant outcome of chronic hepatitis C virus (HCV) infection. A serum biomarker for predicting progression to HCC would have a major impact on patient monitoring and clinical management. We explored circulating liver-expressed lectins, ficolin-2, ficolin-3 and mannose binding lectin (MBL), as potential biomarkers for the development of HCC. The activity of these three lectins were analysed in HCV positive patients who developed HCC (n = 31) with comparable HCV-positive HCC-negative patients (n = 106) and healthy controls (n = 79). Serum binding activity of ficolin-2 and MBL were elevated compared to controls. Analysis of pre-HCC onset samples revealed that MBL levels were significantly elevated up to 3 years, and ficolin-2 was elevated up to 1 year, prior to diagnosis of HCC over controls. This preliminary study identifies MBL and ficolin-2 as potential biomarkers for the development of HCC in chronic HCV infection.
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Affiliation(s)
- Paywast J Jalal
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust & University of Nottingham, UK; Biology Department, Faculty of Science, University of Sulaimani, Iraq
| | - Barnabas J King
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust & University of Nottingham, UK
| | - Amanj Saeed
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust & University of Nottingham, UK; Biology Department, Faculty of Science, University of Sulaimani, Iraq
| | - Yemisi Adedeji
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust & University of Nottingham, UK
| | - Christopher P Mason
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust & University of Nottingham, UK
| | - Jonathan K Ball
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust & University of Nottingham, UK; School of Life Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, UK
| | - William L Irving
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust & University of Nottingham, UK; School of Life Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, UK
| | - C Patrick McClure
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust & University of Nottingham, UK; School of Life Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, UK
| | - Alexander W Tarr
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust & University of Nottingham, UK; School of Life Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, UK.
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5
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Su C, Lin Y, Mao Q, Wu D, Zhu L, Najera I, Garcia-Alcalde F, Niu J. Association study between mannose-binding lectin haplotypes and X gene mutation of hepatitis B virus from treatment naïve patients. Aging (Albany NY) 2017; 8:2862-2870. [PMID: 27824315 PMCID: PMC5191875 DOI: 10.18632/aging.101097] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Accepted: 10/24/2016] [Indexed: 01/26/2023]
Abstract
Mannose binding lectin (MBL) plays important role in the innate immunity of human. Mutations in the MBL2 gene can significantly change the serum level of MBL, and consequently alter the susceptibility and progression of infectious disease. However, the association between the MBL2 profile and the HBV mutation and quasispecies complexity has not yet been reported. Our approach includes the study of the MBL2 gene genotype as well as ultra-deep sequencing of the HBV viruses obtained from the plasma of 50 treatment naïve patients with chronic HBV infection. We found that the liver function was better among patients within the high MBL2 group with respect to those within the medium/low MBL2 group. Likewise, the number of mutations in the HBV X gene as well as the viral quasispecies complexity were significantly higher in medium/low MBL2 production group. Nucleotide substitution rates were also higher within the medium/low MBL2 production group in all positions described to have an influence in liver cancer development, except for A1499G. In this work we show that the MBL2 profile may have an impact on the HBV X gene mutations as well as on viral quasispecies complexity.
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Affiliation(s)
- Chenghao Su
- Xiamen Center for Disease Control and Prevention, Xiamen, Fujian 361021, China
| | - Yong Lin
- Xiamen Center for Disease Control and Prevention, Xiamen, Fujian 361021, China.,School of Public Health, Fujian Medical University, Fuzhou, Fujian 351022, China
| | - Qianguo Mao
- Xiamen Hospital of Traditional Chinses Medicine, Xiamen, Fujian 361001, China
| | - Daitze Wu
- Roche Pharma Research and Early Development, Immunology, Inflammation and Infectious Diseases, Roche Innovation Center Shanghai 201203, China
| | - Lina Zhu
- Roche Pharma Research and Early Development, Immunology, Inflammation and Infectious Diseases, Roche Innovation Center Shanghai 201203, China
| | - Isabel Najera
- Roche Pharma Research and Early Development, Immunology, Inflammation and Infectious Diseases, Roche Innovation Center Basel 4070, Switzerland
| | - Fernando Garcia-Alcalde
- Roche Pharma Research and Early Development, Immunology, Inflammation and Infectious Diseases, Roche Innovation Center Basel 4070, Switzerland
| | - Jianjun Niu
- Zhongshan Hospital, Xiamen University, Xiamen, Fujian 361004, China
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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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7
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Ho CH, Tsai HW, Lee CY, Huang LJ, Chien RN, Wu IC, Chiu YC, Liu WC, Cheng PN, Chang TT, Chen SH. Favorable Response to Long-term Nucleos(t)ide Analogue Therapy in HBeAg-positive Patients with High Serum Fucosyl-Agalactosyl IgG. Sci Rep 2017; 7:1957. [PMID: 28512353 PMCID: PMC5434008 DOI: 10.1038/s41598-017-02158-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 04/11/2017] [Indexed: 12/18/2022] Open
Abstract
Aberrant IgG glycosylation is a feature of hepatitis B virus (HBV) infection but its effect on a long-term efficacy of antiviral therapy has never been addressed. After a screening of 1,085 patients, 132 eligible HBV e antigen (HBeAg)-positive and 101 HBeAg-negative patients with anti-HBV nucleos(t)ide analogue monotherapy were enrolled with on-treatment follow-ups for at least one year. IgG1 N-glycome was profiled using mass spectrometry and evaluated for its relevance in treatment responses. The results indicated that a high level of serum fucosyl-agalactosyl IgG1 (IgG1-G0F) at baseline was associated with the severity of liver inflammation and damage but advanced treatment responses, including HBV DNA loss, HBeAg seroconversion, a reduced drug resistance rate, and a liver histological improvement at year 1, thereby improving the long-term treatment efficacy and the probability of treatment discontinuation in HBeAg-positive patients. Stepwise Cox regression analyses revealed that baseline IgG1-G0F >30% was an independent factor that links to virological response (HR 3.071, 95% CI 1.835–5.141, P < 0.001) or HBeAg seroconversion (HR 2.034, 95% CI 1.011–4.093, P = 0.046). Furthermore, a high IgG1-G0F level at the treatment endpoint was associated with an off-treatment sustained virological response. In conclusion, IgG1-G0F favors the medication outcome for HBeAg-positive chronic hepatitis B.
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Affiliation(s)
- Cheng-Hsun Ho
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Research Center of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hung-Wen Tsai
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Infectious Disease and Signaling Research Center, National Cheng Kung University, Tainan, Taiwan
| | - Chen-Yeh Lee
- Department of Chemistry, National Cheng Kung University, Tainan, Taiwan
| | - Li-Juan Huang
- Department of Chemistry, National Cheng Kung University, Tainan, Taiwan
| | - Rong-Nan Chien
- Liver Research Unit, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Keelung, Taiwan
| | - I-Chin Wu
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Infectious Disease and Signaling Research Center, National Cheng Kung University, Tainan, Taiwan
| | - Yen-Cheng Chiu
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Wen-Chun Liu
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Infectious Disease and Signaling Research Center, National Cheng Kung University, Tainan, Taiwan
| | - Pin-Nan Cheng
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Ting-Tsung Chang
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Infectious Disease and Signaling Research Center, National Cheng Kung University, Tainan, Taiwan.,Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Shu-Hui Chen
- Department of Chemistry, National Cheng Kung University, Tainan, Taiwan.
