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Murugaiah V, Varghese PM, Beirag N, DeCordova S, Sim RB, Kishore U. Complement Proteins as Soluble Pattern Recognition Receptors for Pathogenic Viruses. Viruses 2021; 13:v13050824. [PMID: 34063241 PMCID: PMC8147407 DOI: 10.3390/v13050824] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 04/28/2021] [Indexed: 12/11/2022] Open
Abstract
The complement system represents a crucial part of innate immunity. It contains a diverse range of soluble activators, membrane-bound receptors, and regulators. Its principal function is to eliminate pathogens via activation of three distinct pathways: classical, alternative, and lectin. In the case of viruses, the complement activation results in effector functions such as virion opsonisation by complement components, phagocytosis induction, virolysis by the membrane attack complex, and promotion of immune responses through anaphylatoxins and chemotactic factors. Recent studies have shown that the addition of individual complement components can neutralise viruses without requiring the activation of the complement cascade. While the complement-mediated effector functions can neutralise a diverse range of viruses, numerous viruses have evolved mechanisms to subvert complement recognition/activation by encoding several proteins that inhibit the complement system, contributing to viral survival and pathogenesis. This review focuses on these complement-dependent and -independent interactions of complement components (especially C1q, C4b-binding protein, properdin, factor H, Mannose-binding lectin, and Ficolins) with several viruses and their consequences.
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Affiliation(s)
- Valarmathy Murugaiah
- Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK; (V.M.); (P.M.V.); (N.B.); (S.D.)
| | - Praveen M. Varghese
- Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK; (V.M.); (P.M.V.); (N.B.); (S.D.)
| | - Nazar Beirag
- Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK; (V.M.); (P.M.V.); (N.B.); (S.D.)
| | - Syreeta DeCordova
- Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK; (V.M.); (P.M.V.); (N.B.); (S.D.)
| | - Robert B. Sim
- Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK;
| | - Uday Kishore
- Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK; (V.M.); (P.M.V.); (N.B.); (S.D.)
- Correspondence: or
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Boldt ABW, Oliveira-Toré CDF, Kretzschmar GC, Weinschutz Mendes H, Stinghen ST, Andrade FA, Bumiller-Bini V, Gonçalves LB, Braga ACDM, Stahlke EVRS, Velavan TP, Thiel S, de Messias-Reason IJT. Hepatitis B Virus Infection Among Leprosy Patients: A Case for Polymorphisms Compromising Activation of the Lectin Pathway and Complement Receptors. Front Immunol 2021; 11:574457. [PMID: 33643280 PMCID: PMC7904891 DOI: 10.3389/fimmu.2020.574457] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 12/24/2020] [Indexed: 01/05/2023] Open
Abstract
Thousands of leprosy patients not only suffer from physical deformities, but also either have or have had hepatitis B virus (HBV) coinfection. Polymorphisms of the complement system modulate susceptibility to leprosy, but genetic susceptibility to past or present HBV infection is unknown. We used sequencing and multiplex sequence-specific PCR to genotype 72 polymorphisms of seven genes (MBL2, FCN1, FCN2, FCN3, MASP1, MASP2, C3) encoding components of the lectin pathway, and two genes encoding complement receptors (CR1, VSIG4) in 190 patients, of which 74 were positive for HBsAg and/or anti-HBc (HBV+, 93.2% with a resolved infection) and 116 lepromatous patients, and 408 HBV-blood donors. In addition, we tested for levels of proteins of the lectin pathway. We found no difference between serum concentrations of mannan-binding lectin (MBL), MBL-associated serine proteins (MASP-1, MASP-2, MASP-3, MAp44), ficolin-3 (FCN-3), soluble complement receptor 1 (sCR1) and MBL mediated C4 activation, measured by ELISA or TRIFMA in up to 167 HBV+ and HBV- patients. Haplotypes lowering protein levels or encoding dysfunctional proteins increased susceptibility to HBV infection: MBL2*LYQC (OR = 3.4, p = 0.02), MASP1*AC_CC (OR = 4.0, p = 0.015) and MASP2*1C2-l (OR = 5.4, p = 0.03). Conversely, FCN1*3C2 haplotype, associated with higher gene expression, was protective (OR = 0.56, P = 0.033). Other haplotypes associated with HBV susceptibility were: MASP2*2B1-i (OR = 19.25, P = 0.003), CR1*3A (OR = 2.65, P = 0.011) and VSIG4*TGGRCG (OR = 12.55, P = 0.014). Some polymorphisms in ficolin genes associated with lower protein levels increased susceptibility to leprosy/HBV infection: FCN*1 (OR = 1.66, P = 0.029), FCN2*GGGCAC (OR = 6.73, P = 0.008), and FCN3*del_del_C (OR = 12.54, P = 0.037), and to lepromatous disease/HBV infection: FCN2*TA (OR = 2.5, P = 0.009), whereas FCN2*MAG was associated with increased FCN-2 expression and resistance against coinfection (OR = 0.29, P = 0.026). These associations were independent of demographic factors and did not increase susceptibility to leprosy per se, except MASP2*1C2-l. Associations for FCN2, FCN3, MASP1, MASP2, and VSIG4 variants were also independent of each other. In conclusion, polymorphisms compromising activation of the lectin pathway of complement increase susceptibility to HBV infection, with ficolin polymorphisms playing a major role in modulating the susceptibility among leprosy patients.
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Affiliation(s)
- Angelica Beate Winter Boldt
- Laboratory of Human Molecular Genetics, Postgraduate Program in Genetics, Department of Genetics, Federal University of Paraná, Curitiba, Brazil
- Laboratory of Molecular Immunopathology, Postgraduate Program in Internal Medicine and Health Sciences, Department of Clinical Pathology, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil
| | - Camila de Freitas Oliveira-Toré
- Laboratory of Molecular Immunopathology, Postgraduate Program in Internal Medicine and Health Sciences, Department of Clinical Pathology, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil
| | - Gabriela Canalli Kretzschmar
- Laboratory of Human Molecular Genetics, Postgraduate Program in Genetics, Department of Genetics, Federal University of Paraná, Curitiba, Brazil
| | - Hellen Weinschutz Mendes
- Laboratory of Molecular Immunopathology, Postgraduate Program in Internal Medicine and Health Sciences, Department of Clinical Pathology, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil
| | - Sérvio Túlio Stinghen
- Laboratory of Molecular Immunopathology, Postgraduate Program in Internal Medicine and Health Sciences, Department of Clinical Pathology, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil
| | - Fabiana Antunes Andrade
- Laboratory of Molecular Immunopathology, Postgraduate Program in Internal Medicine and Health Sciences, Department of Clinical Pathology, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil
| | - Valéria Bumiller-Bini
- Laboratory of Human Molecular Genetics, Postgraduate Program in Genetics, Department of Genetics, Federal University of Paraná, Curitiba, Brazil
| | - Letícia Boslooper Gonçalves
- Laboratory of Molecular Immunopathology, Postgraduate Program in Internal Medicine and Health Sciences, Department of Clinical Pathology, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil
| | - Anna Carolina de Moraes Braga
- Laboratory of Molecular Immunopathology, Postgraduate Program in Internal Medicine and Health Sciences, Department of Clinical Pathology, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil
| | | | - Thirumalaisamy P. Velavan
- Institute of Tropical Medicine, Universitätsklinikum Tübingen, Tübingen, Germany
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam
- Faculty of Medicine, Duy Tan University, Da Nang, Vietnam
| | - Steffen Thiel
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Iara José Taborda de Messias-Reason
- Laboratory of Molecular Immunopathology, Postgraduate Program in Internal Medicine and Health Sciences, Department of Clinical Pathology, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil
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Murugaiah V, Tsolaki AG, Kishore U. Collectins: Innate Immune Pattern Recognition Molecules. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1204:75-127. [PMID: 32152944 PMCID: PMC7120701 DOI: 10.1007/978-981-15-1580-4_4] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Collectins are collagen-containing C-type (calcium-dependent) lectins which are important pathogen pattern recognising innate immune molecules. Their primary structure is characterised by an N-terminal, triple-helical collagenous region made up of Gly-X-Y repeats, an a-helical coiled-coil trimerising neck region, and a C-terminal C-type lectin or carbohydrate recognition domain (CRD). Further oligomerisation of this primary structure can give rise to more complex and multimeric structures that can be seen under electron microscope. Collectins can be found in serum as well as in a range of tissues at the mucosal surfaces. Mannanbinding lectin can activate the complement system while other members of the collectin family are extremely versatile in recognising a diverse range of pathogens via their CRDs and bring about effector functions designed at the clearance of invading pathogens. These mechanisms include opsonisation, enhancement of phagocytosis, triggering superoxidative burst and nitric oxide production. Collectins can also potentiate the adaptive immune response via antigen presenting cells such as macrophages and dendritic cells through modulation of cytokines and chemokines, thus they can act as a link between innate and adaptive immunity. This chapter describes the structure-function relationships of collectins, their diverse functions, and their interaction with viruses, bacteria, fungi and parasites.
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Affiliation(s)
- Valarmathy Murugaiah
- College of Health and Life Sciences, Brunel University London, London, UB8 3PH, UK
| | - Anthony G Tsolaki
- College of Health and Life Sciences, Brunel University London, London, UB8 3PH, UK
| | - Uday Kishore
- College of Health and Life Sciences, Brunel University London, London, UB8 3PH, UK.
