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Huang C, Bi J. Expression Regulation and Function of T-Bet in NK Cells. Front Immunol 2021; 12:761920. [PMID: 34675939 PMCID: PMC8524037 DOI: 10.3389/fimmu.2021.761920] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 09/20/2021] [Indexed: 11/14/2022] Open
Abstract
Natural killer (NK) cells are cytotoxic innate lymphocytes that play an important role in immune surveillance. The development, maturation and effector functions of NK cells are orchestrated by the T-box transcription factor T-bet, whose expression is induced by cytokines such as IFN-γ, IL-12, IL-15 and IL-21 through the respective cytokine receptors and downstream JAK/STATs or PI3K-AKT-mTORC1 signaling pathways. In this review, we aim to discuss the expression and regulation of T-bet in NK cells, the role of T-bet in mouse NK cell development, maturation, and function, as well as the role of T-bet in acute, chronic infection, inflammation, autoimmune diseases and tumors.
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Affiliation(s)
- Chen Huang
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Jiacheng Bi
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
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Shu Y, Guo J, Ma X, Yan Y, Wang Y, Chen C, Sun X, Wang H, Yin J, Long Y, Yan X, Lu Z, Petersen F, Yu X, Qiu W. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is associated with IRF7, BANK1 and TBX21 polymorphisms in two populations. Eur J Neurol 2020; 28:595-601. [PMID: 33065758 DOI: 10.1111/ene.14596] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 10/09/2020] [Accepted: 10/10/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND PURPOSE Autoantibodies targeting the GluN1(NR1) subunit of the anti-N-methyl-D-aspartate receptor (NMDAR) cause encephalitis. Although it has been shown that anti-NMDAR encephalitis is associated with human leukocyte antigen (HLA) loci, susceptibility genes for the disease outside the HLA loci remain unidentified. In this study, we aimed to explore the association of anti-NMDAR encephalitis with non-HLA genes. METHODS Two Chinese anti-NMDAR encephalitis cohorts from Han populations were recruited for this study. The North Chinese case-control set consisted of 98 patients and 460 controls, while the South Chinese case-control set included 78 patients and 541 controls. All participants were genotyped for 28 single nucleotide polymorphisms that are associated with autoimmune disorders or infectious diseases. RESULTS In two independent case-control sets, we identified significant associations of anti-NMDAR encephalitis with IRF7 rs1131665 (odds ratio [OR] 3.34, 95% confidence interval [CI] 1.99-5.63; P < 0.000001, Padjusted = 0.00004), BANK1 rs4522865 (OR 1.44, 95% CI 1.15-1.82; P = 0.0017, Padjusted = 0.0149), and TBX21 rs17244587 (OR 2.03, 95% CI 1.35-3.05; P = 0.00051, Padjusted = 0.0066). Furthermore, analysis of the three polymorphisms with clinical features of the disease revealed that the IRF7 rs1131665 was associated with tumor status. CONCLUSION The present study has for the first time identified non-HLA susceptibility genes for anti-NMDAR encephalitis. The association of IRF7, BANK1 and TBX21 with anti-NMDAR encephalitis suggests that B-cell activation, Th1 responses, virus infection and the type I interferon signaling pathway are involved in the pathogenesis of the disease.
