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Wang, Hui
Publikationer (10 of 19) Visa alla publikationer
Hu, H., Wang, H., Xiao, Y., Jin, J., Chang, J.-H., Zou, Q., . . . Sun, S.-C. (2016). Otud7b facilitates T cell activation and inflammatory responses by regulating Zap70 ubiquitination. Journal of Experimental Medicine, 213(3), 399-414
Öppna denna publikation i ny flik eller fönster >>Otud7b facilitates T cell activation and inflammatory responses by regulating Zap70 ubiquitination
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2016 (Engelska)Ingår i: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 213, nr 3, s. 399-414Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Signal transduction from the T cell receptor (TCR) is crucial for T cell-mediated immune responses and, when deregulated, also contributes to the development of autoimmunity. How TCR signaling is regulated is incompletely understood. In this study, we demonstrate a ubiquitin-dependent mechanism in which the deubiquitinase Otud7b has a crucial role in facilitating TCR signaling. Upon TCR ligation, Otud7b is rapidly recruited to the tyrosine kinase Zap70, a central mediator of TCR-proximal signaling. Otud7b deficiency attenuates the activation of Zap70 and its downstream pathways and impairs T cell activation and differentiation, rendering mice refractory to T cell-mediated autoimmune and inflammatory responses. Otud7b facilitated Zap70 activation by deubiquitinating Zap70, thus preventing the association of Zap70 with the negative-regulatory phosphatases Sts1 and Sts2. These findings establish Otud7b as a positive regulator of TCR-proximal signaling and T cell activation, highlighting the importance of deubiquitination in regulating Zap70 function.

Ort, förlag, år, upplaga, sidor
ROCKEFELLER UNIV PRESS, 2016
Nationell ämneskategori
Klinisk medicin
Identifikatorer
urn:nbn:se:liu:diva-127571 (URN)10.1084/jem.20151426 (DOI)000373390300008 ()26903241 (PubMedID)
Anmärkning

Funding Agencies|National Institutes of Health [AI057555, AI064639, GM84459, AI104519]; Center for Inflammation and Cancer at the MD Anderson Cancer Center [P30CA016672]

Tillgänglig från: 2016-05-04 Skapad: 2016-05-03 Senast uppdaterad: 2017-11-30
Gustafsson, M., Gawel, D., Alfredsson, L., Baranzini, S., Bjorkander, J., Blomgran, R., . . . Benson, M. (2015). A validated gene regulatory network and GWAS identifies early regulators of T cell-associated diseases. Science Translational Medicine, 7(313), Article ID 313ra178.
Öppna denna publikation i ny flik eller fönster >>A validated gene regulatory network and GWAS identifies early regulators of T cell-associated diseases
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2015 (Engelska)Ingår i: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 7, nr 313, artikel-id 313ra178Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Early regulators of disease may increase understanding of disease mechanisms and serve as markers for presymptomatic diagnosis and treatment. However, early regulators are difficult to identify because patients generally present after they are symptomatic. We hypothesized that early regulators of T cell-associated diseases could be found by identifying upstream transcription factors (TFs) in T cell differentiation and by prioritizing hub TFs that were enriched for disease-associated polymorphisms. A gene regulatory network (GRN) was constructed by time series profiling of the transcriptomes and methylomes of human CD4(+) T cells during in vitro differentiation into four helper T cell lineages, in combination with sequence-based TF binding predictions. The TFs GATA3, MAF, and MYB were identified as early regulators and validated by ChIP-seq (chromatin immunoprecipitation sequencing) and small interfering RNA knockdowns. Differential mRNA expression of the TFs and their targets in T cell-associated diseases supports their clinical relevance. To directly test if the TFs were altered early in disease, T cells from patients with two T cell-mediated diseases, multiple sclerosis and seasonal allergic rhinitis, were analyzed. Strikingly, the TFs were differentially expressed during asymptomatic stages of both diseases, whereas their targets showed altered expression during symptomatic stages. This analytical strategy to identify early regulators of disease by combining GRNs with genome-wide association studies may be generally applicable for functional and clinical studies of early disease development.