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Akgöllü E. Assessment of HLADP gene rs3128917 and rs9380343 polymorphisms in chronic HBV infection. TURKISH JOURNAL OF GASTROENTEROLOGY 2020; 30:616-623. [PMID: 31290749 DOI: 10.5152/tjg.2019.18480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND/AIMS About 400 million people worldwide have been exposed to Hepatitis B (HBV) infection. A range of 10%-15% of chronic HBV carriers may present with various liver diseases including cirrhosis and hepatic cancer. The chronicity or clearance of HBV infection is dependent on viral and genetic variables. Genome-wide association studies (GWAS) have reported that the variants of human leukocyte antigen (HLA), rs3128917 and rs9380343, are significantly related to persistent HBV infection. HLA molecules are responsible for introducing various antigens into the immune system. These variants might affect antigen presentation by influencing HLA mRNA expression, therefore, antigen presentation may not be performed properly. This study aims to assess the relationship of HLA gene variants to chronic HBV infection. MATERIALS AND METHODS HLA variants were explored in 238 chronic HBV patients and in 238 individuals with spontaneous clearance of HBV using PCR-RFLP assay. RESULTS The allele and genotype of rs9380343 polymorphism were associated with persistent HBV infection risk (allele: p=0.038, genotype: p=0.029), but rs3128917 polymorphism was not significant. Additionally, rs9380343 polymorphism was also related to increased risk of HBV infection in males (p<0.05). CONCLUSION The current study is the first report demonstrating the HLA rs9380343 polymorphism as a genetic risk factor for chronicity of HBV infection. Further independent studies are required to confirm the current findings using a larger sample size in different populations.
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Affiliation(s)
- Ersin Akgöllü
- Department of Gastroenterology, Çukurova University School of Medicine, Adana, Turkey
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Huang C, Ge T, Xia C, Zhu W, Xu L, Wang Y, Wu F, Liu F, Zheng M, Chen Z. Association of rs10204525 genotype GG and rs2227982 CC combination in programmed cell death 1 with hepatitis B virus infection risk. Medicine (Baltimore) 2019; 98:e16972. [PMID: 31464942 PMCID: PMC6736136 DOI: 10.1097/md.0000000000016972] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 07/23/2019] [Accepted: 08/05/2019] [Indexed: 12/12/2022] Open
Abstract
Single nuclear polymorphism (SNP) of programmed cell death 1 (PD-1) was reported associated with hepatitis B virus (HBV) infection, but the SNP sites studied were limited. Whether the combination of 2 or more SNP sites could better represent the relationship between PD-1 SNP and HBV infection was not studied.Eight hundred ninety-eight HBV-infected patients (222 asymptomatic carriers [AsC], 276 chronic hepatitis B, 105 acute-on-chronic liver failure, and 295 liver cirrhosis) and 364 health controls of South China were enrolled in this study. Four PD-1 SNPs (rs10204525, rs2227982, rs41386349, and rs36084323) were selected and detected by TaqMan probe. The frequency of allele, genotype, and combination of different SNPs were compared between different groups.For allele frequency analysis, G allele of rs10204525 was protective factor (odds ratio (OR) = 0.823, 95% confidence interval (CI) = 0.679-0.997, P = .046) and T allele of rs2227982 was predisposing factor (OR = 1.231, 95% CI = 1.036-1.463, P = .018) in HBV infection. When analyzed in genotype frequency, the genotype GG of rs10204525 and CC of rs2227982 were protective factor of HBV infection. Combination of rs10204525 GG and rs2227982 CC was potent protective factor of HBV infection (OR = 0.552, 95% CI = 0.356-0.857, P = .007) and was also associated with lower HBV load (OR = 0.201, 95% CI = 0.056-0.728, P = .008) in AsC. The 4 SNP sites were not associated with progression of HBV-related liver disease.Rs10204525 and rs2227982 of PD-1 associate with HBV infection and combination of the 2 SNP sites can better predict host susceptibility in HBV infection.
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Affiliation(s)
- Chunhong Huang
- State Key Laboratory for Diagnosis and Treatment of Infectious, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital
| | - Tiantian Ge
- State Key Laboratory for Diagnosis and Treatment of Infectious, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital
| | - Caixia Xia
- Department of Infectious Diseases, Affiliated Hangzhou First People's Hospital
| | - Wei Zhu
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lichen Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital
| | - Yunyun Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital
| | - Fengtian Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital
| | - Feifei Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital
| | - Min Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital
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El-Jurdi N, Ghannoum MA. The Mycobiome: Impact on Health and Disease States. Microbiol Spectr 2017; 5:10.1128/microbiolspec.funk-0045-2016. [PMID: 28597821 PMCID: PMC11687503 DOI: 10.1128/microbiolspec.funk-0045-2016] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2016] [Indexed: 12/28/2022] Open
Abstract
The term "microbiome" refers to microorganisms (microbiota) and their genomes (metagenome) coexisting with their hosts. Some researchers coined the term "second genome" to underscore the importance of the microbiota and its collective metagenome on their host's health and/or disease. It is now undeniable that the commensal fungal microorganisms, alongside the other components of the microbiota, play a central role in association with the human host. In recognition, projects were launched nationally and internationally to unify efforts to characterize the microbiome and elucidate the functional role of the microbiota and the mechanism(s) by which these organisms and their metabolites (metabolome) may affect health and disease states. In this article, we will highlight the role of the fungal community as an indispensable component of the microbiome.
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Affiliation(s)
- Najla El-Jurdi
- Department of Medicine, Division of Hematology-Oncology, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH 44106
| | - Mahmoud A Ghannoum
- Center For Medical Mycology, Department of Dermatology, Case Western Reserve University, and University Hospitals Cleveland Medical Center, Cleveland, OH 44106
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Bullman S, Meyerson M, Kostic AD. Emerging Concepts and Technologies for the Discovery of Microorganisms Involved in Human Disease. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2016; 12:217-244. [PMID: 27959634 DOI: 10.1146/annurev-pathol-012615-044305] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Established infectious agents continue to be a major cause of human morbidity and mortality worldwide. However, the causative agent remains unknown for a wide range of diseases; many of these are suspected to be attributable to yet undiscovered microorganisms. The advent of unbiased high-throughput sequencing and bioinformatics has enabled rapid identification and molecular characterization of known and novel infectious agents in human disease. An exciting era of microbe discovery, now under way, holds great promise for the improvement of global health via the development of antimicrobial therapies, vaccination strategies, targeted public health measures, and probiotic-based preventions and therapies. Here, we review the history of pathogen discovery, discuss improvements and clinical applications for the detection of microbially associated diseases, and explore the challenges and strategies for establishing causation in human disease.
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Affiliation(s)
- Susan Bullman
- Dana-Farber Cancer Institute, Boston, Massachusetts 02215; , .,Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142
| | - Matthew Meyerson
- Dana-Farber Cancer Institute, Boston, Massachusetts 02215; , .,Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142.,Harvard Medical School, Boston, Massachusetts 02115
| | - Aleksandar D Kostic
- Research Division, Joslin Diabetes Center, Boston, Massachusetts 02215; .,Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115
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Gu X, Ji Q, Wang H, Jiang M, Yang J, Fang M, Wang M, Gao C. Genetic variants of mannose-binding lectin 2 gene influence progression and prognosis of patients with hepatitis B virus infection in China. Clin Res Hepatol Gastroenterol 2016; 40:614-621. [PMID: 26857650 DOI: 10.1016/j.clinre.2015.12.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Accepted: 12/21/2015] [Indexed: 02/04/2023]
Abstract
AIM Mannose-binding lectin (MBL) is a member of the calcium-dependent collectin family involved in the innate immune system that mediates phagocytosis and activates complement by binding to carbohydrate motifs. We studied allele and haplotype frequencies of -221C/G and codon 54G/A in MBL2 gene to reveal their relationship with the developing and progression of hepatitis B virus (HBV)-related liver diseases. METHODS This study was performed in 171 healthy controls, 133 chronic hepatitis B (CHB) patients, 97 patients with HBV-related liver cirrhosis (LC) and 334 HBV-related hepatocellular carcinoma (HCC) patients. The genotypes of these two polymorphisms in these subjects were detected using polymerase chain reaction-ligation detection reaction (PCR-LDR) method. Stratification analyses by clinical characteristics and survival analysis of HCC patients were also performed according to their genotypes. RESULTS The genotype and allele frequencies at codon 54 manifested a significant difference between healthy controls and patients with progressive HBV-related liver diseases, especially liver cirrhosis. Allele A appeared to have protective effect from developing LC and HCC compared with G allele. The percentages of the patients with G allele at -221C/G increased in HBV-related disease groups. When combined together as a haplotype, lower haplotype AC frequency was associated with a decreased risk for the progression of HBV-related liver diseases and HCC developing. Furthermore, HCC patients with G allele at codon 54 showed to have better survival than those with A allele. CONCLUSION These results indicated that polymorphisms in MBL2 gene may influence susceptibility, progression and prognosis of HBV-related liver diseases.
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Affiliation(s)
- Xing Gu
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, PR China
| | - Qiang Ji
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, PR China
| | - Hao Wang
- Department of Laboratory Medicine, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, PR China
| | - Mingming Jiang
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, PR China
| | - Juan Yang
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, PR China
| | - Meng Fang
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, PR China
| | - Mengmeng Wang
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, PR China
| | - Chunfang Gao
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, PR China.