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Affiliation(s)
- Y Shu
- Department of Neurology, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.,Priority Area Asthma and Allergy, Research Center Borstel, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Borstel, Germany
| | - J Guo
- Department of Neurology, Tangdu Hospital of Fourth Military Medical University, Xi'an, China
| | - X Ma
- Department of Neurology, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Y Yan
- College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Y Wang
- Department of Neurology, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - C Chen
- Department of Neurology, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - X Sun
- Department of Neurology, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - H Wang
- Department of Neurology, Southern Medical University, Guangzhou, China
| | - J Yin
- Priority Area Asthma and Allergy, Research Center Borstel, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Borstel, Germany
| | - Y Long
- Department of Neurology, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - X Yan
- Department of Neurology, Tangdu Hospital of Fourth Military Medical University, Xi'an, China
| | - Z Lu
- Department of Neurology, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - F Petersen
- Priority Area Asthma and Allergy, Research Center Borstel, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Borstel, Germany
| | - X Yu
- Priority Area Asthma and Allergy, Research Center Borstel, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Borstel, Germany
| | - W Qiu
- Department of Neurology, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
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3
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Pritchard GH, Kedl RM, Hunter CA. The evolving role of T-bet in resistance to infection. Nat Rev Immunol 2020; 19:398-410. [PMID: 30846856 DOI: 10.1038/s41577-019-0145-4] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The identification of T-bet as a key transcription factor associated with the development of IFNγ-producing CD4+ T cells predicted a crucial role for T-bet in cell-mediated immunity and in resistance to many intracellular infections. This idea was reinforced by initial reports showing that T-bet-deficient mice were more susceptible to pathogens that survived within the lysosomal system of macrophages. However, subsequent studies revealed IFNγ-dependent, T-bet-independent pathways of resistance to diverse classes of microorganisms that occupy other intracellular niches. Consequently, a more complex picture has emerged of how T-bet and the related transcription factor eomesodermin (EOMES) coordinate many facets of the immune response to bona fide pathogens as well as commensals. This article provides an overview of the discovery and evolutionary relationship between T-bet and EOMES and highlights the studies that have uncovered broader functions of T-bet in innate and adaptive immunity and in the development of the effector and memory T cell populations that mediate long-term resistance to infection.
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Affiliation(s)
- Gretchen Harms Pritchard
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Ross M Kedl
- Department of Immunology and Microbiology, School of Medicine, University of Colorado, Aurora, CO, USA
| | - Christopher A Hunter
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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4
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Kleinstein SE, Shea PR, Allen AS, Koelle DM, Wald A, Goldstein DB. Genome-wide association study (GWAS) of human host factors influencing viral severity of herpes simplex virus type 2 (HSV-2). Genes Immun 2019; 20:112-120. [PMID: 29535370 PMCID: PMC6113125 DOI: 10.1038/s41435-018-0013-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 11/24/2017] [Accepted: 12/01/2017] [Indexed: 12/28/2022]
Abstract
Herpes simplex virus type 2 (HSV-2) is an incurable viral infection with severity ranging from asymptomatic to frequent recurrences. The viral shedding rate has been shown as a reproducible HSV-2 severity end point that correlates with lesion rates. We used a genome-wide association study (GWAS) to investigate the role of common human genetic variation in HSV-2 severity. We performed a GWAS on 223 HSV-2-positive participants of European ancestry. Severity was measured by viral shedding rate, as defined by the percent of days PCR+ for HSV-2 DNA over at least 30 days. Analyses were performed under linear regression models, adjusted for age, sex, and ancestry. There were no genome-wide significant (p < 5E-08) associations with HSV-2 viral shedding rate. The top nonsignificant SNP (rs75932292, p = 6.77E-08) associated with HSV-2 viral shedding was intergenic, with the nearest known biologically interesting gene (ABCA1) ~130 kbp downstream. Several other SNPs approaching significance were in or near genes with viral or neurological associations, including four SNPs in KIF1B. The current study is the first comprehensive genome-wide investigation of human genetic variation in virologic severity of established HSV-2 infection. However, no significant associations were observed with HSV-2 virologic severity, leaving the exact role of human variation in HSV-2 severity unclear.
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Affiliation(s)
- Sarah E Kleinstein
- Institute for Genomic Medicine, Columbia University, New York, NY, 10032, USA
- Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, 27708, USA
| | - Patrick R Shea
- Institute for Genomic Medicine, Columbia University, New York, NY, 10032, USA
| | - Andrew S Allen
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, 27708, USA
| | - David M Koelle
- Department of Medicine, University of Washington, Seattle, WA, 98195, USA
- Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
- Benaroya Research Institute, Seattle, WA, 98101, USA
- Department of Laboratory Medicine, University of Washington, Seattle, WA, 98195, USA
- Department of Global Health, University of Washington, Seattle, WA, 98195, USA
| | - Anna Wald
- Department of Medicine, University of Washington, Seattle, WA, 98195, USA
- Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
- Department of Epidemiology, University of Washington, Seattle, WA, 98195, USA
| | - David B Goldstein
- Institute for Genomic Medicine, Columbia University, New York, NY, 10032, USA.