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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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Association of MBL2 exon1 polymorphisms with high-risk human papillomavirus infection and cervical cancers: a meta-analysis. Arch Gynecol Obstet 2016; 294:1109-1116. [PMID: 27619685 DOI: 10.1007/s00404-016-4201-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Accepted: 09/06/2016] [Indexed: 10/21/2022]
Abstract
PURPOSE High-risk human papillomavirus (HR-HPV) infection is the main known cause of cervical cancer. Mannose-binding lectin (MBL) is a recognition molecule that mediates phagocytosis and activates complement. METHODS We performed a meta-analysis to investigate the association of MBL-2 functional polymorphisms with HPV infection and cervical cancer (CC). RESULTS The meta-analyses indicated an association between the MBL2 exon 1 polymorphisms and susceptibility to HPV infection in the recessive model (OO vs. AA + AO, p = 0.042, 95 % CI 1.02-3.15), and O/O vs. A/A mode (P = 0.023, 95 % CI 1.10-3.40) in Caucasian. Meanwhile, there was a significant association between MBL2 exon 1 polymorphisms and cervical cancer risk in AO vs. AA model (p = 0.035, 95 % CI 1.03-2.26), and Allelic model (O vs. A, p = 0.022, 95 % CI 1.05-1.96) as compared to HR-HPV-infected patients with CC vs. healthy controls in Caucasian. In addition, no an association was observed between MBL2 -550 H/L and -221 X/Y polymorphisms and HPV infection among Caucasians, but we found an association between the MBL2 -550 H/L polymorphism and susceptibility to HR-HPV infection in recessive model (HH vs. LL + LH, p = 0.003, 95 % CI 1.18-2.23), HH vs. LL model (p = 0.021, 95 % CI 1.07-2.19), and allelic model(H vs. L, p = 0.042, 95 % CI 1.01-1.40) in Asians. CONCLUSIONS Collectively, we suggest that the MBL2 gene exon1 polymorphisms are associated with increased risk of high-risk HPV infection and cervical cancer development among Caucasians. Additionally, no significant association was found between the MBL2 -550 H/L or -221 X/Y polymorphisms and HPV infection in Caucasians, but there may be potential links in Asians.
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10
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Madhukaran SP, Alhamlan FS, Kale K, Vatish M, Madan T, Kishore U. Role of collectins and complement protein C1q in pregnancy and parturition. Immunobiology 2016; 221:1273-88. [PMID: 27349595 DOI: 10.1016/j.imbio.2016.06.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 05/27/2016] [Accepted: 06/09/2016] [Indexed: 12/18/2022]
Abstract
Collectins such as surfactant proteins SP-A, SP-D, and mannan-binding lectin (MBL), as well as complement protein C1q are evolutionarily conserved innate immune molecules. They are known to opsonize a range of microbial pathogens (bacteria, fungi, virus, and parasites) and trigger effector clearance mechanisms involving phagocytosis and/or complement activation. Collectins and C1q have also attracted attention in studies involving pregnancy as they are expressed in the female reproductive tissues during pregnancy; a unique state of immune suppression with increased susceptibility to infectious diseases. Recent studies are beginning to unravel their functional significance in implantation, placentation, pregnancy maintenance and parturition in normal and adverse pregnancies. Collectins and C1q, expressed in gestational tissues during pregnancy, might alter the status of mother's immune response to the allogenic fetus and the microenvironment, thereby serving as important regulators of fetus-mother interaction. Here, we discuss the functional roles that have been assigned to SP-A, SP-D, MBL and C1q in pregnancy and parturition.
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Affiliation(s)
- Shanmuga Priyaa Madhukaran
- Biosciences, College of Health and Life Sciences, Brunel University London, Uxbridge UB8 3PH, United Kingdom; Centre for Biotechnology and Bioinformatics, School of Life Sciences, Jawaharlal Nehru Institute for Advanced Studies, Secunderabad, Telangana, India
| | - Fatimah S Alhamlan
- Department of Infection and Immunity, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Kavita Kale
- Department of Innate Immunity, National Institute for Research in Reproductive Health (ICMR), Mumbai 400 012, India
| | - Manu Vatish
- Nuffield Department of Obstetrics & Gynaecology, University of Oxford, Oxford, OX3 9DU, United Kingdom
| | - Taruna Madan
- Department of Innate Immunity, National Institute for Research in Reproductive Health (ICMR), Mumbai 400 012, India
| | - Uday Kishore
- Biosciences, College of Health and Life Sciences, Brunel University London, Uxbridge UB8 3PH, United Kingdom.
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11
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Wang PS, Kuai J, Li H, Wang CG, Shi BJ, Zhong L. Mannose-binding lectin 2 rs11003123 polymorphism is associated with the development of hepatocellular carcinoma in patients with hepatitis B-related cirrhosis in the Chinese population. Hepatobiliary Pancreat Dis Int 2016; 15:282-8. [PMID: 27298104 DOI: 10.1016/s1499-3872(16)60050-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Mannose-binding lectin 2 (MBL2) plays a key role in the host immune response, but whether it is associated with hepatocellular carcinoma (HCC) is not clear. The present study aimed to identify the association between MBL2 gene polymorphisms and HCC in patients with hepatitis B virus (HBV)-related cirrhosis in the Chinese population. METHODS A single-nucleotide polymorphism of MBL2, rs11003123, was genotyped and analyzed in a case-control study of HBV-related cirrhotic patients with HCC (n=77) and without HCC (n=40). RESULTS We found that Child-Pugh profiles, model for end-stage liver disease score, and the incidence of encephalopathy were all higher in the non-HCC group (P<0.05). A significant association between allele mutants and HCC occurrence was demonstrated by allele comparison (A vs G) (OR=0.34; 95% CI: 0.15-0.76; P=0.006). Heterozygous comparison (GA vs GG) revealed that the individuals with GA mutants had a reduced risk of HCC occurrence compared with those with GG wild type (adjusted OR=0.28; 95% CI: 0.10-0.80; P=0.004). In a dominant model (GA+AA vs GG), a decreased risk of HCC occurrence was observed in individuals with variant genotypes (GA and AA) compared with those with the wild type (adjusted OR=0.30; 95% CI: 0.11-0.85; P=0.004). However, no statistically significant associations were observed between rs11003123 and prognosis of patients with HCC after liver transplantation in both recurrence-free survival and overall survival (P=0.449 and P=0.384, respectively). CONCLUSION MBL2 rs11003123 polymorphism may be a marker for the risk of HCC occurrence in patients with HBV-related cirrhosis in the Chinese population.
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Affiliation(s)
- Pu-Sen Wang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, 100 Haining Road, Shanghai 200080, China.
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12
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Awan FM, Naz A, Obaid A, Ali A, Ahmad J, Anjum S, Janjua HA. Identification of Circulating Biomarker Candidates for Hepatocellular Carcinoma (HCC): An Integrated Prioritization Approach. PLoS One 2015; 10:e0138913. [PMID: 26414287 PMCID: PMC4586137 DOI: 10.1371/journal.pone.0138913] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Accepted: 09/06/2015] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the world's third most widespread cancer. Currently available circulating biomarkers for this silently progressing malignancy are not sufficiently specific and sensitive to meet all clinical needs. There is an imminent and pressing need for the identification of novel circulating biomarkers to increase disease-free survival rate. In order to facilitate the selection of the most promising circulating protein biomarkers, we attempted to define an objective method likely to have a significant impact on the analysis of vast data generated from cutting-edge technologies. Current study exploits data available in seven publicly accessible gene and protein databases, unveiling 731 liver-specific proteins through initial enrichment analysis. Verification of expression profiles followed by integration of proteomic datasets, enriched for the cancer secretome, filtered out 20 proteins including 6 previously characterized circulating HCC biomarkers. Finally, interactome analysis of these proteins with midkine (MDK), dickkopf-1 (DKK-1), current standard HCC biomarker alpha-fetoprotein (AFP), its interacting partners in conjunction with HCC-specific circulating and liver deregulated miRNAs target filtration highlighted seven novel statistically significant putative biomarkers including complement component 8, alpha (C8A), mannose binding lectin (MBL2), antithrombin III (SERPINC1), 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1), alcohol dehydrogenase 6 (ADH6), beta-ureidopropionase (UPB1) and cytochrome P450, family 2, subfamily A, polypeptide 6 (CYP2A6). Our proposed methodology provides a swift assortment process for biomarker prioritization that eventually reduces the economic burden of experimental evaluation. Further dedicated validation studies of potential putative biomarkers on HCC patient blood samples are warranted. We hope that the use of such integrative secretome, interactome and miRNAs target filtration approach will accelerate the selection of high-priority biomarkers for other diseases as well, that are more amenable to downstream clinical validation experiments.