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Wang M, Zou X, Tian D, Hu S, Jiang L. Role of Dendritic Cell-Specific ICAM-3-Grabbing Nonintegrin on Dendritic Cells in the Recognition of Hepatitis B Virus. Viral Immunol 2016; 28:331-8. [PMID: 26133046 DOI: 10.1089/vim.2014.0128] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN) is an essential process for virus infection, such as HIV and hepatitis C, and plays a role in immune escape. However, the role of DC-SIGN in hepatitis B virus (HBV) infection is still unknown. The aim of this study was to investigate the role of DC-SIGN in mediating the maturation and activation of dendritic cells (DCs) when infected by HBV. Highly mannosylated HBV particles were obtained by treating HBV-producing HepG2.2.15 cells with the a-mannosidase I-inhibitor kifunensine. Highly mannosylated HBV or wild type HBV was added to infect the DCs of the DC-SIGN gene-silencing group and normal group, respectively. Then, the expression of CDla, CD80, CD83, CD86 and HLA-DR on DCs was detected by flow cytometry, the capacity of stimulating lymphocyte proliferation was tested by MTT assay, the level of IL-12p70 that was released by DCs was measured by enzyme-linked immunosorbent assay, and the expression of the proteins NF-κBp65 and p38 was detected by western blot. Both wild type and highly mannosylated HBV could promote DCs maturation and activation. However, the highly mannosylated HBV could promote DCs immune activation more strongly. The difference in the effect on DCs between the two types of HBV could be eliminated by DC-SIGN gene silencing. DC-SIGN can promote the maturation and activation of DCs when recognized HBV, but wild type HBV can escape recognition by DC-SIGN to a certain extent with the help of demannosylated modification, leading to defective DCs function and chronic HBV infection.
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Affiliation(s)
- Minxin Wang
- 1 Department of Infectious Disease, Huazhong University of Science and Technology , Wuhan, China
| | - Xiaojing Zou
- 2 Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China
| | - Deying Tian
- 1 Department of Infectious Disease, Huazhong University of Science and Technology , Wuhan, China
| | - Song Hu
- 1 Department of Infectious Disease, Huazhong University of Science and Technology , Wuhan, China
| | - Libin Jiang
- 1 Department of Infectious Disease, Huazhong University of Science and Technology , Wuhan, China
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Jiang L, Hu S, Tian D, Zou X, He M. α-Mannosidase I Protein Expression in Peripheral Blood Mononuclear Cells Is Upregulated During Hepatitis B Virus Infection. Viral Immunol 2015; 29:33-9. [PMID: 26569026 DOI: 10.1089/vim.2015.0079] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Hepatitis B virus (HBV) has been reported to be recognized by dendritic cell-specific ICAM-3-grabbing nonintegrin in the presence of the α-mannosidase I inhibitor kifunensine, whereas native HBV is not. The aim of our study was to determine whether changes in α-mannosidase I expression in peripheral blood mononuclear cells (PBMCs) occur in patients with HBV infection. Peripheral blood was collected from 90 HBV-infected patients (grouped into immune tolerance, chronic hepatitis B, or inactive carrier group based on their clinical states) and 30 healthy donors. Expression of the three α-mannosidase I subtypes, MAN1A1, MAN1A2, and MAN1C1, was measured using western blot analyses. Compared with the healthy controls, significant increases in the MAN1A1, MAN1A2, and MAN1C1 expression levels were observed in the three HBV-infected groups, among whom the immune tolerance group showed the largest increase. For the patients in the immune tolerance phase, the expression levels of both MAN1A1 and MAN1A2 were linearly and positively correlated with the hepatitis B e antigen (HBeAg) titer and HBV DNA level, although a positive correlation was only found between MAN1C1 expression and the HBeAg titer. These results indicate that increased α-mannosidase I expression in PBMCs may play an important role in HBV immune escape and that its expression level is closely related to viral replication activity.
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Affiliation(s)
- Libin Jiang
- 1 Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China
| | - Song Hu
- 1 Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China
| | - Deying Tian
- 1 Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China
| | - Xiaojing Zou
- 2 Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China
| | - Man He
- 1 Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China
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Quantitative assessment of common genetic variations in HLA-DP with hepatitis B virus infection, clearance and hepatocellular carcinoma development. Sci Rep 2015; 5:14933. [PMID: 26462556 PMCID: PMC4604517 DOI: 10.1038/srep14933] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 09/11/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is the predominant risk factor for chronic hepatitis B (CHB), liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Recently, genome-wide association studies have identified human leukocyte antigen (HLA)-DP polymorphisms (rs3077 and rs9277535) as a new chronic HBV infection susceptibility locus. Since then, the relationship between HLA-DP polymorphisms and various outcomes of HBV infection has been reported. However, the results have been inconclusive. To derive a more precise estimation of the relationship between HLA-DP polymorphisms and various outcomes of HBV infection, a meta-analysis of 62,050 subjects from 29 case-control studies was performed. We found that rs3077 and rs9277535 in HLA-DP significantly decreased HBV infection risks and increased HBV clearance possibility in a dose-dependent manner. In the subgroup analysis by ethnicity, study design and sample size, significant associations were found for these polymorphisms in almost all comparisons. Meanwhile, haplotype analyses of the two polymorphisms revealed a significant association between the combination of these alleles and HBV infection outcomes. However, no significant results were observed in HCC development. Our results further confirm that genetic variants in the HLA-DP locus are strongly associated with reduced HBV infection and increased the likelihood of spontaneous viral clearance.
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Abstract
New insights gained through the use of state-of-the-art technologies, including next-generation sequencing, are starting to reveal that the association between the gastrointestinal tract and the resident mycobiota (fungal community) is complex and multifaceted, in which fungi are active participants influencing health and disease. Characterizing the human mycobiome (the fungi and their genome) in healthy individuals showed that the gastrointestinal tract contains 66 fungal genera and 184 fungal species, with Candida as the dominant fungal genera. Although fungi have been associated with a number of gastrointestinal diseases, characterization of the mycobiome has mainly been focused on patients with IBD and graft-versus-host disease. In this Review, we summarize the findings from studies investigating the relationship between the gut mycobiota and gastrointestinal diseases, which indicate that fungi contribute to the aggravation of the inflammatory response, leading to increased disease severity. A model explaining the mechanisms underlying the role of the mycobiota in gastrointestinal diseases is also presented. Our understanding of the contribution of the mycobiota to health and disease is still in its infancy and leaves a number of questions to be addressed. Answering these questions might lead to novel approaches to prevent and/or manage acute as well as chronic gastrointestinal disease.
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Human lectins and their roles in viral infections. Molecules 2015; 20:2229-71. [PMID: 25642836 PMCID: PMC6272597 DOI: 10.3390/molecules20022229] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Revised: 01/21/2015] [Accepted: 01/23/2015] [Indexed: 12/20/2022] Open
Abstract
Innate recognition of virus proteins is an important component of the immune response to viral pathogens. A component of this immune recognition is the family of lectins; pattern recognition receptors (PRRs) that recognise viral pathogen-associated molecular patterns (PAMPs) including viral glycoproteins. In this review we discuss the contribution of soluble and membrane-associated PRRs to immunity against virus pathogens, and the potential role of these molecules in facilitating virus replication. These processes are illustrated with examples of viruses including human immunodeficiency virus (HIV), hepatitis C virus (HCV) and Ebola virus (EBOV). We focus on the structure, function and genetics of the well-characterised C-type lectin mannose-binding lectin, the ficolins, and the membrane-bound CD209 proteins expressed on dendritic cells. The potential for lectin-based antiviral therapies is also discussed.
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Keizer MP, Wouters D, Schlapbach LJ, Kuijpers TW. Restoration of MBL-deficiency: redefining the safety, efficacy and viability of MBL-substitution therapy. Mol Immunol 2014; 61:174-84. [PMID: 25044097 DOI: 10.1016/j.molimm.2014.06.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Revised: 05/30/2014] [Accepted: 06/03/2014] [Indexed: 12/28/2022]
Abstract
MBL-deficiency is a commonly occurring deficiency of the innate immune system, affecting a substantial part of the population and has been extensively studied. MBL appears to function as a disease modifier. The role of MBL in different conditions is context-dependent. Many clinical studies show conflicting results, which can be partially explained by different definitions of MBL-deficiency, including phenotype- and genotype-based approaches. In this review we give an overview of literature of MBL, its role in different pathologies, diseases and patient populations. We review MBL replacement studies, and discuss the potential of MBL substitution therapy. We finally suggest that new MBL substitution trials should be conducted within a predefined patient population. MBL-deficiency should be based on serum levels and confirmed by genotyping.
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Affiliation(s)
- M P Keizer
- Department of Immunopathology, Sanquin Blood Supply, Division Research and Landsteiner Laboratory of the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Pediatric Hematology, Immunology & Infectious Diseases, Emma Children's Hospital, AMC, University of Amsterdam, Amsterdam, The Netherlands.
| | - D Wouters
- Department of Immunopathology, Sanquin Blood Supply, Division Research and Landsteiner Laboratory of the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - L J Schlapbach
- Paediatric Critical Care Research Group, Mater Research, University of Queensland, Brisbane, Australia
| | - T W Kuijpers
- Department of Pediatric Hematology, Immunology & Infectious Diseases, Emma Children's Hospital, AMC, University of Amsterdam, Amsterdam, The Netherlands; Department of Blood Cell Research, Sanquin Blood Supply, Division Research and Landsteiner Laboratory of the AMC, University of Amsterdam, Amsterdam, The Netherlands
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Jiang X, Ma Y, Cui W, Li MD. Association of variants in HLA-DP on chromosome 6 with chronic hepatitis B virus infection and related phenotypes. Amino Acids 2014; 46:1819-26. [DOI: 10.1007/s00726-014-1767-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2014] [Accepted: 04/21/2014] [Indexed: 01/07/2023]
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Jiang M, Chen Y, Zhang Y, Chen L, Zhang N, Huang T, Cai YD, Kong X. Identification of hepatocellular carcinoma related genes with k-th shortest paths in a protein-protein interaction network. MOLECULAR BIOSYSTEMS 2014; 9:2720-8. [PMID: 24056857 DOI: 10.1039/c3mb70089e] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide and one of the deadliest cancers in Asia. But at present, effective targets for HCC clinical therapy are still limited. The "guilt by association" rule suggests that interacting proteins share the same or similar functions and hence may be involved in the same pathway. This assumption can be used to identify disease related genes from protein association networks constructed from existing PPI data. Given the close association between Hepatitis B virus and Hepatitis B which may lead to HCC, here we develop a computational method to identify hepatocellular carcinoma related genes based on k-th shortest paths in the protein-protein interaction (PPI) network (we set k=1, 2 in this study). Finally, we found 33 genes whose p-values were less than 0.05, and most of them have been reported to be involved in HCC tumorigenesis and development. The results also provide a new reference for research into HCC oncogenesis and for development of new strategies for HCC clinical therapies.