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Kenney AD, Dowdle JA, Bozzacco L, McMichael TM, St Gelais C, Panfil AR, Sun Y, Schlesinger LS, Anderson MZ, Green PL, López CB, Rosenberg BR, Wu L, Yount JS. Human Genetic Determinants of Viral Diseases. Annu Rev Genet 2017; 51:241-263. [PMID: 28853921 DOI: 10.1146/annurev-genet-120116-023425] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Much progress has been made in the identification of specific human gene variants that contribute to enhanced susceptibility or resistance to viral diseases. Herein we review multiple discoveries made with genome-wide or candidate gene approaches that have revealed significant insights into virus-host interactions. Genetic factors that have been identified include genes encoding virus receptors, receptor-modifying enzymes, and a wide variety of innate and adaptive immunity-related proteins. We discuss a range of pathogenic viruses, including influenza virus, respiratory syncytial virus, human immunodeficiency virus, human T cell leukemia virus, human papilloma virus, hepatitis B and C viruses, herpes simplex virus, norovirus, rotavirus, parvovirus, and Epstein-Barr virus. Understanding the genetic underpinnings that affect infectious disease outcomes should allow tailored treatment and prevention approaches in the future.
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Affiliation(s)
- Adam D Kenney
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio 43210, USA; , , ,
| | - James A Dowdle
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio 43210, USA;
| | - Leonia Bozzacco
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.,Current affiliation: Target Information Group, Regeneron Pharmaceuticals, Inc., Tarrytown, New York 10591, USA;
| | - Temet M McMichael
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio 43210, USA; , , ,
| | - Corine St Gelais
- Center of Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210, USA; , , ,
| | - Amanda R Panfil
- Center of Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210, USA; , , ,
| | - Yan Sun
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; ,
| | - Larry S Schlesinger
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio 43210, USA; , , , .,Texas Biomedical Research Institute, San Antonio, Texas 78227, USA;
| | - Matthew Z Anderson
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio 43210, USA; , , ,
| | - Patrick L Green
- Center of Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210, USA; , , ,
| | - Carolina B López
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; ,
| | - Brad R Rosenberg
- Program in Immunogenomics, John C. Whitehead Presidential Fellows Program, The Rockefeller University, New York, NY 10065, USA.,Current affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
| | - Li Wu
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio 43210, USA; , , , .,Center of Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210, USA; , , ,
| | - Jacob S Yount
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio 43210, USA; , , ,
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HLA Class I and II alleles, heterozygosity and HLA-KIR interactions are associated with rates of genital HSV shedding and lesions. Genes Immun 2016; 17:412-418. [PMID: 27853144 PMCID: PMC5133162 DOI: 10.1038/gene.2016.42] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 10/10/2016] [Accepted: 10/17/2016] [Indexed: 01/02/2023]
Abstract
Variation at HLA and KIR loci is associated with the severity of viral infections. To assess associations of genital HSV-2 infection with human HLA and KIR genetic loci, we measured the frequencies of genital HSV DNA detection and of genital lesions in HSV-2 seropositive persons. We followed 267 HSV-2 seropositive persons who collected daily genital swabs and recorded lesions for ≥30 days. All persons were laboratory- documented as HIV-seronegative, and all were Caucasian by self-report. HSV detection rate and lesion frequency were compared by genotype using Poisson regression. Overall, HSV was detected on 19.1% of days and lesions on 11.6% of days. The presence of HLA-A*01 was directly associated with HSV detection frequency while the presence of HLA-C*12 was inversely associated with HSV detection frequency. The presence of HLA-A*01 was directly associated with lesion rate, while HLA-A*26, -C*01 and -DQB1*0106 were associated with decreased lesions. We observed an interaction between the absence of both 2DS4del and HLA-Bw4 and higher lesion rate. Heterozygosity of HLA was also associated with reduced lesion frequency. Immune control of genital HSV infection relies on multiple interacting immunogenetic elements, including epistatic interactions between HLA and KIR.