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Affiliation(s)
- Faryal Mehwish Awan
- Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12 Islamabad, Pakistan
| | - Anam Naz
- Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12 Islamabad, Pakistan
| | - Ayesha Obaid
- Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12 Islamabad, Pakistan
| | - Amjad Ali
- Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12 Islamabad, Pakistan
| | - Jamil Ahmad
- Research Center for Modeling and Simulation (RCMS), National University of Sciences and Technology (NUST), H-12 Islamabad, Pakistan
| | - Sadia Anjum
- Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12 Islamabad, Pakistan
| | - Hussnain Ahmed Janjua
- Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12 Islamabad, Pakistan
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13
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Pifferi M, Bush A, Michelucci A, Di Cicco M, Piras M, Caramella D, Mazzei F, Neri M, Pioggia G, Tartarisco G, Saggese G, Simi P, Boner AL. Mannose-binding lectin 2 gene polymorphism and lung damage in primary ciliary dyskinesia. Pediatr Pulmonol 2015; 50:179-86. [PMID: 24753481 DOI: 10.1002/ppul.23026] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2013] [Accepted: 02/10/2014] [Indexed: 11/09/2022]
Abstract
BACKGROUND Mannose-binding lectin (MBL) plays an important role in innate immunity and has been reported to be associated with the age-related decline in lung function in cystic fibrosis. HYPOTHESIS MBL polymorphisms are associated with lung function decline in Primary Ciliary Dyskinesia (PCD). METHODS We performed sputum microbiology, spirometry pre- and post-administration of salbutamol, ciliary motion analysis, ultrastructural assessment of cilia, ciliogenesis in culture, and chest high resolution computed tomography in children with a clinical history of respiratory tract infections and/or presence of bronchiectasis suggestive of PCD or secondary ciliary dyskinesia (SCD). All subjects were evaluated for single nucleotide polymorphisms in the gene encoding MBL-2. RESULTS The diagnosis of PCD was established in 45 subjects, while in the remaining 53 the diagnosis was SCD. A significant bronchodilator response was observed only in PCD associated with the MBL2-3 genotype, which is known to be associated with low/undetectable MBL serum levels. Also, bronchiectasis severity was significantly greater in subjects with MBL2-3 in both PCD and SCD. No other association was found between MBL genotypes and clinical findings. CONCLUSIONS MBL plays a relatively minor role as a disease modifier in PCD. A similar finding in SCD supports the likely significance of this result.
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Affiliation(s)
- Massimo Pifferi
- Department of Pediatrics, University Hospital of Pisa, Pisa, Italy
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14
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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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15
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Thio CL, Hawkins C. Hepatitis B Virus and Hepatitis Delta Virus. MANDELL, DOUGLAS, AND BENNETT'S PRINCIPLES AND PRACTICE OF INFECTIOUS DISEASES 2015:1815-1839.e7. [DOI: 10.1016/b978-1-4557-4801-3.00148-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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16
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Geller G, Dvoskin R, Thio CL, Duggal P, Lewis MH, Bailey TC, Sutherland A, Salmon DA, Kahn JP. Genomics and infectious disease: a call to identify the ethical, legal and social implications for public health and clinical practice. Genome Med 2014; 6:106. [PMID: 25593592 PMCID: PMC4295297 DOI: 10.1186/s13073-014-0106-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Advances in genomics are contributing to the development of more effective, personalized approaches to the prevention and treatment of infectious diseases. Genetic sequencing technologies are furthering our understanding of how human and pathogen genomic factors - and their interactions - contribute to individual differences in immunologic responses to vaccines, infections and drug therapies. Such understanding will influence future policies and procedures for infectious disease management. With the potential for tailored interventions for particular individuals, populations or subpopulations, ethical, legal and social implications (ELSIs) may arise for public health and clinical practice. Potential considerations include balancing health-related benefits and harms between individuals and the larger community, minimizing threats to individual privacy and autonomy, and ensuring just distribution of scarce resources. In this Opinion, we consider the potential application of pathogen and host genomic information to particular viral infections that have large-scale public health consequences but differ in ELSI-relevant characteristics such as ease of transmission, chronicity, severity, preventability and treatability. We argue for the importance of anticipating these ELSI issues in advance of new scientific discoveries, and call for the development of strategies for identifying and exploring ethical questions that should be considered as clinical, public health and policy decisions are made.
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Affiliation(s)
- Gail Geller
- Berman Institute of Bioethics, Johns Hopkins University, Baltimore, MD 21205 USA ; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA ; Department of Health, Behavior & Society, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205 USA ; Department of Health Policy and Management, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205 USA
| | - Rachel Dvoskin
- Berman Institute of Bioethics, Johns Hopkins University, Baltimore, MD 21205 USA
| | - Chloe L Thio
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA
| | - Priya Duggal
- Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205 USA
| | - Michelle H Lewis
- Berman Institute of Bioethics, Johns Hopkins University, Baltimore, MD 21205 USA
| | - Theodore C Bailey
- Berman Institute of Bioethics, Johns Hopkins University, Baltimore, MD 21205 USA ; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA
| | - Andrea Sutherland
- Department of International Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205 USA
| | - Daniel A Salmon
- Department of Health, Behavior & Society, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205 USA ; Department of International Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205 USA
| | - Jeffrey P Kahn
- Berman Institute of Bioethics, Johns Hopkins University, Baltimore, MD 21205 USA ; Department of Health Policy and Management, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205 USA
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17
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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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18
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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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20
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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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21
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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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22
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Alonso A, Marsal S, Tortosa R, Canela-Xandri O, Julià A. GStream: improving SNP and CNV coverage on genome-wide association studies. PLoS One 2013; 8:e68822. [PMID: 23844243 PMCID: PMC3700900 DOI: 10.1371/journal.pone.0068822] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Accepted: 06/03/2013] [Indexed: 11/22/2022] Open
Abstract
We present GStream, a method that combines genome-wide SNP and CNV genotyping in the Illumina microarray platform with unprecedented accuracy. This new method outperforms previous well-established SNP genotyping software. More importantly, the CNV calling algorithm of GStream dramatically improves the results obtained by previous state-of-the-art methods and yields an accuracy that is close to that obtained by purely CNV-oriented technologies like Comparative Genomic Hybridization (CGH). We demonstrate the superior performance of GStream using microarray data generated from HapMap samples. Using the reference CNV calls generated by the 1000 Genomes Project (1KGP) and well-known studies on whole genome CNV characterization based either on CGH or genotyping microarray technologies, we show that GStream can increase the number of reliably detected variants up to 25% compared to previously developed methods. Furthermore, the increased genome coverage provided by GStream allows the discovery of CNVs in close linkage disequilibrium with SNPs, previously associated with disease risk in published Genome-Wide Association Studies (GWAS). These results could provide important insights into the biological mechanism underlying the detected disease risk association. With GStream, large-scale GWAS will not only benefit from the combined genotyping of SNPs and CNVs at an unprecedented accuracy, but will also take advantage of the computational efficiency of the method.