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Affiliation(s)
- Min Jiang
- State Key Laboratory of Medical Genomics, Institute of Health Sciences, Shanghai Jiaotong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, P.R. China.
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Association between Mannose-binding lectin gene polymorphisms and hepatitis B virus infection: a meta-analysis. PLoS One 2013; 8:e75371. [PMID: 24116040 PMCID: PMC3792921 DOI: 10.1371/journal.pone.0075371] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2013] [Accepted: 08/11/2013] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE The results of studies on the relation between Mannose-binding lectin gene (mbl2) polymorphism and HBV infection were contradictory and inconclusive. In order to shed a light on these inconsistent findings and to clarify the role of mbl2 polymorphisms in susceptibility or progression of chronic hepatitis B (CHB), a meta-analysis was performed. METHODS PubMed and Embase were searched for available articles. A meta-analysis was performed to examine the association between mbl2 polymorphisms and chronicity or progression of hepatitis B infection. Odds ratio (OR) and its 95% confidence interval (CI) served as indexes. RESULTS A total of 17 eligible studies were involved, including 2151 healthy controls (HC), 1293 spontaneous recovered (SR) patients with acute infection, 2337 cases with chronic hepatitis B (CHB) and 554 cases with progressive hepatitis B. There was no evidence of significant association between mbl2 exon1 polymorphisms and CHB risk in any genetic model or pairwise comparisons when compared with HC group or SR group. In the stratified analysis of ethnic groups, also no obvious relation between mbl2 polymorphism and CHB risk was identified. There was still no significant association between the complete mbl2 genotypic profile (including both the exon1 and the promoter gene) polymorphisms and CHB risk, as compared with SR group. However, it was found that there was an association between the mbl2 AO/OO genotype and severe hepatitis B (SHB) or liver cirrhosis (LC) (LC vs. HC:OR=3.66, 95%CI, 2.38-5.63; SHB vs. HC, OR=3.88, 95%CI, 2.26-6.64), but there was no relationship between the mbl2 AO/OO genotype and hepatocellular carcinoma (HCC) (OR=1.26, 95%CI, 0.82-1.94). CONCLUSION The present meta-analysis indicated that mbl2 exon1 polymorphisms might not significantly associate with chronicity of HBV infection, but might be significantly related to the progressive HBV such as SHB and LC.
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Zhang TC, Liu W, Liu XQ, Pan FM, Gao YF, Yan F, Li X. Single nucleotide polymorphisms rs2120131, rs4935047, and rs7095891 in the MBL2 gene show no association with susceptibility to chronic hepatitis B in a Chinese Han population. J Med Virol 2013; 85:602-7. [PMID: 23417614 DOI: 10.1002/jmv.23514] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/05/2012] [Indexed: 11/12/2022]
Abstract
Thus far, many studies have evaluated the correlation between MBL2 gene polymorphisms and hepatitis B infection. Tag single nucleotide polymorphisms (SNPs) were used to investigate the relationship between MBL2 gene polymorphisms and susceptibility to chronic hepatitis B virus (HBV) infection by comparing 996 chronic HBV infection cases to 301 acute infection controls. There was no significant correlation between rs2120131, rs4935047, and rs7095891 and chronic HBV infection. This suggested that the new SNPs within MBL2 were not associated with susceptibility to chronic hepatitis B in a Chinese Han population.
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Affiliation(s)
- Tian-Chen Zhang
- Jiangxi Center for Disease Control and Prevention, 555 Beijing East Road, Nanchang, Jiangxi 330000, China
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Wong DKH, Watanabe T, Tanaka Y, Seto WK, Lee CK, Fung J, Lin CK, Huang FY, Lai CL, Yuen MF. Role of HLA-DP polymorphisms on chronicity and disease activity of hepatitis B infection in Southern Chinese. PLoS One 2013; 8:e66920. [PMID: 23825586 PMCID: PMC3692552 DOI: 10.1371/journal.pone.0066920] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2013] [Accepted: 05/12/2013] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND AND AIMS The association between HLA-DP single nucleotide polymorphisms (SNPs) and chronic hepatitis B virus (HBV) infection varies between different populations. We aimed to study the association between HLA-DP SNPs and HBV infection and disease activity in the Chinese population of Hong Kong. METHODS We genotyped SNPs rs3077 (near HLA-DPA1) and rs9277378 and rs3128917 (both near HLA-DPB1) in 500 HBV carriers (hepatitis B surface antigen [HBsAg]-positive), 245 non-HBV infected controls (HBsAg- and antibody to hepatitis B core protein [anti-HBc]-negative), and 259 subjects with natural HBV clearance (HBsAg-negative, anti-HBc-positive). Inactive HBV carriers state was defined by HBV DNA levels <2,000 IU/ml and persistently normal alanine aminotransferase level for least 12 months. RESULTS Compared to the non-HBV infected subjects, the HBV carriers had a significantly lower frequency of the rs3077 T allele (p = 0.0040), rs9277378 A allele (p = 0.0068) and a trend for lower frequency of rs3128917 T allele (p = 0.054). These alleles were associated with an increased chance of HBV clearance (rs3077: OR = 1.41, p = 0.0083; rs9277378: OR = 1.61, p = 0.00011; rs3128917: OR = 1.54, p = 0.00017). Significant associations between HLA-DP genotypes and HBV clearance were also found under different genetic models. Haplotype TAT was associated with an increased chance of HBV clearance (OR = 1.64, p = 0.0013). No association was found between these SNPs and HBV disease activity. CONCLUSION HLA-DP SNPs rs3077, rs9277378 and rs3128917 were associated with chronicity of HBV disease in the Chinese. Further studies are required to determine whether these SNPs influence the disease endemicity in different ethnic populations.
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Affiliation(s)
- Danny Ka-Ho Wong
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
- State Key Laboratory for Liver Research, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Tsunamasa Watanabe
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Wai-Kay Seto
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Cheuk-Kwong Lee
- Hong Kong Red Cross Blood Transfusion Service, Hospital Authority, Hong Kong
| | - James Fung
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
- State Key Laboratory for Liver Research, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Che-Kit Lin
- Hong Kong Red Cross Blood Transfusion Service, Hospital Authority, Hong Kong
| | - Fung-Yu Huang
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Ching-Lung Lai
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
- State Key Laboratory for Liver Research, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
- State Key Laboratory for Liver Research, The University of Hong Kong, Queen Mary Hospital, Hong Kong
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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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MBL Deficiency as Risk of Infection and Autoimmunity. ANIMAL LECTINS: FORM, FUNCTION AND CLINICAL APPLICATIONS 2012:933-953. [PMCID: PMC7122001 DOI: 10.1007/978-3-7091-1065-2_42] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/30/2023]
Abstract
In pathogen recognition by C-type lectins, several levels of complexity can be distinguished; these might modulate the immune response in different ways. Firstly, the pathogen-associated molecular pattern repertoire expressed at the microbial surface determines the interactions with specific receptors (Fig. 42.1). Secondly, each immune cell type possesses a specific set of pathogen-recognition receptors. Thirdly, changes in the cell-surface distribution of C-type lectins regulate carbohydrate binding by modulating receptor affinity for different ligands. Crosstalk between these receptors results in a network of multimolecular complexes, adding a further level of complexity in pathogen recognition (Cambi and Figdor 2005; Thiel et al. 2006) (see 10.1007/978-3-7091-1065-2_23). MBL deficiency is genetically determined and predisposes to recurrent infections and chronic inflammatory diseases. MBL deficiency has been implicated in susceptibility and course of viral, bacterial, fungal, and protozoan infection. More than 10% of the general population may, depending on definition, be classified as MBL deficient, underlining the redundancy of the immune system. MBL-disease association studies have been a fruitful area of research, which implicates a role for MBL in infective, inflammatory and autoimmune disease processes. MBL deficiency predisposes both to infection by extra-cellular pathogens and to autoimmune disease.
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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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An P, the HBV Study Consortium, Winkler C, the HBV Study Consortium, Guan L, the HBV Study Consortium, O'Brien SJ, the HBV Study Consortium, Zeng Z, the HBV Study Consortium. A Common HLA–DPA1 Variant is a Major Determinant of Hepatitis B Virus Clearance in Han Chinese. J Infect Dis 2011; 203:943-947. [DOI: https:/doi.org/10.1093/infdis/jiq154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/02/2023] Open
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An P, Winkler C, Guan L, O'Brien SJ, Zeng Z. A common HLA-DPA1 variant is a major determinant of hepatitis B virus clearance in Han Chinese. J Infect Dis 2011; 203:943-947. [PMID: 21402545 PMCID: PMC3068033 DOI: 10.1093/infdis/jiq154] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2010] [Accepted: 11/12/2010] [Indexed: 12/27/2022] Open
Abstract
A recent genome-wide study showed that the single nucleotide polymorphisms (SNPs) in the HLA-DP region were associated with chronic hepatitis B virus (HBV) infection in Japanese and Thai persons. We tested the effects of HLA-DP SNPs for all major HBV outcomes in Han Chinese (n = 1742): HBV resistance, clearance, chronic infection, cirrhosis, and hepatocellular carcinoma. HLA - DPA1 rs3077 T was strongly associated with decreased risk of chronic HBV infection (odds ratio, .62; P = .001), consistent with the previous report. We showed for the first time to our knowledge that it is a predictor for HBV clearance (odds ratio, 2.41; P < .001). However, rs3077 was not associated with the development of cirrhosis or hepatocellular carcinoma.