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Sicurella M, Nicoli F, Gallerani E, Volpi I, Berto E, Finessi V, Destro F, Manservigi R, Cafaro A, Ensoli B, Caputo A, Gavioli R, Marconi PC. An attenuated herpes simplex virus type 1 (HSV1) encoding the HIV-1 Tat protein protects mice from a deadly mucosal HSV1 challenge. PLoS One 2014; 9:e100844. [PMID: 25033084 PMCID: PMC4102458 DOI: 10.1371/journal.pone.0100844] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Accepted: 05/30/2014] [Indexed: 12/22/2022] Open
Abstract
Herpes simplex virus types 1 and 2 (HSV1 and HSV2) are common infectious agents in both industrialized and developing countries. They cause recurrent asymptomatic and/or symptomatic infections, and life-threatening diseases and death in newborns and immunocompromised patients. Current treatment for HSV relies on antiviral medications, which can halt the symptomatic diseases but cannot prevent the shedding that occurs in asymptomatic patients or, consequently, the spread of the viruses. Therefore, prevention rather than treatment of HSV infections has long been an area of intense research, but thus far effective anti-HSV vaccines still remain elusive. One of the key hurdles to overcome in anti-HSV vaccine development is the identification and effective use of strategies that promote the emergence of Th1-type immune responses against a wide range of epitopes involved in the control of viral replication. Since the HIV1 Tat protein has several immunomodulatory activities and increases CTL recognition of dominant and subdominant epitopes of heterologous antigens, we generated and assayed a recombinant attenuated replication-competent HSV1 vector containing the tat gene (HSV1-Tat). In this proof-of-concept study we show that immunization with this vector conferred protection in 100% of mice challenged intravaginally with a lethal dose of wild-type HSV1. We demonstrate that the presence of Tat within the recombinant virus increased and broadened Th1-like and CTL responses against HSV-derived T-cell epitopes and elicited in most immunized mice detectable IgG responses. In sharp contrast, a similarly attenuated HSV1 recombinant vector without Tat (HSV1-LacZ), induced low and different T cell responses, no measurable antibody responses and did not protect mice against the wild-type HSV1 challenge. These findings strongly suggest that recombinant HSV1 vectors expressing Tat merit further investigation for their potential to prevent and/or contain HSV1 infection and dissemination.
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Affiliation(s)
- Mariaconcetta Sicurella
- Department of Life Sciences and Biotechnology, Section of Applied Microbiology and Pathology, University of Ferrara, Ferrara, Italy
- Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Francesco Nicoli
- Department of Life Sciences and Biotechnology, Section of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, Italy
| | - Eleonora Gallerani
- Department of Life Sciences and Biotechnology, Section of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, Italy
| | - Ilaria Volpi
- Department of Life Sciences and Biotechnology, Section of Applied Microbiology and Pathology, University of Ferrara, Ferrara, Italy
| | - Elena Berto
- Department of Life Sciences and Biotechnology, Section of Applied Microbiology and Pathology, University of Ferrara, Ferrara, Italy
| | - Valentina Finessi
- Department of Life Sciences and Biotechnology, Section of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, Italy
| | - Federica Destro
- Department of Life Sciences and Biotechnology, Section of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, Italy
- Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Roberto Manservigi
- Department of Life Sciences and Biotechnology, Section of Applied Microbiology and Pathology, University of Ferrara, Ferrara, Italy
| | - Aurelio Cafaro
- National AIDS Center, Istituto Superiore di Sanità, Rome, Italy
| | - Barbara Ensoli
- National AIDS Center, Istituto Superiore di Sanità, Rome, Italy
| | - Antonella Caputo
- Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Riccardo Gavioli
- Department of Life Sciences and Biotechnology, Section of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, Italy
| | - Peggy C. Marconi
- Department of Life Sciences and Biotechnology, Section of Applied Microbiology and Pathology, University of Ferrara, Ferrara, Italy
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Svensson A, Tunbäck P, Nordström I, Shestakov A, Padyukov L, Eriksson K. STAT4 regulates antiviral gamma interferon responses and recurrent disease during herpes simplex virus 2 infection. J Virol 2012; 86:9409-15. [PMID: 22718836 PMCID: PMC3416106 DOI: 10.1128/jvi.00947-12] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2012] [Accepted: 06/15/2012] [Indexed: 01/09/2023] Open
Abstract
STAT4 is an important transcription factor that contributes to the incidence and severity of different autoimmune diseases and is implicated in the antiviral immune responses in mice. In this study, we evaluated the role of STAT4 in human and murine herpes simplex virus 2 (HSV-2) infections. We show that STAT4 regulates antiviral gamma interferon (IFN-γ) responses and disease severity during chronic HSV-2 infections in humans and vaccine-induced IFN-γ-mediated protection against HSV-2 infection in mice. In a cohort of 228 HSV-2-infected individuals, representing both patients with recurrent disease and asymptomatic HSV-2 carriers, we found that genetic variations in the STAT4 gene were associated with asymptomatic HSV-2 infection, as well as with increased in vitro secretion of IFN-γ in response to the virus. Mice that lacked STAT4 had impaired HSV-2-specific IFN-γ production and delayed-type hypersensitivity responses following vaccination, which led to impaired viral clearance in the genital tract of vaccinated animals after a genital HSV-2 challenge. We conclude that STAT4 plays an important role in IFN-γ-mediated HSV-2-specific immunity, affecting the severity of genital HSV-2 infection.