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Affiliation(s)
- Arnald Alonso
- Rheumatology Research Group, Vall d'Hebron Hospital Research Institute, Barcelona, Spain
- Department of ESAII, Polytechnical University of Catalonia, Barcelona, Spain
| | - Sara Marsal
- Rheumatology Research Group, Vall d'Hebron Hospital Research Institute, Barcelona, Spain
| | - Raül Tortosa
- Rheumatology Research Group, Vall d'Hebron Hospital Research Institute, Barcelona, Spain
| | - Oriol Canela-Xandri
- Rheumatology Research Group, Vall d'Hebron Hospital Research Institute, Barcelona, Spain
| | - Antonio Julià
- Rheumatology Research Group, Vall d'Hebron Hospital Research Institute, Barcelona, Spain
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Genetic variants associated with susceptibility to mother-to-child transmission of hepatitis B virus. Eur J Gastroenterol Hepatol 2012; 24:1185-90. [PMID: 22772094 DOI: 10.1097/meg.0b013e328356440f] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE The mechanisms of immune tolerance to hepatitis B virus (HBV) in children infected perinatally or early in infancy still remain unclarified. We aimed to study the genetic variants of immune factors implicated in viral-host interaction in children who were born to HBV-positive mothers and who had different clinical outcome. METHODS Mannose-binding lectin gene (mbl2) codon 54, codon 57, and promoter 221 variants, tumor necrosis factor α (TNF-α) 308G/A, and vitamin D receptor (VDR) ApaI and TaqI genotypes were analyzed in three groups of children born to HBV-positive mothers: children with chronic infection (n=33), those with resolved infection (n=36), and those naive for HBV (n=33). RESULTS TNF-α -308G allele frequency was found to be increased in children with chronic infection compared with children who were not affected by HBV [risk ratio (RR) 1.12, 95% confidence interval (CI) 1.0-1.25; P=0.050]. The VDR ApaI A allele tended to be more frequent in children with chronic infection than in those with resolved HBV infection (RR 1.27, 95% CI 0.95-1.67; P=0.071). The VDR ApaI α allele in ApaI and TaqI joint haplotype αT was more frequent in children with resolved infection than in those with chronic infection (RR 1.74, 95% CI 0.97-3.13; P=0.049). CONCLUSION Our results suggest that TNF-α and vitamin D pathways may be involved in the susceptibility to and outcome of HBV infection acquired early in life.
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Park GH, Kim KY, Cheong JY, Cho SW, Kwack K. Association of GNLY genetic polymorphisms with chronic liver disease in a Korean population. DNA Cell Biol 2012; 31:1492-8. [PMID: 22788687 DOI: 10.1089/dna.2012.1709] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Granulysin (GNLY) is found in cytotoxic granules of cytolytic T lymphocytes and natural killer (NK) cells, which are critical for hepatitis B virus (HBV) clearance. GNLY cytotoxicity plays an important role in the defense against viruses or intracellular bacteria. We hypothesized that genetic variation in the GNLY gene could affect the resistance of hosts against HBV infection. We compared the distribution frequencies of GNLY polymorphisms between an HBV-induced chronic liver disease (CLD) group and a spontaneous recovery (SR) control group to determine whether GNLY polymorphisms play a role in HBV clearance. A total of 117 patients in the SR group and 230 patients in the CLD group were enrolled. Samples derived from complex infections, including hepatitis C and human immunodeficiency virus, and those associated with insufficient clinical information (10 samples in SR and 24 samples in CLD) were excluded from the study. The final analysis included 107 SR and 206 CLD samples. DNA was extracted from peripheral blood, and GNLY genotypes were determined by the GoldenGate(®) method. The genotype distribution of the single-nucleotide polymorphisms (SNPs) rs2886767 (C>T), rs1561285 (G>C), and rs11127 (T>C) were significantly different between the SR and CLD groups in a recessive model (p<0.015). These three SNPs were in a complete linkage disequilibrium (LD) block. Diplotype distributions of haplotype (HT) 1 (C-G-T) and HT2 (T-C-C) were significantly different between the SR and CLD groups in a recessive model (p=0.025) and a dominant model (p=0.008). All p-values remained significant after multiple comparisons. GNLY polymorphism genotypes and diplotypes were associated with the chronicity of HBV. These data suggested that genetic variation of GNLY may be an important factor in HBV clearance through the CD8+ T or NK cell-mediated removal of HBV-infected cells from the host.
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Affiliation(s)
- Geun-Hee Park
- Department of Biomedical Science, College of Life Science, CHA University, Seongnam, Republic of Korea
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Hoang TV, Toan NL, Song LH, Ouf EA, Bock CT, Kremsner PG, Kun JFJ, Velavan TP. Ficolin-2 levels and FCN2 haplotypes influence hepatitis B infection outcome in Vietnamese patients. PLoS One 2011; 6:e28113. [PMID: 22140517 PMCID: PMC3222672 DOI: 10.1371/journal.pone.0028113] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2011] [Accepted: 11/01/2011] [Indexed: 01/16/2023] Open
Abstract
Human Ficolin-2 (L-ficolins) encoded by FCN2 gene is a soluble serum protein that plays an important role in innate immunity and is mainly expressed in the liver. Ficolin-2 serum levels and FCN2 single nucleotide polymorphisms were associated to several infectious diseases. We initially screened the complete FCN2 gene in 48 healthy individuals of Vietnamese ethnicity. We genotyped a Vietnamese cohort comprising of 423 clinically classified hepatitis B virus patients and 303 controls for functional single nucleotide polymorphisms in the promoter region (-986G>A, -602G>A, -4A>G) and in exon 8 (+6424G>T) by real-time PCR and investigated the contribution of FCN2 genotypes and haplotypes to serum Ficolin-2 levels, viral load and liver enzyme levels. Haplotypes differed significantly between patients and controls (P = 0.002) and the haplotype AGGG was found frequently in controls in comparison to patients with hepatitis B virus and hepatocellular carcinoma (P = 0.0002 and P<0.0001) conferring a protective effect. Ficolin-2 levels differed significantly between patients and controls (p<0.0001). Patients with acute hepatitis B had higher serum Ficolin-2 levels compared to other patient groups and controls.The viral load was observed to be significantly distributed among the haplotypes (P = 0.04) and the AAAG haplotype contributed to higher Ficolin-2 levels and to viral load. Four novel single nucleotide polymorphisms in introns (-941G>T, -310G>A, +2363G>A, +4882G>A) and one synonymous mutation in exon 8 (+6485G>T) was observed. Strong linkage was found between the variant -986G>A and -4A>G. The very first study on Vietnamese cohort associates both Ficolin-2 serum levels and FCN2 haplotypes to hepatitis B virus infection and subsequent disease progression.
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Affiliation(s)
- Tong V Hoang
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.
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Heitzeneder S, Seidel M, Förster-Waldl E, Heitger A. Mannan-binding lectin deficiency - Good news, bad news, doesn't matter? Clin Immunol 2011; 143:22-38. [PMID: 22377282 DOI: 10.1016/j.clim.2011.11.002] [Citation(s) in RCA: 123] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2011] [Revised: 11/03/2011] [Accepted: 11/04/2011] [Indexed: 01/13/2023]
Abstract
Mannan-binding lectin (MBL) deficiency has been classified as a commonly occurring immune disorder, affecting approximately 30% of the human population. MBL, being part of the innate immune system, supports the recognition of infectious pathogens by binding to carbohydrate moieties expressed on microorganisms and activates the lectin pathway of the complement system. MBL2 gene polymorphisms are associated with quantitative and qualitative MBL abnormalities in the serum. The clinical impact of MBL deficiency and its association to a wide variety of diseases has been extensively studied. The picture is puzzling as the studies suggest a detrimental or beneficial or no impact of low or high MBL serum levels on disease susceptibility. In this review we attempt to extract what is relevant from the literature and address controversial issues. We finally suggest that a comprehensive understanding of the role of MBL in human diseases requires considering its context-dependency.