Ort, förlag, år, upplaga, sidor
AMER ASSOC ADVANCEMENT SCIENCE, 2015
Nationell ämneskategori
Biologiska vetenskaper Klinisk medicin
Identifikatorer
urn:nbn:se:liu:diva-123522 (URN)10.1126/scitranslmed.aad2722 (DOI)000365237400003 ()26560356 (PubMedID)
Anmärkning

Funding Agencies|Cancer fund, Swedish Medical Research Council [K2013-61X-22310-01-04, 2012-3168]; Academy of Finland Centre of Excellence in Molecular Systems Immunology and Physiology Research [250114]; Sigrid Juselius Foundation; Generalitat de Catalunya AGAUR [2014-SGR364]; Spanish Association Against Cancer; Spanish Ministry of Health ISCIII FIS [PI12/01528]; RTICC [RD12/0036/0008]

Tillgänglig från: 2015-12-22 Skapad: 2015-12-21 Senast uppdaterad: 2018-04-10Bibliografiskt granskad
Zhou, Y., Wang, H., Wang, C., Qiu, X., Benson, M., Yin, X., . . . Han, X. (2015). Roles of miRNAs in microcystin-LR-induced Sertoli cell toxicity. Toxicology and Applied Pharmacology, 287(1)
Öppna denna publikation i ny flik eller fönster >>Roles of miRNAs in microcystin-LR-induced Sertoli cell toxicity
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2015 (Engelska)Ingår i: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 287, nr 1Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Microcystin (MC)-LR, a cyclic heptapeptide, is a potent reproductive system toxin. To understand the molecular mechanisms of MC-induced reproductive system cytotoxicity, we evaluated global changes of miRNA and mRNA expression in mouse Sertoli cells following MC-LR treatment. Our results revealed that the exposure to MC-LR resulted in an altered miRNA expression profile that might be responsible for the modulation of mRNA expression. Bio-functional analysis indicated that the altered genes were involved in specific cellular processes, including cell death and proliferation. Target gene analysis suggested that junction injury in Sertoli cells exposed to MC-LR might be mediated by miRNAs through the regulation of the Sertoli cell-Sertoli cell pathway. Collectively, these findings may enhance our understanding on the modes of action of MC-LR on mouse Sertoli cells as well as the molecular mechanisms underlying the toxicity of MC-LR on the male reproductive system.

Ort, förlag, år, upplaga, sidor
Elsevier, 2015
Nyckelord
Microcystin-LR; microRNA; mRNA; Sertoli cell; Bioinformatics; Toxicity
Nationell ämneskategori
Klinisk medicin
Identifikatorer
urn:nbn:se:liu:diva-120328 (URN)10.1016/j.taap.2015.05.008 (DOI)000357766400001 ()25986756 (PubMedID)
Anmärkning

Funding Agencies|National Natural Science Foundation of China [31370524, 31200401, 21377052, 81170054]; Natural Science Foundation of Jiangsu Province of China [BK2012307, BK20131281, BK2011570]; Specialized Research Fund for Doctoral Program of Higher Education (SRFDP) of Peoples Republic of China [20130091110050]; Open Research Fund of State Key Laboratory of Bioelectronics, Southeast University [G5]

Tillgänglig från: 2015-07-31 Skapad: 2015-07-31 Senast uppdaterad: 2017-12-04
Bruhn, S., Fang, Y., Barrenäs, F., Gustafsson, M., Zhang, H., Konstantinell, A., . . . Benson, M. (2014). A Generally Applicable Translational Strategy Identifies S100A4 as a Candidate Gene in Allergy. Science Translational Medicine, 6(218)
Öppna denna publikation i ny flik eller fönster >>A Generally Applicable Translational Strategy Identifies S100A4 as a Candidate Gene in Allergy
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2014 (Engelska)Ingår i: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 6, nr 218Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The identification of diagnostic markers and therapeutic candidate genes in common diseases is complicated by the involvement of thousands of genes. We hypothesized that genes co-regulated with a key gene in allergy, IL13, would form a module that could help to identify candidate genes. We identified a T helper 2 (T(H)2) cell module by small interfering RNA-mediated knockdown of 25 putative IL13-regulating transcription factors followed by expression profiling. The module contained candidate genes whose diagnostic potential was supported by clinical studies. Functional studies of human TH2 cells as well as mouse models of allergy showed that deletion of one of the genes, S100A4, resulted in decreased signs of allergy including TH2 cell activation, humoral immunity, and infiltration of effector cells. Specifically, dendritic cells required S100A4 for activating T cells. Treatment with an anti-S100A4 antibody resulted in decreased signs of allergy in the mouse model as well as in allergen-challenged T cells from allergic patients. This strategy, which may be generally applicable to complex diseases, identified and validated an important diagnostic and therapeutic candidate gene in allergy.