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Affiliation(s)
- Alexandra Svensson
- Department of Rheumatology & Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg
| | - Petra Tunbäck
- Department of Dermatovenerology, Sahlgrenska University Hospital, Gothenburg
| | - Inger Nordström
- Department of Rheumatology & Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg
| | - Andrey Shestakov
- Department of Rheumatology & Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg
| | - Leonid Padyukov
- Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Kristina Eriksson
- Department of Rheumatology & Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg
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Svensson A, Tunbäck P, Nordström I, Padyukov L, Eriksson K. Polymorphisms in Toll-like receptor 3 confer natural resistance to human herpes simplex virus type 2 infection. J Gen Virol 2012; 93:1717-1724. [PMID: 22552940 DOI: 10.1099/vir.0.042572-0] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Lack of Toll-like receptor 3 (TLR3) functional activity predisposes children to human herpesvirus 1 (HSV-1) encephalitis. In this study, we have investigated whether there is any link between TLR3 and adult HSV-2 infection by studying genetic variations in TLR3. The frequency of four single-nucleotide polymorphisms (SNPs) in the TLR3 gene in 239 patients with genital HSV-2 infection and 162 healthy controls, as well as the impact of these variants on TLR3 gene-expression levels, were compared. Two SNPs in the TLR3 gene (rs13126816 and rs3775291) were associated with a reduced incidence of HSV-2 infection. The minor allelic variants at both rs13126816 and rs3775291 were more common among healthy HSV-2-seronegative subjects than among HSV-2-infected individuals. This was even more apparent in HSV-1-seronegative individuals. There was, however, no association between any of the four TLR3 SNPs and HSV-2 disease severity, as they were expressed at similar proportions in asymptomatic and symptomatic HSV-2-infected patients alike. Furthermore, when assessing TLR3 mRNA expression in a limited number of HSV-2-infected individuals, we found that individuals carrying the homozygous genotypes for the minor alleles had significantly higher levels of TLR3 mRNA expression in peripheral blood mononuclear cells in response to HSV-2 stimulation than individuals that were homozygous for the major allele variants. Taken together, these results suggest that genetic variations in TLR3 may affect the susceptibility to HSV-2 infection in humans.
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Affiliation(s)
- Alexandra Svensson
- Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Sweden
| | - Petra Tunbäck
- Department of Dermatovenerology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Inger Nordström
- Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Sweden
| | - Leonid Padyukov
- Rheumatology Unit, Department of Medicine, Karolinska Institute, Stockholm, Sweden
| | - Kristina Eriksson
- Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Sweden
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10
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Fyall KM, Fong AM, Rao SB, Ibrahim JG, Waxweiler WT, Thomas NE. The TBX21 transcription factor T-1993C polymorphism is associated with decreased IFN-γ and IL-4 production by primary human lymphocytes. Hum Immunol 2012; 73:673-6. [PMID: 22521571 DOI: 10.1016/j.humimm.2012.03.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2011] [Revised: 03/18/2012] [Accepted: 03/19/2012] [Indexed: 01/17/2023]
Abstract
T-bet is a transcription factor that drives the Th1 immune response primarily through promoting expression of the IFN-γ gene. Polymorphisms in the T-bet gene, TBX21, have been associated with immune-mediated diseases such as asthma and systemic sclerosis. We found that the TBX21 promoter polymorphism T-1993C is associated with a significant decrease in IL-4 and IFN-γ production by stimulated primary human lymphocytes from healthy participants.