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Børresen ML, Koch A, Biggar RJ, Andersson M, Wohlfahrt J, Ladefoged K, Melbye M. Hepatocellular carcinoma and other liver disease among Greenlanders chronically infected with hepatitis B virus: a population-based study. J Natl Cancer Inst 2011; 103:1676-85. [PMID: 22021665 DOI: 10.1093/jnci/djr405] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND In Greenland, the prevalence of hepatitis B surface antigen carriers, reflecting chronic hepatitis B virus (HBV) infection, is 5%-10%. However, the incidence of cirrhosis and hepatocellular carcinoma in this population has been reported to be low. We investigated this discrepancy in a large population-based cohort study. METHODS In total, 8879 Greenlanders (16% of the population) were recruited for population-based surveys performed from May 5 to July 7, 1987, and from November 1 to November 21, 1998, with follow-up until March 31, 2010. HBV status was based on serological testing, supplemented by data from all available HBV registries in Greenland to determine changes in HBV status over time. Information on morbidity and mortality was obtained from the Patient Discharge Registry, the Cancer Registry, and the Central Registration System. Sex, age, ethnicity, and period-adjusted incidence rate ratios (IRRs) were estimated using Poisson regression. World standardized rates were derived from these and World Health Organization data. RESULTS The 650 chronically HBV-infected persons had higher rates of hepatocellular carcinoma (adjusted IRR = 8.70; 95% CI = 2.06 to 36.7), liver disease (adjusted IRR = 5.73, 95% CI = 3.52 to 9.34), and all-cause mortality (adjusted IRR = 1.47; 95% CI = 1.21 to 1.79) than the 5160 HBV-negative persons. However, the world standardized incidence rates of hepatocellular carcinoma (38.5 cancers per 100 000 person-years) and cirrhosis (24 cases per 100 000 person-years) among chronically HBV-infected persons were low compared with results from population-based studies from countries with low, intermediate, and high rates of endemic HBV infection. CONCLUSION The relatively low incidence of hepatocellular carcinoma and other HBV-related morbidity among chronic HBV-infected persons in Greenland suggest a more benign course of HBV among the Greenlandic Inuit than in populations in other parts of the world.
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Affiliation(s)
- Malene L Børresen
- Department of Epidemiology Research, Statens Serum Institut, Ørestads Boulevard 5, Copenhagen, Denmark.
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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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Identification of Single Nucleotide Polymorphisms in the Nicastrese Goat and Sardinia Sheep Mannose-Binding Lectin. Biochem Genet 2011; 50:73-83. [DOI: 10.1007/s10528-011-9461-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2010] [Accepted: 05/12/2011] [Indexed: 11/26/2022]
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30
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Plasma proteomic profiles of bovine growth hormone transgenic mice as they age. Transgenic Res 2011; 20:1305-20. [PMID: 21365322 DOI: 10.1007/s11248-011-9499-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2010] [Accepted: 02/20/2011] [Indexed: 12/17/2022]
Abstract
Attenuation of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis results in extended lifespan in many organisms including mice. Conversely, GH transgenic mice have excess GH action and die prematurely. We have studied bovine (b) GH transgenic mice (n = 9) and their wild type (WT) littermates (n = 8) longitudinally and have determined several age-related changes. Compared to WT mice, bGH mice lost fat mass, became hypoglycemic and had lower insulin levels at older ages despite being hyperinsulinemic when young. To examine plasma protein differences in bGH mice relative to controls, samples at 2, 4, 8, 12 and 16 months of age were analyzed by two-dimensional gel electrophoresis followed by identification using mass spectrometry. We found several differences in plasma proteins of bGH mice compared to controls, including increased apolipoprotein E (five isoforms), haptoglobin (four isoforms) and mannose-binding protein-C (one out of three isoforms), and decreased transthyretin (six isoforms). In addition, clusterin (two out of six isoforms) and haptoglobin (four isoforms) were up-regulated in bGH mice as a function of age. Finally, alpha-2 macroglobulin (seven isoforms) was altered in an isoform-specific manner with two isoforms increased and two decreased in bGH mouse plasma compared to controls. In conclusion, identification of these proteins suggests that bGH mice exhibit an increased inflammatory state with an adverse lipid profile, possibly contributing to their diminished life expectancy. Also, these newly discovered plasma proteins may be indicative or 'biomarkers' of a shortened lifespan.
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The role of mannose-binding lectin gene polymorphisms in susceptibility to HIV-1 infection in Southern Brazilian patients. AIDS 2011; 25:411-8. [PMID: 21192229 DOI: 10.1097/qad.0b013e328342fef1] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
OBJECTIVE This study investigates the role of mannose-binding lectin (MBL) in the susceptibility to HIV-1 infection analyzing polymorphisms located at the MBL2 promoter and exon 1 regions. MATERIALS AND METHODS The prevalence of MBL2 variant alleles was investigated in 410 HIV-1-infected patients from the South Brazilian HIV cohort and in 345 unexposed uninfected healthy individuals. The promoter variants were genotyped using polymerase chain reaction with sequence-specific primers (PCR-SSP) and exon 1 variants were analyzed by real-time PCR using a melting temperature assay and were confirmed by PCR-restriction fragment length polymorphism (RFLP). MBL2 genotypic and allelic frequencies were compared between HIV-1-infected patients and controls using the chi-squared tests. RESULTS The analyses were performed subdividing the individuals according to their ethnic origin. Among Euro-derived individuals a higher frequency of the LX/LX genotype was observed in patients when compared to controls (P < 0.001). The haplotypic analysis also showed a higher frequency of the haplotypes associated with lower MBL levels among HIV-1-infected patients (P = 0.0001). Among Afro-derived individuals the frequencies of LY/LY and HY/HY genotypes were higher in patients when compared to controls (P = 0.009 and P = 0.02). CONCLUSIONS An increased frequency of MBL2 genotypes associated with low MBL levels was observed in Euro-derived patients, suggesting a potential role for MBL in the susceptibility to HIV-1 infection in Euro-derived individuals.
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Filho RM, Carmo RF, Catsman C, Souza C, Silva A, Moura P, Tenorio AL, Vasconcelos LRS, Cavalcanti MDSM, Pereira LMMB. High frequency of variant alleles of the mannose-binding lectin 2 (MBL2) gene are associated with patients infected by hepatitis B virus. Viral Immunol 2011; 23:449-53. [PMID: 20712490 DOI: 10.1089/vim.2009.0105] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Patients with hepatitis B virus (HBV) infection may develop severe chronic liver disease. Carriers of HBV have an increased risk of developing cirrhosis, hepatic decompensation, and hepatocellular carcinoma. Worldwide an estimated 350 million people are infected with HBV, and 15-40% will develop serious sequelae in their lifetime. In our study we investigated the association of single nucleotide polymorphisms (SNPs) in the first exon and promoter region of the mannose-binding lectin gene 2 (MBL2) situated on chromosome 10, with susceptibility to HBV infection. One-hundred and two patients infected with HBV were included in this study, and 232 uninfected individuals were used as healthy controls. Genotyping of the first exon (alleles A/O) was performed using a melting temperature assay. Genotyping of the promoter region (-550 H/L; -221 Y/X) was performed using the Taqman PCR technique. In the HBV-infected group we found a significantly increased frequency of haplotypes associated with low serum MBL. Our findings may indicate that MBL has a protective role against HBV infection in the studied population.
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Kim YJ, Kim HY, Kim JS, Lee JH, Yoon JH, Kim CY, Park BL, Cheong HS, Bae JS, Kim S, Shin HD, Lee HS. Putative association of transforming growth factor-alpha polymorphisms with clearance of hepatitis B virus and occurrence of hepatocellular carcinoma in patients with chronic hepatitis B virus infection. J Viral Hepat 2010; 17:518-526. [PMID: 19780938 DOI: 10.1111/j.1365-2893.2009.01205.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Previous studies showed that several genetic polymorphisms might influence the clinical outcome of chronic hepatitis B virus (HBV) infection, including HBV clearance or development of hepatocellular carcinoma (HCC). The aim of this study was to determine whether polymorphisms of the transforming growth factor-alpha (TGF-alpha) gene are associated with clinical outcome of HBV infection. A total of 1096 Korean subjects having either present or past evidence of HBV infection were prospectively enrolled between January 2001 and August 2003. Among 16 genetic variants in TGFA gene, nine variants were genotyped using TaqMan assay and the genetic association with HBV clearance and HCC occurrence was analysed. Statistical analyses revealed that TGFA+103461T>C, TGFA+106151C>G and TGFA-ht2 were marginally associated with clearance of HBV infection. However, only TGFA-ht2 retained significance after multiple correction (OR = 0.39, P(corr) = 0.007 in recessive model). Although no variants were significant after multiple correction, TGFA+88344G>A and TGFA+103461T>C were weakly associated in recessive model in the analysis of HCC occurrence. In addition, Cox relative hazards model also revealed that TGFA+88344G>A was associated with onset age of HCC occurrence in subjects (RH = 1.46, P(corr) = 0.04). TGF-alpha polymorphisms might be an important factor in immunity, progression of inflammatory process and carcinogenesis, which explains the variable outcome of HBV infection at least in part. Further biological evidence is warranted in the future to support these suggestive associations.