Ort, förlag, år, upplaga, sidor
American Association for the Advancement of Science, 2014
Nationell ämneskategori
Klinisk medicin Medicinska och farmaceutiska grundvetenskaper
Identifikatorer
urn:nbn:se:liu:diva-104118 (URN)10.1126/scitranslmed.3007410 (DOI)000329789600003 ()
Tillgänglig från: 2014-02-07 Skapad: 2014-02-07 Senast uppdaterad: 2018-01-11
Nestor, C., Barrenäs, F., Wang, H., Lentini, A., Zhang, H., Bruhn, S., . . . Benson, M. (2014). DNA Methylation Changes Separate Allergic Patients from Healthy Controls and May Reflect Altered CD4(+) T-Cell Population Structure. PLoS Genetics, 10(1), e1004059
Öppna denna publikation i ny flik eller fönster >>DNA Methylation Changes Separate Allergic Patients from Healthy Controls and May Reflect Altered CD4(+) T-Cell Population Structure
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2014 (Engelska)Ingår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, nr 1, s. e1004059-Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Altered DNA methylation patterns in CD4(+) T-cells indicate the importance of epigenetic mechanisms in inflammatory diseases. However, the identification of these alterations is complicated by the heterogeneity of most inflammatory diseases. Seasonal allergic rhinitis (SAR) is an optimal disease model for the study of DNA methylation because of its welldefined phenotype and etiology. We generated genome-wide DNA methylation (N-patients = 8, N-controls = 8) and gene expression (N-patients = 9, N-controls = 10) profiles of CD4(+) T-cells from SAR patients and healthy controls using Illuminas HumanMethylation450 and HT-12 microarrays, respectively. DNA methylation profiles clearly and robustly distinguished SAR patients from controls, during and outside the pollen season. In agreement with previously published studies, gene expression profiles of the same samples failed to separate patients and controls. Separation by methylation (N-patients = 12, N-controls = 12), but not by gene expression (N-patients = 21, N-controls = 21) was also observed in an in vitro model system in which purified PBMCs from patients and healthy controls were challenged with allergen. We observed changes in the proportions of memory T-cell populations between patients (N-patients = 35) and controls (N-controls = 12), which could explain the observed difference in DNA methylation. Our data highlight the potential of epigenomics in the stratification of immune disease and represents the first successful molecular classification of SAR using CD4(+) T cells.

Ort, förlag, år, upplaga, sidor
Public Library of Science, 2014
Nationell ämneskategori
Klinisk medicin Medicinska och farmaceutiska grundvetenskaper
Identifikatorer
urn:nbn:se:liu:diva-107871 (URN)10.1371/journal.pgen.1004059 (DOI)000336525000030 ()
Tillgänglig från: 2014-06-23 Skapad: 2014-06-23 Senast uppdaterad: 2019-02-11
Schoenrock, A., Samanfar, B., Pitre, S., Hooshyar, M., Jin, K., Phillips, C. A., . . . Golshani, A. (2014). Efficient prediction of human protein-protein interactions at a global scale. BMC bioinformatics, 15(1), 383
Öppna denna publikation i ny flik eller fönster >>Efficient prediction of human protein-protein interactions at a global scale
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2014 (Engelska)Ingår i: BMC bioinformatics, ISSN 1471-2105, Vol. 15, nr 1, s. 383-Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

BackgroundOur knowledge of global protein-protein interaction (PPI) networks in complex organisms such as humans is hindered by technical limitations of current methods.ResultsOn the basis of short co-occurring polypeptide regions, we developed a tool called MP-PIPE capable of predicting a global human PPI network within 3 months. With a recall of 23% at a precision of 82.1%, we predicted 172,132 putative PPIs. We demonstrate the usefulness of these predictions through a range of experiments.ConclusionsThe speed and accuracy associated with MP-PIPE can make this a potential tool to study individual human PPI networks (from genomic sequences alone) for personalized medicine.