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Affiliation(s)
- K M Fyall
- Department of Dermatology, University of North Carolina, Chapel Hill, NC , USA
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Zhang LH, Li Q, Li P, Zhu ST, Wang J, Yang HL, Xu CQ, Guo XH. Association between gastric cancer and -1993 polymorphism of TBX21 gene. World J Gastroenterol 2012; 18:1117-22. [PMID: 22416188 PMCID: PMC3296987 DOI: 10.3748/wjg.v18.i10.1117] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2011] [Revised: 09/01/2011] [Accepted: 09/08/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the association between the polymorphism of TBX21 gene and the risk of gastric cancer in a Chinese population.
METHODS: The -1993 polymorphism located in TBX21 gene promoter region was identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The risk between TBX21 gene genotype and gastric cancer was determined by multivariate logistic regression analysis in 220 gastric cancer patients and 262 cancer-free controls matched by age, sex and ethnicity.
RESULTS: Compared with the TBX21 -1993TT genotype, the -1993CC genotype exhibited a significantly elevated risk for gastric cancer [Odds ratio (OR) = 3.42, 95% confidence interval (CI): 1.41-8.31]. The relationship between the -1993 polymorphic genotype and the invasive status such as lymph node and distant metastasis was found among the gastric cancer patients (OR = 4.02, 95% CI: 1.87-8.66; OR = 7.02, 95% CI: 3.44-14.34, respectively).
CONCLUSION: TBX21 -1993 polymorphism might contribute to the risk of gastric cancer, especially to the distant metastasis.
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12
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Rubicz R, Leach CT, Kraig E, Dhurandhar NV, Duggirala R, Blangero J, Yolken R, Göring HHH. Genetic factors influence serological measures of common infections. Hum Hered 2011; 72:133-41. [PMID: 21996708 DOI: 10.1159/000331220] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2011] [Accepted: 07/15/2011] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND/AIMS Antibodies against infectious pathogens provide information on past or present exposure to infectious agents. While host genetic factors are known to affect the immune response, the influence of genetic factors on antibody levels to common infectious agents is largely unknown. Here we test whether antibody levels for 13 common infections are significantly heritable. METHODS IgG antibodies to Chlamydophila pneumoniae, Helicobacter pylori, Toxoplasma gondii, adenovirus 36 (Ad36), hepatitis A virus, influenza A and B, cytomegalovirus, Epstein-Barr virus, herpes simplex virus (HSV)-1 and -2, human herpesvirus-6, and varicella zoster virus were determined for 1,227 Mexican Americans. Both quantitative and dichotomous (seropositive/seronegative) traits were analyzed. Influences of genetic and shared environmental factors were estimated using variance components pedigree analysis, and sharing of underlying genetic factors among traits was investigated using bivariate analyses. RESULTS Serological phenotypes were significantly heritable for most pathogens (h(2) = 0.17-0.39), except for Ad36 and HSV-2. Shared environment was significant for several pathogens (c(2) = 0.10-0.32). The underlying genetic etiology appears to be largely different for most pathogens. CONCLUSIONS Our results demonstrate, for the first time for many of these pathogens, that individual genetic differences of the human host contribute substantially to antibody levels to many common infectious agents, providing impetus for the identification of underlying genetic variants, which may be of clinical importance.