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Affiliation(s)
- Y J Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Chongno Gu, Seoul, Korea
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He XX, Chang Y, Jiang HJ, Tang F, Meng FY, Xie QH, Li PY, Song YH, Lin JS. Persistent effect of IFNAR-1 genetic polymorphism on the long-term pathogenesis of chronic HBV infection. Viral Immunol 2010; 23:251-257. [PMID: 20565290 DOI: 10.1089/vim.2009.0102] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Genetic polymorphism of IFNAR-1 plays a large role in determining the clearance or chronicity after hepatitis B virus (HBV) exposure. However, it is not clear whether type I interferon receptor-1 (IFNAR-1) variations continuously exert their effects to influence the final outcomes following HBV chronicity, including acute-on-chronic hepatitis B liver failure (ACLF-HBV), chronic hepatitis B (CHB), liver cirrhosis (LC), and hepatocellular carcinoma (HCC). Here we report that these four potential outcomes of chronic HBV infection are strongly associated with IFNAR-1 polymorphisms through a hospital-based case-control study of 663 cases. ACLF-HBV and HCC were each compared with CHB+LC. In comparison with the G/G genotype, the C/G and C/C genotypes at both single-nucleotide polymorphism (SNP) sites (rs1012335 and rs2257167) showed significant susceptibility to ACLF-HBV (the highest odds ratio [OR] reached 2.374; 95% CI = 1.488, 3.788; p < 0.001 for the C/G genotype at rs2257167), as well as HCC (OR = 2.475; 95% CI = 1.435, 4.426; p < 0.001 for the C/C genotype at rs1012335). The C allele at both loci was a susceptibility allele for ACLF-HBV and HCC, with the highest ORs reaching 1.653 (95% CI = 1.233, 2.216; p < 0.01 at rs1012335) in the ACLF-HBV group, and 1.659 (95% CI = 1.274, 2.159; p < 0.01 at rs1012335) in the HCC group. A strongly linked disequilibrium was also found within these two alleles (p < 0.001). Our research indicates that genetic polymorphisms of IFNAR-1 not only contribute to the determination of clearance or chronicity in the early stages of HBV exposure, but they also persistently influence pathogenesis over the long-term process of chronic HBV infection.
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Affiliation(s)
- Xing-Xing He
- Institute of Liver Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Davila S, Froeling FEM, Tan A, Bonnard C, Boland GJ, Snippe H, Hibberd ML, Seielstad M. New genetic associations detected in a host response study to hepatitis B vaccine. Genes Immun 2010; 11:232-8. [PMID: 20237496 DOI: 10.1038/gene.2010.1] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The immune response to hepatitis B vaccination differs greatly among individuals, with 5-10% of healthy people failing to produce protective levels of antibodies. Several factors have been implicated in determining this response, chiefly individual genetic variation and age. Aiming to identify genes involved in the response to hepatitis B vaccination, a two-stage investigation of 6091 single-nucleotide polymorphisms (SNPs) in 914 immune genes was performed in an Indonesian cohort of 981 individuals showing normal levels of anti-HBs versus 665 individuals displaying undetectable levels of anti-HBs 18 months after initial dose of the vaccine. Of 275 SNPs identified in the first stage (476 normal/372 nonresponders) with P<0.05, significant associations were replicated for 25 polymorphisms in 15 genes (503 normal/295 nonresponders). We validated previous findings (HLA-DRA, rs5000563, P-value combined=5.57 x 10(-10); OR (95%CI)=0.61 (0.52-0.71)). In addition, we detected a new association outside of the human leukocyte antigen loci region that passed correction for multiple testing. This SNP is in the 3' downstream region of FOXP1, a transcription factor involved in B-cell development (P-value combined=9.2 x 10(-6); OR (95%CI)=1.38 (1.2-1.6)).These findings might help to understand the biological reasons behind vaccine failure and other aspects of variation in the immune responses of healthy individuals.
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Affiliation(s)
- S Davila
- Genome Institute of Singapore, Singapore
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Chen DQ, Zeng Y, Zhou J, Yang L, Jiang S, Huang JD, Lu L, Zheng BJ. Association of candidate susceptible loci with chronic infection with hepatitis B virus in a Chinese population. J Med Virol 2010; 82:371-8. [PMID: 20087947 DOI: 10.1002/jmv.21716] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
A number of genetic loci have been proposed to be associated with persistent hepatitis B virus (HBV) infection. This study aimed to evaluate the association and interaction of susceptible genes with HBV persistence in a Chinese population. A total of 17 polymorphisms in 9 candidate genes were studied in 361 Chinese chronic hepatitis B patients and 304 patients who recovered spontaneously. Distributions of susceptible polymorphisms were examined in healthy Chinese and Caucasian populations. Gene-gene interactions were tested by the multifactor dimensionality reduction (MDR) method. The TNF -308 G/G genotype and G allele, IL-10RB codon 47 A allele, and MCP-1 -2518 G/G genotype and G allele were more frequent in patients than controls (P < 0.01, after multiple corrections Pc < 0.05), while the frequencies of TNF -308 A/G genotype and IL-10 -592 A/A genotype were significantly higher in controls than in the patient group (Pc < 0.05). The frequencies of the risk allele MCP-1 -2518 G and CTLA4 6230 G were much higher in Chinese than in the Caucasian groups (P < 0.001). An interaction between CCR5 -2459, TNFA -863, IL-10RB codon 47, and MCP-1 -2518 was detected by MDR (P = 0.001). The results indicate that genetic determinants may affect the outcome of HBV infection in both independent and synergic manners. J. Med. Virol. 82:371-378, 2010. (c) 2010 Wiley-Liss, Inc.
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Affiliation(s)
- Ding-Qiang Chen
- Department of Microbiology, The University of Hong Kong, Hong Kong SAR, China
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Fletcher GJ, Gnanamony M, Samuel P, Ismail AM, Kannangai R, Daniel D, Eapen CE, Abraham P. Association of mannose-binding lectin polymorphisms and HBV outcome in a South Indian population. Int J Immunogenet 2010; 37:177-84. [PMID: 20193030 DOI: 10.1111/j.1744-313x.2010.00908.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Mannose binding lectin (MBL) is an important innate immune system pattern recognition molecule. The MBL gene polymorphisms are reported to play a crucial role in outcome of hepatitis B virus (HBV) infection. In this study, we ascertained the association of MBL genotypes with HBV outcome in a South Indian population. The MBL gene polymorphisms at codons 52, 54 and 57 of exon I, and promoter polymorphisms at -221 were typed by polymerase chain reaction-sequence specific primer in spontaneously recovered and in chronic HBV group. The allele frequency of codon 52 'C' was significantly higher in chronic HBV group than in the recovered group (98.5% vs. 93.6%; P = 0.003) and codon 52 'T' was significantly higher in recovered group than in the chronic group (6.4% vs. 1.5%; P = 0.003). In multivariate analysis, after adjusting for age, sex and state of origin, codon 52 'CC' and 'CT' genotypes were significantly associated with chronicity and recovery respectively [odds ratio (OR), 0.25; 95% confidence interval (CI), 0.08-0.80, P = 0.02] in co-dominant analyzing models. This was re-affirmed in analysis performed exclusively on Tamil Nadu subjects (OR, 0.23; 95% CI, 0.06-0.93, P = 0.039). The frequency of low/none haplotype (XY/O) was significantly higher in recovered group than in chronic group (15.6% vs 7.5%) and associated with spontaneous recovery (OR, 2.28; 95% CI, 1.04-4.99, P = 0.035). Our results provide preliminary evidence that inheritance of codon 52 genotypes and XY/O haplotype associated with low MBL level substantially determine the outcome of HBV infection in a sympatrically isolated South Indian population.