Ort, förlag, år, upplaga, sidor
BioMed Central, 2014
Nationell ämneskategori
Klinisk medicin
Identifikatorer
urn:nbn:se:liu:diva-114135 (URN)10.1186/s12859-014-0383-1 (DOI)000347647900001 ()25492630 (PubMedID)
Tillgänglig från: 2015-02-10 Skapad: 2015-02-10 Senast uppdaterad: 2015-04-10Bibliografiskt granskad
Gustafsson, M., Edström, M., Gawel, D., Nestor, C., Wang, H., Zhang, H., . . . Benson, M. (2014). Integrated genomic and prospective clinical studies show the importance of modular pleiotropy for disease susceptibility, diagnosis and treatment. Genome Medicine, 6(17)
Öppna denna publikation i ny flik eller fönster >>Integrated genomic and prospective clinical studies show the importance of modular pleiotropy for disease susceptibility, diagnosis and treatment
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2014 (Engelska)Ingår i: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 6, nr 17Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background: Translational research typically aims to identify and functionally validate individual, disease-specific genes. However, reaching this aim is complicated by the involvement of thousands of genes in common diseases, and that many of those genes are pleiotropic, that is, shared by several diseases. Methods: We integrated genomic meta-analyses with prospective clinical studies to systematically investigate the pathogenic, diagnostic and therapeutic roles of pleiotropic genes. In a novel approach, we first used pathway analysis of all published genome-wide association studies (GWAS) to find a cell type common to many diseases. Results: The analysis showed over-representation of the T helper cell differentiation pathway, which is expressed in T cells. This led us to focus on expression profiling of CD4(+) T cells from highly diverse inflammatory and malignant diseases. We found that pleiotropic genes were highly interconnected and formed a pleiotropic module, which was enriched for inflammatory, metabolic and proliferative pathways. The general relevance of this module was supported by highly significant enrichment of genetic variants identified by all GWAS and cancer studies, as well as known diagnostic and therapeutic targets. Prospective clinical studies of multiple sclerosis and allergy showed the importance of both pleiotropic and disease specific modules for clinical stratification. Conclusions: In summary, this translational genomics study identified a pleiotropic module, which has key pathogenic, diagnostic and therapeutic roles.

Ort, förlag, år, upplaga, sidor
BioMed Central, 2014
Nationell ämneskategori
Klinisk medicin Medicinska och farmaceutiska grundvetenskaper
Identifikatorer
urn:nbn:se:liu:diva-106873 (URN)10.1186/gm534 (DOI)000334631300002 ()
Tillgänglig från: 2014-05-28 Skapad: 2014-05-23 Senast uppdaterad: 2018-04-10
Zhang, H., Cardell, L. O., Björkander, J., Benson, M. & Wang, H. (2013). Comprehensive Profiling of Peripheral Immune Cells and Subsets in Patients with Intermittent Allergic Rhinitis Compared to Healthy Controls and After Treatment with Glucocorticoids. Inflammation, 36(4), 821-829
Öppna denna publikation i ny flik eller fönster >>Comprehensive Profiling of Peripheral Immune Cells and Subsets in Patients with Intermittent Allergic Rhinitis Compared to Healthy Controls and After Treatment with Glucocorticoids
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2013 (Engelska)Ingår i: Inflammation, ISSN 0360-3997, E-ISSN 1573-2576, Vol. 36, nr 4, s. 821-829Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Intermittent allergic rhinitis (IAR) is a common allergic disease, which is associated with local infiltration of T cells, eosinophils, and basophils. However, changes of circulating inflammatory cells may reflect local and systemic allergic inflammation and potentially, also the response to treatment with glucocorticoids (GCs). In this study, we comprehensively profiled peripheral blood immune cells and subsets from 12 patients with IAR during the birch pollen season before and after GC treatment and nine healthy controls by flow cytometry. Orthogonal partial least squares discriminant analysis (OPLS-DA) identified that peripheral immune cells and subsets markedly separated symptomatic patients and controls. Eosinophils, basophils, and Th2 cells contributed most to the separation. However, there was no good separation between patients before and after GC treatment. Local allergic inflammation in the nasal mucosa is associated with increased circulating Th2 cells, eosinophils, and basophils. Local GC treatment has limited effects on circulating immune cells.