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Affiliation(s)
- Rohina Rubicz
- Department of Genetics, Texas Biomedical Research Institute, University of Texas Health Science Center at San Antonio, USA. rohina @ TxBiomedGenetics.org
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Li JR, Li JG, Deng GH, Zhao WL, Dan YJ, Wang YM, Chen S. A common promoter variant of TBX21 is associated with allele specific binding to Yin-Yang 1 and reduced gene expression. Scand J Immunol 2011; 73:449-58. [PMID: 21272048 DOI: 10.1111/j.1365-3083.2011.02520.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
T-bet is a key regulator for the lineage commitment in CD4 T helper (Th) 1 cells by activating the hallmark production of interferon-γ, and its expression level is linked to autoimmune, infectious, and allergic diseases. A T to C base substitution has been identified at position -1993 in the TBX21 (encoding T-bet) promoter and has been associated with asthma and systemic lupus erythematosus. This study aimed to investigate the molecular mechanisms responsible for the influence of the T-1993C polymorphism on transcription and its functional effect by luciferase reporter, EMSAs, Chromatin immunoprecipitation assay, and flow cytometric analysis of intracellular T-bet, IFN-γ and IL-4 expression in activated CD4(+) T cells. The presence of a -1993T allele obviously increases promoter activity compared with that of a promoter with a -1993C allele. TBX21 promoter carrying -1993C allele possesses significantly stronger binding affinity to the Yin Yang 1 (YY1) transcription factor than that carrying -1993T allele. YY1 overexpression decreased TBX21 promoter function in a T cell line, demonstrating that this element functions as a repressor. The C to T base exchange relieves the repression mediated by YY1. The individuals carrying -1993C allele were determined to have significantly diminished expression of TBX21 and IFN-γ and increased IL-4 production in cells compared with the individuals carrying -1993T allele (P < 0.05). These findings demonstrate that the TBX21 T-1993C polymorphism represses TBX21 expression and Th1 cytokine production through control of YY1, which might result in the imbalance between Th1 and Th2 immune responses in autoimmune or allergic diseases.
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Affiliation(s)
- J-R Li
- Institute of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China
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Abstract
The immune system faces the arduous task of defending the mucosal surfaces from invading pathogens, but must simultaneously repress responses against commensal organisms and other inert antigens that are abundant in the external environment, as inappropriate immune activation might expose the host to increased risk of autoimmunity. The behavior of individual immune cells is governed by the expression of transcription factors that are responsible for switching immune response genes on and off. T-bet (T-box expressed in T cells) has emerged as one of the key transcription factors responsible for controlling the fate of both innate and adaptive immune cells, and its expression in different immune cells found at mucosal surfaces is capable of dictating the critical balance between permitting robust host immunity and limiting susceptibility to autoimmunity and allergy.
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Chen S, Zhao W, Tan W, Xu B, Dan Y, Mao Q, Kuang X, Wang Y, Deng G. Association of TBX21 T-1993C polymorphism with viral persistence but not disease progression in hepatitis B virus carriers. Hepatol Res 2009; 39:716-23. [PMID: 19473434 DOI: 10.1111/j.1872-034x.2009.00503.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
AIM Transcription factor T-bet is responsible for the differentiation of naive T lymphocytes, and its expression level is linked with different responses to some viral infections, including hepatitis B virus (HBV) infection. In this report we examine whether promoter polymorphisms of the TBX21 gene (encoding T-bet) are associated with susceptibility to HBV persistence or disease progression in chronic HBV carriers. METHODS Three previously reported promoter polymorphisms, T-1993C, T-1514C and G-1499A, were analyzed by polymerase chain reaction restriction fragment length polymorphism analysis. Two common polymorphisms, T-1993C and T-1514C, were selected for genotyping in 1074 chronic HBV carriers, 310 spontaneously recovered controls and 374 HBV naive controls. Of 1074 HBV carriers, 234 were considered to be asymptomatic carriers and 840 were found to have chronic progressive liver disease including cirrhosis and hepatocellular carcinoma. Haplotypes were constructed for each subject and associations with the susceptibility to persistent HBV infection were estimated by logistic regression. RESULTS The -1993C allele in the TBX21 promoter was significantly more common among chronic HBV carriers compared with recovered controls (chi(2) = 6.65, P = 0.01). In contrast, the frequency of TT haplotype at positions -1993/-1514, was significantly higher in recovered controls than chronic HBV carriers (P = 0.0027, odds ratio = 1.57; 95% confidence interval, 1.16-2.12). In HBV carriers, the TBX21 promoter polymorphisms were not linked to disease progression. CONCLUSION The TBX21 promoter polymorphisms do not appear to be determinant of disease progression in Chinese HBV carriers. The T-1993C polymorphism in the TBX21 promoter influences susceptibility to persistent HBV infection.
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Affiliation(s)
- Song Chen
- Department of Infectious Diseases, Southwest Hospital, the Third Military Medical University, Chongqing, China
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