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Affiliation(s)
- G J Fletcher
- Department of Gastrointestinal Sciences, Christian Medical College, Vellore, Tamil Nadu, India
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Carmolli M, Duggal P, Haque R, Lindow J, Mondal D, Petri WA, Mourningstar P, Larsson CJ, Sreenivasan M, Khan S, Kirkpatrick BD. Deficient serum mannose-binding lectin levels and MBL2 polymorphisms increase the risk of single and recurrent Cryptosporidium infections in young children. J Infect Dis 2009; 200:1540-7. [PMID: 19827946 DOI: 10.1086/606013] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Mannose-binding lectin (MBL) is an evolutionarily conserved protein that functions in human innate immunity by binding to microbial surfaces and promoting opsonophagocytosis. MBL has been shown to bind to Cryptosporidium sporozoites, and earlier work has suggested that the protective role of MBL may be most important in childhood. We evaluated the association between polymorphisms in the MBL gene (MBL2), serum MBL deficiency, and infection with Cryptosporidium, Entamoeba histolytica, and Giardia intestinalis in children. A large, prospective cohort of Bangladeshi preschool children was followed up for >3 years. Clinical outcomes, serum MBL levels, and MBL2 polymorphisms and haplotypes were determined. Statistically significant associations with E. histolytica and G. intestinalis were not found. Serum MBL deficiency, polymorphisms in the -221 promoter region, and the YO/XA MBL2 haplotype were strongly associated with Cryptosporidium infections, particularly recurrent infection. Children with multiple infections with Cryptosporidium were more likely to be MBL deficient (odds ratio [OR], 10.45), carry the -221 promoter variant (OR, 4.02), and have the YO/XA haplotype (OR, 4.91). We have identified a potentially important component of the human innate immune response to Cryptosporidum infection. Further work is needed to evaluate the mechanism of protection of MBL in Cryptosporidium infection.
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Affiliation(s)
- Marya Carmolli
- University of Vermont College of Medicine, Unit of Infectious Diseases, Burlington, VT, USA
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Complement activation and disease: protective effects of hyperbilirubinaemia. Clin Sci (Lond) 2009; 118:99-113. [DOI: 10.1042/cs20080540] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Complement, an important effector mechanism of the immune system, is an enzymatic cascade of approx. 30 serum proteins leading to the amplification of a specific humoral response. It can be activated through the classical or alternative pathways, or through the mannose-binding lectin pathway. The activation of the classical pathway is initiated by the binding of the C1 component to antigen-bound antibodies, known as immunocomplexes. C1 is a complex of one molecule of C1q, two molecules of C1r and two molecules of C1s. C1q contains three copies of a Y-shaped fundamental unit with globular heads included in its structure, which play a major role in the interaction with the Fc portion of immunoglobulins. Deficient or exacerbated activation of the complement system leads to diseases of variable severity, and pharmacological inhibition of the complement system is considered as a therapeutic strategy to ameliorate the inflammatory effects of exacerbated complement activation. Bilirubin is a product of haem degradation by the concerted action of haem oxygenase, which converts haem into biliverdin, and biliverdin reductase, which reduces biliverdin to UCB (unconjugated bilirubin). UCB exerts both cytoprotective and cytotoxic effects in a variety of tissues and cells, acting either as an antioxidant at low concentrations or as an oxidant at high concentrations. In the present review, we describe in detail the anti-complement properties of bilirubin, occurring at levels above the UCB concentrations found in normal human serum, as a beneficial effect of potential clinical relevance. We provide evidence that UCB interferes with the interaction between C1q and immunoglobulins, thus inhibiting the initial step in the activation of complement through the classical pathway. A molecular model is proposed for the interaction between UCB and C1q.
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Ruseva M, Kolev M, Dagnaes-Hansen F, Hansen SB, Takahashi K, Ezekowitz A, Thiel S, Jensenius JC, Gadjeva M. Mannan-binding lectin deficiency modulates the humoral immune response dependent on the genetic environment. Immunology 2009; 127:279-88. [PMID: 19476514 PMCID: PMC2691793 DOI: 10.1111/j.1365-2567.2008.03016.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2008] [Revised: 11/06/2008] [Accepted: 11/12/2008] [Indexed: 01/25/2023] Open
Abstract
Mannan-binding lectin (MBL) is a plasma protein implicated in innate immune defence against a broad range of microorganisms, including viruses. It is also thought that MBL plays a role in the recruitment of the specific clonal immune response. This was studied by injecting soluble hepatitis B surface antigen (HBsAg) intravenously into mice deficient in both MBL-A and MBL-C (MBL DKO mice). The MBL DKO animals on mixed genetic background (SV129EvSv x C57BL/6) produced higher antibody titres than the wild-type littermates. After primary challenge with the antigen the immunoglobulin M anti-HBsAg antibody titres were threefold higher in the MBL DKO mice than in the wild-type mice. Following the boost, the immunoglobulin G anti-HBsAg antibody titres were 10-fold higher in the MBL DKO mice, suggesting that MBL plays a role in a negative feedback regulation of adaptive immunity. However, the modulating effect of MBL was dependent on the genetic environment. The MBL DKO mice backcrossed on a C57BL/6 background showed the opposite response with the MBL DKO mice now producing fewer antibodies than the wild-type animals, whereas MBL deficiency in mice with the SV129EvSv background did not show any effect in antibody production. These findings indicate that the modifying effect of MBL on the humoral immune response is influenced by the genetic environment.
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Affiliation(s)
- Marieta Ruseva
- Department of Medical Microbiology and Immunology, University of Aarhus, Denmark
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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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Maenz C, Loscher C, Iwanski A, Bruns M. Inhibition of duck hepatitis B virus infection of liver cells by combined treatment with viral e antigen and carbohydrates. J Gen Virol 2009; 89:3016-3026. [PMID: 19008388 DOI: 10.1099/vir.0.2008/003541-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The e antigen (eAg) of duck hepatitis B virus (DHBV) is a glycosylated secretory protein with a currently unknown function. We concentrated this antigen from the supernatants of persistently infected primary duck liver cell cultures by ammonium sulphate precipitation, adsorption chromatography over concanavalin A Sepharose, preparative isoelectric focusing and molecular sieve chromatography. The combined treatment of duck liver cells with DHBV eAg (DHBe) concentrate and alpha-methyl-d-mannopyranoside strongly inhibited DHBV replication at de novo infection. When DHBe was added to non-infected primary duck liver cells, it was found to be associated with liver sinusoidal endothelial cells. This binding could be inhibited by the addition of alpha-methyl-d-mannopyranoside and other sugar molecules. The inhibitory effect of DHBe on infection could play a role in maintaining viral persistence.
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Affiliation(s)
- Claudia Maenz
- Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie an der Universität Hamburg, 20251 Hamburg, Germany
| | - Christine Loscher
- Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie an der Universität Hamburg, 20251 Hamburg, Germany
| | - Alicja Iwanski
- Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie an der Universität Hamburg, 20251 Hamburg, Germany
| | - Michael Bruns
- Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie an der Universität Hamburg, 20251 Hamburg, Germany
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Zhou J, Smith DK, Lu L, Poon VKM, Ng F, Chen DQ, Huang JD, Yuen KY, Cao KY, Zheng BJ. A non-synonymous single nucleotide polymorphism in IFNAR1 affects susceptibility to chronic hepatitis B virus infection. J Viral Hepat 2009; 16:45-52. [PMID: 18761606 DOI: 10.1111/j.1365-2893.2008.01040.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The type I interferon (IFN-alpha/beta) receptor 1 (IFNAR1) mediates the potent antiviral and immuno-regulatory effects of IFN-alpha/beta that are believed to be pivotal to eradicate hepatitis B virus (HBV) infection. IFNAR1 promoter polymorphisms (at -568/-77) have been shown to be associated with susceptibility to chronic HBV infection; however, whether these markers are genetic determinants of HBV infection remains unknown. The functional significance of promoter -568/-77 polymorphisms was assessed by mutagenesis and luciferase assays. Sequencing and restriction fragment length polymorphisms in 328 chronic HBV patients, 130 spontaneous resolvers and 148 healthy blood donors identified other polymorphism at IFNAR1 open reading frame. IFNAR1 expression levels in peripheral blood cells were detected by flow cytometry. We found that the -568/-77 promoter variants were unlikely to affect transcription levels. A C/G single nucleotide polymorphism, in strong linkage disequilibrium with the promoter polymorphisms, was found in the coding sequence of IFNAR1 (nt19158). This resulted in a nonsynonymous substitution in the extracellular region of IFNAR1 protein and correlated with susceptibility to chronic HBV infection. Bioinformatic analysis suggested decreased stability of the IFNAR1 protein. Chronic HBV patients with the 19158C/C genotype (Leu141) exhibited higher IFNAR1 protein expression levels in peripheral blood monocytes than those with the 19158G/G genotype (Val141). In conclusion, IFNAR1 19158C/G polymorphism is primarily associated with susceptibility to chronic HBV infection.