Ort, förlag, år, upplaga, sidor
Springer, 2013
Nyckelord
glucocorticoids, orthogonal partial least squares, discriminant analysis, peripheral blood, intermittent allergic rhinitis
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-91691 (URN)10.1007/s10753-013-9608-0 (DOI)000321641300005 ()23413042 (PubMedID)
Tillgänglig från: 2013-04-29 Skapad: 2013-04-29 Senast uppdaterad: 2017-12-06
Couto Alves, A., Bruhn, S., Ramasamy, A., Wang, H., Holloway, J. W., Hartikainen, A.-L., . . . Coin, L. J. (2013). Dysregulation of Complement System and CD4+T Cell Activation Pathways Implicated in Allergic Response. PLoS ONE, 8(10)
Öppna denna publikation i ny flik eller fönster >>Dysregulation of Complement System and CD4+T Cell Activation Pathways Implicated in Allergic Response
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2013 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 10Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Allergy is a complex disease that is likely to involve dysregulated CD4+ T cell activation. Here we propose a novel methodology to gain insight into how coordinated behaviour emerges between disease-dysregulated pathways in response to pathophysiological stimuli. Using peripheral blood mononuclear cells of allergic rhinitis patients and controls cultured with and without pollen allergens, we integrate CD4+ T cell gene expression from microarray data and genetic markers of allergic sensitisation from GWAS data at the pathway level using enrichment analysis; implicating the complement system in both cellular and systemic response to pollen allergens. We delineate a novel disease network linking T cell activation to the complement system that is significantly enriched for genes exhibiting correlated gene expression and protein-protein interactions, suggesting a tight biological coordination that is dysregulated in the disease state in response to pollen allergen but not to diluent. This novel disease network has high predictive power for the gene and protein expression of the Th2 cytokine profile (IL-4, IL-5, IL-10, IL-13) and of the Th2 master regulator (GATA3), suggesting its involvement in the early stages of CD4+ T cell differentiation. Dissection of the complement system gene expression identifies 7 genes specifically associated with atopic response to pollen, including C1QR1, CFD, CFP, ITGB2, ITGAX and confirms the role of C3AR1 and C5AR1. Two of these genes (ITGB2 and C3AR1) are also implicated in the network linking complement system to T cell activation, which comprises 6 differentially expressed genes. C3AR1 is also significantly associated with allergic sensitisation in GWAS data.

Ort, förlag, år, upplaga, sidor
Public Library of Science, 2013
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-100479 (URN)10.1371/journal.pone.0074821 (DOI)000325552200004 ()
Anmärkning

Funding Agencies|European Commission|223367|Academy of Finland (Centre of Excellence in Complex Disease Genetics and SALVE)|1047811203151292691114194139900/24300796|University Hospital Oulu||Biocenter||University of Oulu|75617|NHLBI through STAMPEED program|5R01HL087679-021RL1MH083268-01|NIH/NIMH|5R01MH63706:02|ENGAGE project|HEALTH-F4-2007-201413|Medical Research Council, UK (PrevMetSyn/SALVE)||Academy of Finland||Biocentrum Helsinki||

Tillgänglig från: 2013-11-08 Skapad: 2013-11-08 Senast uppdaterad: 2017-12-06
Chavali, S., Bruhn, S., Tiemann, K., Sætrom, P., Barrenäs, F., Saito, T., . . . Benson, M. (2013). MicroRNAs act complementarily to regulate disease-related mRNA modules in human diseases. RNA: A publication of the RNA Society, 19(11), 1552-1562
Öppna denna publikation i ny flik eller fönster >>MicroRNAs act complementarily to regulate disease-related mRNA modules in human diseases
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2013 (Engelska)Ingår i: RNA: A publication of the RNA Society, ISSN 1355-8382, E-ISSN 1469-9001, Vol. 19, nr 11, s. 1552-1562Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

MicroRNAs (miRNAs) play a key role in regulating mRNA expression, and individual miRNAs have been proposed as diagnostic and therapeutic candidates. The identification of such candidates is complicated by the involvement of multiple miRNAs and mRNAs as well as unknown disease topology of the miRNAs. Here, we investigated if disease-associated miRNAs regulate modules of disease-associated mRNAs, if those miRNAs act complementarily or synergistically, and if single or combinations of miRNAs can be targeted to alter module functions. We first analyzed publicly available miRNA and mRNA expression data for five different diseases. Integrated target prediction and network-based analysis showed that the miRNAs regulated modules of disease-relevant genes. Most of the miRNAs acted complementarily to regulate multiple mRNAs. To functionally test these findings, we repeated the analysis using our own miRNA and mRNA expression data from CD4+ T cells from patients with seasonal allergic rhinitis. This is a good model of complex diseases because of its well-defined phenotype and pathogenesis. Combined computational and functional studies confirmed that miRNAs mainly acted complementarily and that a combination of two complementary miRNAs, miR-223 and miR-139-3p, could be targeted to alter disease-relevant module functions, namely, the release of type 2 helper T-cell (Th2) cytokines. Taken together, our findings indicate that miRNAs act complementarily to regulate modules of disease-related mRNAs and can be targeted to alter disease-relevant functions.

Ort, förlag, år, upplaga, sidor
Cold Spring Harbor Laboratory Press (CSHL), 2013
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-99867 (URN)10.1261/rna.038414.113 (DOI)000325813900010 ()24062574 (PubMedID)
Tillgänglig från: 2013-10-22 Skapad: 2013-10-22 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
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