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Affiliation(s)
| | | | - Li Guan
- Laboratory of Genomic Diversity, SAIC-Frederick
| | - Stephen J. O'Brien
- Laboratory of Genomic Diversity, National Cancer Institute-Frederick, Maryland
| | - Zheng Zeng
- Department of Infectious Diseases, Peking University First Hospital, Beijing, People’s Republic of China
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Guo X, Zhang Y, Li J, Ma J, Wei Z, Tan W, O’Brien SJ. Strong influence of human leukocyte antigen (HLA)-DP gene variants on development of persistent chronic hepatitis B virus carriers in the Han Chinese population. Hepatology 2011; 53:422-8. [PMID: 21274863 PMCID: PMC3056070 DOI: 10.1002/hep.24048] [Citation(s) in RCA: 114] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2010] [Accepted: 07/10/2010] [Indexed: 12/28/2022]
Abstract
Chronic hepatitis B virus (HBV) infection is a major health issue, especially in Asia. A recent genome-wide association study (GWAS) implicated genetic variants in the human leukocyte antigen (HLA)-DP locus associated with chronic hepatitis B in Japanese and Thai populations. To confirm whether the polymorphisms at the HLA-DP genes are associated with persistent chronic HBV infection in Han Chinese, we conducted an independent case-control study using 521 persistent chronic HBV carriers and 819 controls that included 571 persons with HBV natural clearance and 248 never HBV-infected (healthy) individuals. Eleven single nucleotide polymorphisms (SNPs) in a region including HLA-DPA and HLA-DPB and an adjacent SNP in strong linkage disequilibrium (LD) with a neighboring HLA-DR13 locus were genotyped using the TaqMan SNP genotyping assay. Eleven variants at HLA-DP showed a strong association with persistent chronic HBV carrier status (P = 1.82 × 10(-12) to 0.01). We also stratified the analysis by HBV clearance status to test the association between these polymorphisms and HBV natural clearance; similar results were obtained (P = 2.70 × 10(-11) to 0.003). Included SNPs define highly structured haplotypes that were also strongly associated with HBV chronic infection (block 1: odds ratio [OR] = 0.54, P = 8.73 × 10(-7) ; block 2: OR = 1.98, P = 1.37 × 10(-10) ). These results further confirm that genetic variants in the HLA-DP locus are strongly associated with persistent HBV infection in the Han Chinese population.
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Affiliation(s)
- Xiuchan Guo
- Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Science, Wenzhou Medical College, Zhejiang, China
- State Key Laboratory for Infectious Diseases Prevention and Control, Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
- Laboratory of Genomic Diversity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD
| | - Yong Zhang
- State Key Laboratory for Infectious Diseases Prevention and Control, Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Ji Li
- Laboratory of Genomic Diversity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD
| | - Jingchen Ma
- Hebei Province’s Center for Disease Control and Prevention, Shijiazhuang, China
| | - Zuli Wei
- Luohe’s Center for Disease Control and Prevention, Luohe City, Henan Province, China
| | - Wenjie Tan
- Biotech Center for Viral Disease Emergency, Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Stephen J. O’Brien
- Laboratory of Genomic Diversity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD
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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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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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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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30
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Sun W, Zhong F, Zhi L, Zhou G, He F. Systematic -omics analysis of HBV-associated liver diseases. Cancer Lett 2009; 286:89-95. [PMID: 19144459 DOI: 10.1016/j.canlet.2008.12.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2008] [Revised: 11/25/2008] [Accepted: 12/02/2008] [Indexed: 12/23/2022]
Abstract
Hepatitis B virus (HBV) infection causes acute and chronic liver diseases and increases the risk of developing hepatocellular carcinoma (HCC). However, the pathogenesis of HBV infection and carcinogenesis of HBV-associated HCC are still elusive. In this review, systematic -omics studies made in the scales of genomics, transcriptomics and proteomics were discussed. The susceptibility to HBV infection and the course of disease progress are greatly different among individuals. Using population- or/and family-based approaches, relevant genes have been mapped or identified to be associated with host immune responses to HBV antigens and susceptibility to HCC. Comprehensive transcriptomic analyses have shown that the HBV-induced hepatocarcinogenesis may involve the whole course from signal transduction, transcription, translation to protein degradation, which differs in some measure from HCV-induced hepatocarcinogenesis, and that exogenous transcription factor HBX and endogenous NF-kappaB are likely two key points of the course. By the means of proteomics, dozens of important dysregulated proteins (including isoforms or fragments) were identified from carcinogenesis mechanism analysis and biomarker validation. Of them, the alteration of heat shock proteins and impairment of methylation cycle were found to be associated with clinical HBV-associated HCC. As a whole, the systematic -omics analysis of HBV-associated liver diseases has offered multi-scale pathological information in the process from HBV infection to HCC onset.
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Affiliation(s)
- Wei Sun
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, 33 Life Science Park, Beijing 102206, China
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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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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: 29] [Impact Index Per Article: 1.7] [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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Methylenetetrahydrofolate reductase 677 T allele protects against persistent HBV infection in West Africa. J Hepatol 2008; 48:532-9. [PMID: 18222012 DOI: 10.1016/j.jhep.2007.11.017] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2007] [Revised: 10/06/2007] [Accepted: 11/08/2007] [Indexed: 01/12/2023]
Abstract
BACKGROUND/AIMS Homocysteine metabolism is linked to DNA methylation, a mechanism potentially involved in the course of hepatitis B virus (HBV) infection. We evaluated the association of determinants of homocysteine metabolism with the outcome of HBV infection. METHODS Four hundred and fifty-five healthy adults from Togo and Benin were tested for HBV serologic markers, HLA DR alleles, folate, vitamin B12, methylenetetrahydrofolate reductase (MTHFR) 677 C-->T, 1298 A-->C and methionine synthase 2756 A-->G polymorphisms. RESULTS Seventy-eight percent of the study population was anti-HBc positive. Among them, 202 (56.9%) were anti-HBs positive and 58 (16.3%) were HBsAg positive. After stepwise logistic regression, the MTHFR 677 T allele was independently associated with persistence of detectable anti-HBs antibodies (OR: 2.47; 95% CI: 1.29-4.71; p=0.006). The mean HBV DNA level was significantly lower in HBsAg positive subjects carrying the 677 T allele than in those with the 677 CC genotype (1000+/-1406 vs. 2,400,000+/-214,000 copies/ml, p=0.005). Beninese origin and HLA-DRB1*09 allele were the other determinants independently associated with favorable outcome of HBV infection. CONCLUSIONS The methylenetetrahydrofolate reductase 677 T allele seems to protect against chronic HBV infection in young African adults.
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Deng G, Zhou G, Zhang R, Zhai Y, Zhao W, Yan Z, Deng C, Yuan X, Xu B, Dong X, Zhang X, Zhang X, Yao Z, Shen Y, Qiang B, Wang Y, He F. Regulatory polymorphisms in the promoter of CXCL10 gene and disease progression in male hepatitis B virus carriers. Gastroenterology 2008; 134:716-26. [PMID: 18325387 DOI: 10.1053/j.gastro.2007.12.044] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2007] [Accepted: 12/13/2007] [Indexed: 01/12/2023]
Abstract
BACKGROUND & AIMS The importance of expression of interferon gamma-inducible protein of 10 kilodaltons (IP-10, CXCL10) during chronic hepatitis B virus (HBV) infection has been recently emphasized. In this report, we investigated whether the naturally occurred sequence variations in the CXCL10 gene impact liver damage and disease progression of chronic HBV infection. METHODS A hospital-based case-control study was conducted, and a total of 613 and 1787 unrelated Han Chinese HBV carriers were recruited from Beijing and Chongqing, respectively. We systematically screened sequence variations in the CXCL10 gene and examined the association between the variations in this gene and susceptibility to disease progression of chronic HBV infection in Chinese populations from Beijing and Chongqing. Functional analyses were conducted to verify the biological significances of the associated genetic variation. RESULTS We identified that the polymorphism G-201A, located in the promoter region of CXCL10, was associated with susceptibility to disease progression in male HBV carriers (dominant model; odds ratio, 1.53; P = .001). Functional analyses show that the G-201A polymorphism alters the binding affinity of nuclear protein and regulates CXCL10 expression. We observed higher CXCL10 transcription in interferon gamma-stimulated peripheral blood mononuclear cells with the disease-susceptible genotypes. Enzyme-linked immunosorbent assay and immunohistochemical analysis showed augmented CXCL10 production in serum and liver tissues of progressed HBV carriers. CONCLUSIONS The novel regulatory polymorphism G-201A [corrected] in the promoter of CXCL10 gene could be a part of the genetic variation underlying the susceptibility of individuals to disease progression of chronic HBV infection.