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Affiliation(s)
- J Zhou
- Department of Microbiology, The University of Hong Kong, Hong Kong, China
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Yang ZT, Zhang XX, Kong XF, Zhang DH, Zhang SY, Jiang JH, Gong QM, Jin GD, Lu ZM. Polymorphisms of microsomal triglyceride transfer protein in different hepatitis B virus-infected patients. World J Gastroenterol 2008; 14:5454-60. [PMID: 18803359 PMCID: PMC2744166 DOI: 10.3748/wjg.14.5454] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To identify the two polymorphisms of microsomal triglyceride transfer protein (MTP) gene in the Chinese population and to explore their correlation with both hepatitis B virus (HBV) self-limited infection and persistent infection.
METHODS: A total of 316 subjects with self-limited HBV infection and 316 patients with persistent HBV infection (195 subjects without familial history), matched with age and sex, from the Chinese Han population were enrolled in this study. Polymorphisms of MTP at the promoter region -493 and at H297Q were determined by the allele specific polymerase chain reaction (PCR).
RESULTS: The ratio of males to females was 2.13:1 for each group and the average age in the self-limited and chronic infection groups was 38.36 and 38.28 years, respectively. None of the allelic distributions deviated significantly from that predicted by the Hardy-Weinberg equilibrium. There was a linkage disequilibrium between H297Q and -493G/T (D’ = 0.77). As the χ2 test was used, the genotype distribution of MTP-493G/T demonstrated a significant difference between the self-limited infection group and the entire chronic group or the chronic patients with no family history (χ2 = 8.543, P = 0.015 and χ2 = 7.199, P = 0.019). The allele distribution at the MTP-493 position also demonstrated a significant difference between the study groups without family history (χ2 = 6.212, P = 0.013). The T allele emerged as a possible protective factor which may influence the outcomes of HBV infection (OR: 0.59; 95% CI: 0.389-0.897).
CONCLUSION: The polymorphism of the MTP gene, T allele at -493, may be involved in determining the HBV infection outcomes, of which the mechanism needs to be further investigated.
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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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Brown EE, Zhang M, Zarin-Pass R, Bernig T, Tseng FC, Xiao N, Yeager M, Edlin BR, Chanock SJ, O'Brien TR. MBL2 and hepatitis C virus infection among injection drug users. BMC Infect Dis 2008; 8:57. [PMID: 18452612 PMCID: PMC2413243 DOI: 10.1186/1471-2334-8-57] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2007] [Accepted: 05/01/2008] [Indexed: 11/10/2022] Open
Abstract
Background Genetic variations in MBL2 that reduce circulating levels and alter functional properties of the mannose binding lectin (MBL) have been associated with many autoimmune and infectious diseases. We examined whether MBL2 variants influence the outcome of hepatitis C virus (HCV) infection. Methods Participants were enrolled in the Urban Health Study of San Francisco Bay area injection drug users (IDU) during 1998 through 2000. Study subjects who had a positive test for HCV antibody were eligible for the current study. Participants who were positive for HCV RNA were frequency matched to those who were negative for HCV RNA on the basis of ethnicity and duration of IDU. Genotyping was performed for 15 single nucleotide polymorphisms in MBL2. Statistical analyses of European American and African American participants were conducted separately. Results The analysis included 198 study subjects who were positive for HCV antibody, but negative for HCV RNA, and 654 IDUs who were positive for both antibody and virus. There was no significant association between any of the genetic variants that cause MBL deficiency and the presence of HCV RNA. Unexpectedly, the MBL2 -289X promoter genotype, which causes MBL deficiency, was over-represented among European Americans who were HCV RNA negative (OR = 1.65, 95% CI 1.05–2.58), although not among the African Americans. Conclusion This study found no association between genetic variants that cause MBL deficiency and the presence of HCV RNA. The observation that MBL2 -289X was associated with the absence of HCV RNA in European Americans requires validation.
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Affiliation(s)
- Elizabeth E Brown
- Division of Cancer Epidemiology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
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Capparelli R, Parlato M, Amoroso MG, Roperto S, Marabelli R, Roperto F, Iannelli D. Mannose-binding lectin haplotypes influence Brucella abortus infection in the water buffalo (Bubalus bubalis). Immunogenetics 2008; 60:157-65. [PMID: 18330558 DOI: 10.1007/s00251-008-0284-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2008] [Accepted: 02/12/2008] [Indexed: 10/22/2022]
Abstract
A case-control study established that the haplotype pair HYA/HYA at the MBL (mannose binding lectin) locus of water buffalo is associated with resistance to Brucella abortus infection (P < 10(-7)) and the haplotype pairs LYD/LYD with susceptibility to the same pathogen (P < 10(-7)). The subjects included in the present study were tested twice-at a 1-month interval-for the presence of anti-B. abortus antibodies in the serum by agglutination, complement fixation and flow cytometry. Cases (335 subjects) included animals consistently positive to all these tests; controls (335 subjects) comprised animals exposed yet negative by the same tests. The serum from genetically resistant subjects displayed in vitro significantly higher antibacterial activity compared to the serum from genetically susceptible subjects, lending biological significance to the results from the association study. Inhibition of the antibacterial activity following heat treatment of the serum, addition of specific MBL inhibitors (EDTA, mannose, N-acetyl-D: -glucosamine) or anti-human MBL antiserum provide convincing evidence that the antibacterial activity present in the serum results from the interaction between MBL and B. abortus. A replication study (comprising 100 cases and 100 controls) confirmed the results from the original study.
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Affiliation(s)
- R Capparelli
- Faculty of Biotechnological Sciences, University of Naples Federico II, Naples, Italy
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Ratnam D, Visvanathan K. New concepts in the immunopathogenesis of chronic hepatitis B: the importance of the innate immune response. Hepatol Int 2008; 2:12-8. [PMID: 19669294 DOI: 10.1007/s12072-008-9067-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2007] [Accepted: 01/29/2008] [Indexed: 02/07/2023]
Abstract
Acute and chronic infection with hepatitis B virus (HBV) is associated with an increased risk of developing liver disease including cirrhosis, decompensated liver disease, and hepatocellular carcinoma. The clinical presentation and natural history of HBV infection is mediated through complex interactions between the virus and the host immune response. HBV is not directly cytopathic to heptocytes; however, the interaction between the virus and the host immune response plays a central role in the pathogenesis of necroinflammation and liver fibrosis. Emerging data from immunopathogenesis studies in animal models and in vitro studies of liver biopsies from patients with chronic hepatitis B demonstrate a potentially important interaction between hepatitis B e antigen, HBV, and components of the innate immune response including Toll-like receptors, Kupffer cells, natural killer T-cells, and dendritic cells. These findings suggest that the innate immune response has an important role in influencing the outcome of acute and chronic HBV infection. The current knowledge regarding the interaction between HBV and components of the innate immune response during acute and chronic HBV infection is reviewed.
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Affiliation(s)
- Dilip Ratnam
- Innate Immunity Laboratory, Centre for Inflammatory Diseases, Department of Medicine, Monash University, Level 5, Block E, 246 Clayton Rd., Clayton, VIC, 3168, Australia,
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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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