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Affiliation(s)
- Guohong Deng
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China
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Zeng Z, Guan L, An P, Sun S, O'Brien SJ, Winkler CA, the HBV study consortium. A population-based study to investigate host genetic factors associated with hepatitis B infection and pathogenesis in the Chinese population. BMC Infect Dis 2008; 8:1. [PMID: 18171470 PMCID: PMC2238742 DOI: 10.1186/1471-2334-8-1] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2007] [Accepted: 01/02/2008] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is a significant public health problem that may lead to chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). Approximately 30% of the world's population has been infected with HBV and approximately 350 million (5-6%) are persistent carriers. More than 120 million Chinese are infected with HBV. The role of host genetic factors and their interactions with environmental factors leading to chronic HBV infection and its complications are not well understood. We believe that a better understanding of these factors and interactions will lead to more effective diagnostic and therapeutic options. METHODS/DESIGN This is a population-based, case-control study protocol to enroll 2200 Han Chinese from medical centers in northern and western China. Adult subjects in the following groups are being enrolled: healthy donors (n = 200), HBV infected persons achieving virus clearance (n = 400), asymptomatic HBV persistent carriers (n = 400), chronic hepatitis B cases (n = 400), decompensated liver cirrhosis with HBV infection cases (n = 400), and hepatocellular carcinoma with HBV infection cases (n = 400). In addition, for haplotype inference and quality control of sample handling and genotyping results, children of 1000 cases will be asked to provide a buccal sample for DNA extraction. With the exception of adult patients presenting with liver cirrhosis or HCC, all other cases and controls will be 40 years or older at enrollment. A questionnaire is being administered to capture dietary and environmental risk factors. Both candidate-gene and genome-wide association approaches will be used to assess the role of single genetic factors and higher order interactions with other genetic or environmental factors in HBV diseases. CONCLUSION This study is designed and powered to detect single gene effects as well as gene-gene and environmental-gene interactions. The identification of allelic polymorphisms in genes involved in the pathway leading to chronic viral infection, liver cirrhosis and, ultimately, hepatocellular carcinoma would provide insights to those factors leading to HBV replication, liver inflammation, fibrosis, and the carcinogenic process. An understanding of the contribution of host genetic factors and their interactions may inform public health policy, improve diagnostics and clinical management, and provide targets for drug development.
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Affiliation(s)
- Zheng Zeng
- Department of Infectious Diseases, Peking University First Hospital, Beijing, P.R.China
| | - Li Guan
- SAIC/Laboratory of Genomic Diversity, National Cancer Institute-Frederick, National Institutes of Health, Frederick, USA
| | - Ping An
- SAIC/Laboratory of Genomic Diversity, National Cancer Institute-Frederick, National Institutes of Health, Frederick, USA
| | - Shan Sun
- Conservation International (CI) China program, Beijing, P.R.China
| | - Stephen J O'Brien
- Laboratory of Genomic Diversity, National Cancer Institute-Frederick, National Institutes of Health, Frederick, USA
| | - Cheryl A Winkler
- SAIC/Laboratory of Genomic Diversity, National Cancer Institute-Frederick, National Institutes of Health, Frederick, USA
| | - the HBV study consortium
- HBV study consortium: Department of Infectious Diseases, Peking University First Hospital, Beijing, P.R.China (Zheng Zeng, Yanyan Yu, Xiaoyuan Xu, Haiying Lu); Institute of Liver Diseases Research, Beijing Military General Hospital, Beijing, P.R.China (Darong Hu); Beijing Ditan Hospital (Rongbing Wang, Yifan Chen); Department of Surgery, Beijing Institute of Tumor Prevention and Therapy, Beijing, P.R.China (Cunyi Hao); Department of Infectious Diseases, Shanxi Medical University, Taiyuan, P.R.China (Heping Zhou); Department of Infectious Diseases, Qinhuangdao No. 3 Hospital, Qinhuangdao, P.R.China (Zhonghou Han); Department of Surgery, Inner Mongolia Medical College, Hohhot, P.R.China (Lidao Bao, Xiping Zhang); Department of Infectious Diseases, Xuzhou No. 3 Hospital, Xuzhou, P.R.China (Dasi Guo); Department of Infectious Diseases, Xinjian Medical University, Urumoqi, P.R.China (Yaoxin Zhang); Department of Infectious Diseases, the Second Affiliate Hospital of China Medical University, Shenyang, P.R.China (Xiaoguang Dou); Institute of Liver Diseases Research, Peking University Second Hospital, Beijing, P.R.China (Lai Wei); Department of Surgery, Peking Union Medical College, Beijing, P.R.China (Jingan Rui, Qiang Qu)
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Zhang X, Hong X, Deng G, Bai X. Single nucleotide polymorphisms and functional analysis of class II transactivator (CIITA) promoter IV in persistent HBV infection. J Clin Virol 2007; 40:197-201. [PMID: 17919972 DOI: 10.1016/j.jcv.2007.08.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2007] [Revised: 06/30/2007] [Accepted: 08/21/2007] [Indexed: 11/20/2022]
Abstract
BACKGROUND/AIMS CIITA plays a pivotal role in immune response, and the outcome of HBV infection is influenced by immune response. The aims of this study were to analyze the effect of CIITA promoter IV polymorphisms on its activity, and their association with persistent HBV infection. METHODS The polymorphisms in promoter IV (C-1350T and G-944C) were analyzed by tetra-primer amplification refractory mutation system polymerase chain reaction (ARMS-PCR), and four haplotypes were assigned in 1420 HBV infected subjects. The functional analysis on haplotypes of promoter IV was studied using pGL3-basic and pGL3-promoter vectors. RESULTS There were significantly decreased-TG and increased-CC haplotype frequencies in persistent HBV infected subjects (34.8% and 41.3%), compared with spontaneously recovered subjects (46.5% and 36.2%). There were significantly higher CC/CC and lower TG/TG genotype frequencies in persistent infected subjects (20.3% and 11.1%) than in spontaneously recovered subjects (10.9% and 23.1%). The mean relative luciferase activity of promoter IV were the highest in TG haplotype (0.558+/-0.023), and the lowest in CC haplotype (0.302+/-0.016). CONCLUSIONS The polymorphisms of CIITA promoter IV are associated with persistent HBV infection. The CC haplotype with the lowest activity of promoter and CC/CC genotype are responsible for persistent HBV infection.
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Affiliation(s)
- Xuqing Zhang
- Department of Infectious Diseases, Southwest Hospital, Chongqing 400038, PR China.
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Swierzko AS, Florczak K, Cedzyński M, Szemraj J, Wydra D, Bak-Romaniszyn L, Emerich J, Sułowska Z. Mannan-binding lectin (MBL) in women with tumours of the reproductive system. Cancer Immunol Immunother 2007; 56:959-71. [PMID: 17131120 PMCID: PMC11031024 DOI: 10.1007/s00262-006-0250-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2006] [Accepted: 10/28/2006] [Indexed: 11/27/2022]
Abstract
Mannan-binding lectin (MBL) is an important factor of innate immunity contributing to the clearance of microorganisms. Recently, an antitumourigenic role of MBL has been suggested. We investigated mbl2 genotypes, MBL concentrations, and MBL-MASP-2 complex activity in patients with ovarian cancer. The expression of both mbl2 and masp-2 genes were investigated in ovarian tissue sections. Additionally, samples from patients with other malignant and benign tumours of the reproductive tract were tested. A significantly higher incidence of MBL deficiency/insufficiency-associated genotypes was found among patients with malignant disease compared to age-matched controls. Unexpectedly, no differences in median MBL level or MBL-MASP-2 complex activity were found between the groups. This was partly a reflection of higher MBL concentrations and MBL-MASP-2 activity in cancer patients compared with healthy women carrying corresponding genotypes. MBL-specific mRNA expression was detected in several normal and malignant ovarian tissues, as well as in ovarian epithelial cell lines. Intracellular staining with MBL-specific antibodies demonstrated the presence of MBL in ovarian cell lines, and in normal as well as malignant ovarian tissue sections. In contrast, MASP-2-specific mRNA expression was detected only in the ovary tissues of patients with malignant disease. No significant changes in MBL concentration during 3 months of chemotherapy were noticed. MBL was detected in ascites and in the fluid of benign ovarian cysts. Our findings may reflect anti-tumourigenic activity of MBL protein which might suggest potential therapeutic application. However, it cannot be excluded that mbl-2 mutant alleles may be in linkage disequilibrium with an unidentified tumour susceptibility gene(s).
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Affiliation(s)
- A St Swierzko
- Laboratory of Immunobiology of Infections, Centre of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Łódź, Poland.
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Cui JJ, Zeng Z, Tian GB, Tian D, Lu HY. Advance in genetic factors influencing hepatitis B virus infection. Shijie Huaren Xiaohua Zazhi 2007; 15:1246-1251. [DOI: 10.11569/wcjd.v15.i11.1246] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [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
Hepatitis B virus (HBV) infection is a major global health problem. A complex combination of environment and virus, especially host genetic factors, play a critical role in determining both susceptibility to HBV persistence and different clinical outcomes after HBV infection. In this review, we summarized the main relevant genes such as human leukocyte antigen (HLA), tumor necrosis factor (TNF), interleukins (ILs), interferons (IFNs), etc. However, in order to identify all the relevant polymorphisms that affect the outcome of HBV infection, alternative strategies such as genome-wide association studies with large sample sizes are required to define the majority of the related genes.
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40
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Gong MN, Zhou W, Williams PL, Thompson BT, Pothier L, Christiani DC. Polymorphisms in the mannose binding lectin-2 gene and acute respiratory distress syndrome. Crit Care Med 2007; 35:48-56. [PMID: 17133182 PMCID: PMC3090269 DOI: 10.1097/01.ccm.0000251132.10689.f3] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE The variant alleles in the mannose binding lectin-2 (MBL-2) gene have been associated with MBL deficiency and increased susceptibility to sepsis. We postulate that the variant MBL-2 genotypes are associated with increased susceptibility to and mortality in acute respiratory distress syndrome (ARDS). DESIGN Nested case-control study. SETTING Tertiary academic medical center. PATIENTS Two hundred and twelve Caucasians with ARDS and 442 controls genotyped for the variant X, D, B, and C alleles of codon -221, 52, 54, and 57, respectively. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Patients homozygous for the variant codon 54B allele (54BB) had worse severity of illness on admission (p = .007), greater likelihood of septic shock (p = .04), and increased odds of ARDS (adjusted odds ratio, 6.7; 95% confidence interval, 1.5-31) when compared with heterozygotes and homozygotes for the wild-type allele. This association with ARDS was especially strong among the 311 patients with septic shock (adjusted odds ratio, 12.0; 95% confidence interval, 1.9-74). Among the patients with ARDS, the 54BB genotype was associated with more daily organ dysfunction (p = .01) and higher mortality (adjusted hazard rate, 4.0; 95% confidence interval, 1.6-10). Development of ARDS and outcomes in ARDS did not vary significantly with variant alleles of codon -221, 52, and 57, but the power to detect an effect was limited secondary to the low allele frequencies. CONCLUSIONS The MBL-2 codon 54BB genotype may be important in ARDS susceptibility and outcome. Additional studies are needed to confirm these findings in other populations.
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Affiliation(s)
- Michelle N Gong
- Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA
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Brown KS, Ryder SD, Irving WL, Sim RB, Hickling TP. Mannan binding lectin and viral hepatitis. Immunol Lett 2006; 108:34-44. [PMID: 17157924 DOI: 10.1016/j.imlet.2006.10.006] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2006] [Revised: 10/29/2006] [Accepted: 10/29/2006] [Indexed: 01/04/2023]
Abstract
Mannan binding lectin (MBL) is a pattern recognition molecule of the innate immune system that binds to sugars on the surface of invading micro-organisms. Target binding, complement activation and other functions of MBL are dependent on the presence of multiple carbohydrate recognition domains. Several polymorphisms in the promoter and structural regions of MBL2 adversely affect the plasma concentration and oligomeric state of MBL. The possession of mutant alleles has been linked to disease outcome for a variety of bacterial and viral infections. Viral hepatitis is caused by unrelated viruses referred to as hepatitis virus A-E. The disease usually has both acute and chronic phases, the latter leading to cirrhosis and hepatocellular carcinoma. Hepatitis viruses B and C (HBV and HCV, respectively) are a significant cause of morbidity worldwide. HBV encodes envelope glycoproteins termed large, middle, and small that may exist in glycosylated or unglycosylated forms on the virion. An interaction between HBV glycoproteins and MBL has been demonstrated in vitro. Significant associations between MBL levels, determined by MBL2 haplotypes, and HBV persistence and disease progression have been described. HCV encodes two highly glycosylated envelope proteins, E1 and E2, which are potential targets for interaction with MBL. Mutant MBL2 haplotypes have been linked to disease progression and response to therapy in HCV infection. Here we summarise the effect of MBL2 polymorphisms on MBL function and how this may relate to disease outcome in HBV and HCV infection.
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Affiliation(s)
- Kristelle S Brown
- Institute of Infection, Immunity and Inflammation, School of Molecular Medical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
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42
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Bouwman LH, Roep BO, Roos A. Mannose-Binding Lectin: Clinical Implications for Infection, Transplantation, and Autoimmunity. Hum Immunol 2006; 67:247-56. [PMID: 16720204 DOI: 10.1016/j.humimm.2006.02.030] [Citation(s) in RCA: 125] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2005] [Indexed: 01/24/2023]
Abstract
Mannose-binding lectin (MBL) is a recognition molecule of the lectin pathway of complement and a key component of innate immunity. MBL variant alleles have been described in the coding region of the MBL gene, which are associated with low MBL serum concentration and impaired MBL structure and function. Both high and low serum levels of functional MBL have been associated with a variety of diseases and disease complications. Functioning as double-edged sword, low MBL serum levels have been shown to enhance the risk for infections. On the other hand, high MBL serum levels and high MBL activity have been associated with inflammatory diseases, transplant rejection, and diabetic nephropathy. Underscoring the Jekyll-and-Hyde character of MBL, both high and low serum MBL levels are associated with several aspects of autoimmune diseases. This review provides a general outline of the genetic and molecular characteristics of MBL and discusses MBL-disease association and its consequence in infection, transplantation, and autoimmunity.
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Affiliation(s)
- Lee H Bouwman
- Department of Surgery, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
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43
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Bak-Romaniszyn L, Cedzyński M, Szemraj J, St Swierzko A, Zeman K, Kałuzyński A, Płaneta-Małecka I. Mannan-binding lectin in children with chronic gastritis. Scand J Immunol 2006; 63:131-5. [PMID: 16476012 DOI: 10.1111/j.1365-3083.2005.01719.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The involvement of mannan-binding lectin (MBL) insufficiency in the pathogenesis of chronic gastritis (CG) in children was investigated. Blood samples were collected from 78 paediatric patients suffering from CG associated with Helicobacter pylori infection (group Hp(+)) and from 41 with the disease not associated with such an infection (group Hp(-)). Control group consisted of 77 children. The frequency of mbl-2 gene mutations and serum protein concentrations did not differ significantly in both groups as compared with controls. An expression of mbl-2 gene in gastric biopsies of CG patients was demonstrated. It was found to be stronger in H. pylori-infected children. The results presented in this paper suggest that MBL deficit/dysfunction probably does not contribute to an increased risk of CG (both associated and not associated with H. pylori infection) in children. However, MBL opsonic effect and/or the lectin pathway of complement activation may be taken into account as possible host defence mechanisms in gastric patients.
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Affiliation(s)
- L Bak-Romaniszyn
- Department of Paediatrics, Preventive Cardiology and Clinical Immunology, Medical University of Łódź, Łódź, Poland
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Chong WP, To YF, Ip WK, Yuen MF, Poon TP, Wong WHS, Lai CL, Lau YL. Mannose-binding lectin in chronic hepatitis B virus infection. Hepatology 2005; 42:1037-45. [PMID: 16231358 DOI: 10.1002/hep.20891] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Mannose binding lectin (MBL) is a pattern-recognition molecule of the innate immune system. The roles of MBL and its gene (mbl2) polymorphisms, -221X/Y and codon 54A/B, in hepatitis B virus (HBV) infection were investigated in this study. We recruited 320 nonprogressed hepatitis B surface antigen (HBsAg) carriers; 199 progressed HBsAg carriers with hepatocellular carcinoma or cirrhosis; 87 spontaneously recovered individuals who were HBsAg negative and anti-HBs and anti HBc positive; and 484 controls who were naïve to HBV. There was no significant difference between nonprogressed carriers, spontaneously recovered individuals, and controls in terms of serum MBL levels and mbl2 polymorphisms distributions. However, the low MBL genotypes had a dose-dependent correlation with the cirrhosis and hepatocellular carcinoma in progressed carriers with odds ratios of 1.36 and 3.21 for the low and extremely low MBL genotypes, respectively (P = .01). The low-expression promoter haplotype XA (OR = 1.97) and the mutant haplotype YB (OR = 1.90) were also associated with the cirrhosis and hepatocellular carcinoma (P = .002). As expected, the lower serum MBL levels in progressed carriers as compared with nonprogressed carriers were due to an overrepresentation of low and extremely low MBL genotypes. Moreover, MBL could bind HBsAg in a dose- and calcium-dependent and mannan-inhibitable manner in vitro, suggesting that binding occurs via the carbohydrate recognition domains. This binding also enhanced C4 deposition. In conclusion, these results suggest that low MBL genotypes associate with the occurrence of cirrhosis and hepatocellular carcinoma in progressed HBsAg carriers, and MBL can bind HBsAg.
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Affiliation(s)
- Wai Po Chong
- Department of Paediatrics and Adolescent Medicine, Hong Kong Jockey Club Clinical Research Centre, Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
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45
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Feo F, De Miglio MR, Simile MM, Muroni MR, Calvisi DF, Frau M, Pascale RM. Hepatocellular carcinoma as a complex polygenic disease. Interpretive analysis of recent developments on genetic predisposition. Biochim Biophys Acta Rev Cancer 2005; 1765:126-47. [PMID: 16216419 DOI: 10.1016/j.bbcan.2005.08.007] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2005] [Revised: 08/25/2005] [Accepted: 08/26/2005] [Indexed: 01/11/2023]
Abstract
The different frequency of hepatocellular carcinoma (HCC) in humans at risk suggests a polygenic predisposition. However, detection of genetic variants is difficult in genetically heterogeneous human population. Studies on mouse and rat models identified 7 hepatocarcinogenesis susceptibility (Hcs) and 2 resistance (Hcr) loci in mice, and 7 Hcs and 9 Hcr loci in rats, controlling multiplicity and size of neoplastic liver lesions. Six liver neoplastic nodule remodeling (Lnnr) loci control number and volume of re-differentiating lesions in rat. A Hcs locus, with high phenotypic effects, and various epistatic gene-gene interactions were identified in rats, suggesting a genetic model of predisposition to hepatocarcinogenesis with different subset of low-penetrance genes, at play in different subsets of population, and a major locus. This model is in keeping with human HCC epidemiology. Several putative modifier genes in rodents, deregulated in HCC, are located in chromosomal segments syntenic to sites of chromosomal aberrations in humans, suggesting possible location of predisposing loci. Resistance to HCC is associated with lower genomic instability and downregulation of cell cycle key genes in preneoplastic and neoplastic lesions. p16(INK4A) upregulation occurs in susceptible and resistant rat lesions. p16(INK4A)-induced growth restraint was circumvented by Hsp90/Cdc37 chaperons and E2f4 nuclear export by Crm1 in susceptible, but not in resistant rats and human HCCs with better prognosis. Thus, protective mechanisms seem to be modulated by HCC modifiers, and differences in their efficiency influence the susceptibility to hepatocarcinogenesis and probably the prognosis of human HCC.
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Affiliation(s)
- F Feo
- Department of Biomedical Sciences, Division of Experimental Pathology and Oncology, University of Sassari, Via P. Manzella 4, 07100 Sasssari, Italy.
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46
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Thio CL, Mosbruger T, Astemborski J, Greer S, Kirk GD, O'Brien SJ, Thomas DL. Mannose binding lectin genotypes influence recovery from hepatitis B virus infection. J Virol 2005; 79:9192-6. [PMID: 15994813 PMCID: PMC1168757 DOI: 10.1128/jvi.79.14.9192-9196.2005] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Mannose binding lectin (MBL) is a central component of the innate immune response and thus may be important for determining hepatitis B virus (HBV) persistence. Since single-nucleotide polymorphisms (SNPs) in the gene encoding MBL (mbl2) alter the level of functional MBL, we hypothesized that mbl2 genotypes are a determinant of HBV persistence or recovery from viral infection. We tested this hypothesis by using a nested case control design with 189 persons with HBV persistence matched to 338 individuals who had naturally recovered from HBV infection. We determined genotypes of two promoter and three exon 1 SNPs in mbl2 and grouped these genotypes according to the amount of functional MBL production. We found that the promoter SNP -221C, which leads to deficient MBL production, was more common in those subjects with viral persistence (odds ratio [OR], 1.38; 95% confidence interval [CI], 1.01 to 1.89; P = 0.04). Those subjects homozygous for the combination of promoter and exon 1 genotypes associated with the highest amount of functional MBL had significantly increased odds of recovery from infection (OR, 0.55; 95% CI, 0.37 to 0.84; P = 0.005). Conversely, those homozygous for the combination of promoter and exon 1 genotypes which produce the lowest amount of functional MBL were more likely to have viral persistence (OR, 1.76; 95% CI, 1.02 to 3.01; P = 0.04). These data are consistent with the hypothesis that functional MBL plays a central role in the pathogenesis of acute hepatitis B.
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Affiliation(s)
- Chloe L Thio
- Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
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47
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Cheong JY, Cho SW, Lim SK, Shin DH, Yoon SK, Lee JE, Hahm KB, Kim JH. Lack of association between hepatitis B virus infection and polymorphism of mannose-binding lectin gene in Korean population. J Korean Med Sci 2005; 20:65-9. [PMID: 15716605 PMCID: PMC2808578 DOI: 10.3346/jkms.2005.20.1.65] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Mannose-binding lectin (MBL) plays an important role in immune defense. This study was undertaken to investigate the association between hepatitis B virus infection and polymorphisms of MBL gene. We assessed the single nucleotide polymorphism at codon 54 in exon 1 of MBL in patients with hepatitis B virus infection and HBsAg negative controls in Korean population. A total of 498 enrolled subjects was classified into four groups. Group 1; Clearance, Group 2; Inactive healthy carrier, Group 3; Chronic hepatitis, Group 4; Liver cirrhosis. MBL gene polymorphisms at codon 54 led to three genotypes (G/G, G/A, A/A). When we divided subjects into clearance group (group 1) and persistence group (group 2-4), G/G genotype and A-allele carrier were observed in 55.6% and 44.4% in clearance group, 64.8% and 35.2% in persistence group (p=0.081), respectively. When hepatitis B virus persistent cases were divided into inactive healthy carrier (group 2) and disease progression group (group 3 and 4), MBL gene polymorphisms at codon 54 were not related to disease progression (p=0.166). MBL gene polymorphism at codon 54 was not associated with the clearance of hepatitis B virus infection nor progression of disease in chronic hepatitis B virus infection.
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Affiliation(s)
- Jae Youn Cheong
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Sung Won Cho
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Sun Kyo Lim
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Do Hyun Shin
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Seung Kew Yoon
- Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea
| | | | - Ki Baik Hahm
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Jin Hong Kim
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
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Deng G, Zhou G, Zhai Y, Li S, Li X, Li Y, Zhang R, Yao Z, Shen Y, Qiang B, Wang Y, He F. Association of estrogen receptor alpha polymorphisms with susceptibility to chronic hepatitis B virus infection. Hepatology 2004; 40:318-26. [PMID: 15368436 DOI: 10.1002/hep.20318] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Several studies have demonstrated that estrogen receptor alpha (ESR1) participates in the pathogenesis of persistent hepatitis B virus (HBV) infection. To examine whether polymorphisms at the ESR1 gene locus are associated with persistent HBV infection, we resequenced ESR1 genomic region for single nucleotide polymorphisms (SNPs) in 27 unrelated Chinese. Two haplotype-tagged SNPs (htSNP), T29C and A252966G, were selected for genotyping in 1,277 persistent HBV-infected cases, 748 spontaneously recovered controls, and 293 nuclear families using polymerase chain reaction (PCR)-restriction fragment length polymorphism (PCR-RFLP) analysis. We observed that the subjects bearing ESR1 29T/T genotype had an increased susceptibility to persistent HBV infection compared to those bearing at least one 29C allele (odds ratio 1.41; 95% CI, 1.17-1.71, P < .001). Consistent with the results of population-based association study, a significantly greater than expected transmission of the 29T allele (56.4%) from heterozygous parents to offspring with persistent HBV infection was observed (chi2 = 4.60, P = .033) using the transmission-disequilibrium test (TDT) in 293 nuclear families. Linkage disequilibrium (LD) mapping analysis indicated that the T29C polymorphism contained within a LD block located from promoter region to intron 3 of ESR1, suggesting that the strong association detected with T29C in ESR1 originated from ESR1 itself. In conclusion, our results suggest that the genetic variation at the ESR1 locus influences susceptibility to persistent HBV infection in a Chinese population.
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Affiliation(s)
- Guohong Deng
- Department of Infectious Diseases, Southwest Hospital, Chongqing, China
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Cedzynski M, Szemraj J, Swierzko AS, Bak-Romaniszyn L, Banasik M, Zeman K, Kilpatrick DC. Mannan-binding lectin insufficiency in children with recurrent infections of the respiratory system. Clin Exp Immunol 2004; 136:304-11. [PMID: 15086395 PMCID: PMC1809017 DOI: 10.1111/j.1365-2249.2004.02453.x] [Citation(s) in RCA: 118] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Blood samples were collected over a 4-year period from 335 children (aged 1-16 years) suffering from recurrent respiratory infections and 78 controls. The patients were subdivided into four groups: I, children with no immune system defects detected (n = 101); II, children with allergies (n = 94); III, children with humoral response defects (n = 93); and IV, children with disturbances of cellular immunity (n = 66). Nineteen patients had both humoral and cellular abnormalities. All patients and controls were investigated to determine the exon 1 and promoter region variants of the mbl-2 gene. MBL serum concentrations were also determined in samples from 291 patients and 75 controls. The proportion of O (B, D or C) alleles was significantly higher in the patient group compared to controls, and this association was strongest for subgroup III. The promoter LX variant frequency was also commoner in the patients as a whole, and significantly so in subgroups II and IV. Genotypes markedly influenced MBL concentrations in all groups, and correlated with ability to activate the lectin pathway of complement activation. The strongest and most significant inverse correlations between serum MBL and respiratory disease were found in patient group III and in 17 patients with multiple humoral and/or cellular abnormalities. Among nine patients with unexpectedly low LP activity in view of their MBL concentrations, one person was found to be MASP-2 deficient. Our results indicate that mannan-binding lectin insufficiency, with or without a coexisting immune defect, is associated with the occurrence of recurrent respiratory infections in childhood, and this relationship is particularly strong and statistically significant in children with concomitant impairments of humoral immunity.
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Affiliation(s)
- M Cedzynski
- Laboratory of Immunobiology of Infections, Centre of Medical Biology and Microbiology, Polish Academy of Sciences, Lodz, Poland.
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50
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Andrade Júnior DRD, Andrade DRD. The influence of the human genome on chronic viral hepatitis outcome. Rev Inst Med Trop Sao Paulo 2004. [DOI: 10.1590/s0036-46652004000300001] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
The mechanisms that determine viral clearance or viral persistence in chronic viral hepatitis have yet to be identified. Recent advances in molecular genetics have permitted the detection of variations in immune response, often associated with polymorphism in the human genome. Differences in host susceptibility to infectious disease and disease severity cannot be attributed solely to the virulence of microbial agents. Several recent advances concerning the influence of human genes in chronic viral hepatitis B and C are discussed in this article: a) the associations between human leukocyte antigen polymorphism and viral hepatic disease susceptibility or resistance; b) protective alleles influencing hepatitis B virus (HBV) and hepatitis C virus (HCV) evolution; c) prejudicial alleles influencing HBV and HCV; d) candidate genes associated with HBV and HCV evolution; d) other genetic factors that may contribute to chronic hepatitis C evolution (genes influencing hepatic stellate cells, TGF-beta1 and TNF-alpha production, hepatic iron deposits and angiotensin II production, among others). Recent discoveries regarding genetic associations with chronic viral hepatitis may provide clues to understanding the development of end-stage complications such as cirrhosis or hepatocellular carcinoma. In the near future, analysis of the human genome will allow the elucidation of both the natural course of viral hepatitis and its response to therapy.
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