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Article ; Online: High-grade B-cell lymphoma with a quadruple-hit genetic profile including concurrent MYC, BCL2, BCL6, and CCND1 gene rearrangements.

Gagnon, Marie-France / Meyer, Reid G / Weaver, Eric J / Wood, Adam J / Dupuy, Dudley A / Menachery, Sudeep J / Shi, Min / Baughn, Linda B / Ketterling, Rhett P / Peterson, Jess F

Laboratory medicine

2024

Abstract: Several reports of concurrent MYC, BCL2, BCL6, and CCND1 rearrangements in high-grade B-cell ... a retrospective review (2015-2023) at our institution of B-cell lymphoma (BCL) cases that were evaluated ...

Abstract	Several reports of concurrent MYC, BCL2, BCL6, and CCND1 rearrangements in high-grade B-cell lymphoma (HGBL) have been recently described. Herein, we aimed to delineate the scope of this entity through a review of HGBL with a "quadruple-hit" genetic profile identified at our institution. We performed a retrospective review (2015-2023) at our institution of B-cell lymphoma (BCL) cases that were evaluated with concurrent MYC, BCL2, and BCL6 break-apart and IGH::MYC and IGH::CCND1 dual-color dual-fusion fluorescence in situ hybridization studies. Of 203 cases meeting inclusion criteria, 2 (1%) with a quadruple-hit genetic profile were identified. Case 1 represented a 59-year-old female with widespread lymphadenopathy and a diagnosis of HGBL who exhibited primary refractoriness to dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) chemotherapy. Case 2 represented a 58-year-old male with mediastinal and abdominal lymphadenopathy and a diagnosis of large BCL who died from disease after 1 cycle of DA-EPOCH-R chemotherapy. Similarly, a literature review of 7 previously reported cases of HGBL with a quadruple-hit profile also demonstrated aggressive disease behavior. Our study adds 2 new cases to the rarely encountered quadruple-hit HGBL, and a brief meta-analysis of the 9 available cases indicates aggressive disease behavior conferred by this constellation of genetic events.
Language	English
Publishing date	2024-03-24
Publishing country	England
Document type	Journal Article
ZDB-ID	391758-7
ISSN	1943-7730 ; 0007-5027
ISSN (online)	1943-7730
ISSN	0007-5027
DOI	10.1093/labmed/lmae017
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Zs.B 1013: Show issues

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Article ; Online: Human granzyme B regulatory B cells prevent effector CD4+CD25- T cell proliferation through a mechanism dependent from lymphotoxin alpha.

Sailliet, Nicolas / Mai, Hoa-Le / Dupuy, Amandine / Tilly, Gaëlle / Fourgeux, Cynthia / Braud, Martin / Giral, Magali / Robert, Jean-Michel / Degauque, Nicolas / Danger, Richard / Poschmann, Jeremie / Brouard, Sophie

Frontiers in immunology

2023 Volume 14, Page(s) 1183714

Abstract: Introduction: Human Granzyme B (GZMB) regulatory B cells (Bregs) have suppressive properties ... Bregs or total B cells were also co-cultured with T cells and scRNAseq was used to identify receptor ... B cells profile. Notably, Bregs induced a strong inhibition of T cell genes associated to proliferation ...

Abstract	Introduction: Human Granzyme B (GZMB) regulatory B cells (Bregs) have suppressive properties on CD4+ effector T cells by a mechanism partially dependent on GZMB. Moreover, these cells may be easily induced in vitro making them interesting for cell therapy. Methods: We characterized this population of in vitro induced GZMB+Bregs using single cell transcriptomics. To investigate their regulatory properties, Bregs or total B cells were also co-cultured with T cells and scRNAseq was used to identify receptor ligand interactions and to reveal gene expression changes in the T cells. Results: We find that Bregs exhibit a unique set of 149 genes differentially expressed and which are implicated in proliferation, apoptosis, metabolism, and altered antigen presentation capacity consistent with their differentiated B cells profile. Notably, Bregs induced a strong inhibition of T cell genes associated to proliferation, activation, inflammation and apoptosis compared to total B cells. We identified and validated 5 receptor/ligand interactions between Bregs and T cells. Functional analysis using specific inhibitors was used to test their suppressive properties and we identified Lymphotoxin alpha (LTA) as a new and potent Breg ligand implicated in Breg suppressive properties. Discussion: We report for the first time for a role of LTA in GZMB+Bregs as an enhancer of GZMB expression, and involved in the suppressive properties of GZMB+Bregs in human. The exact mechanism of LTA/GZMB function in this specific subset of Bregs remains to be determined.
MeSH term(s)	Humans ; Lymphotoxin-alpha ; Granzymes ; B-Lymphocytes, Regulatory ; Ligands ; CD4-Positive T-Lymphocytes ; Cell Proliferation
Chemical Substances	Lymphotoxin-alpha ; Granzymes (EC 3.4.21.-) ; Ligands
Language	English
Publishing date	2023-07-31
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1183714
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Article ; Online: Targeting immuno-metabolism and anti-viral immune responses in chronic hepatitis B.

Faure-Dupuy, Suzanne / Baumert, Thomas F

Hepatology international

2023 Volume 17, Issue 5, Page(s) 1075–1078

MeSH term(s)	Humans ; Hepatitis B, Chronic/drug therapy ; Hepatitis B Surface Antigens ; Immunity ; Hepatitis B virus ; Hepatitis B
Chemical Substances	Hepatitis B Surface Antigens
Language	English
Publishing date	2023-06-27
Publishing country	United States
Document type	Editorial
ZDB-ID	2270316-0
ISSN	1936-0541 ; 1936-0533
ISSN (online)	1936-0541
ISSN	1936-0533
DOI	10.1007/s12072-023-10546-5
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Article ; Online: Bone involvement in primary cutaneous diffuse large B-cell lymphoma, leg-type.

Laurent, Claire / Ram-Wolff, Caroline / Ingen-Housz-Oro, Saskia / Beylot-Barry, Marie / Barete, Stephane / Saillard, Clemence / Dupuy, Alain / Bagot, Martine / Adamski, Henri

Clinical and experimental dermatology

2023 Volume 48, Issue 2, Page(s) 116–120

Abstract: Primary cutaneous diffuse large B-cell lymphoma, leg-type (PCDLBCL-LT) is an aggressive cutaneous ...

Abstract	Primary cutaneous diffuse large B-cell lymphoma, leg-type (PCDLBCL-LT) is an aggressive cutaneous lymphoma. Bone involvement is rare and poorly described. We present five cases of PCDLBCL-LT with bone localization. In four cases, the bone involvement was diagnosed during the initial staging with positron emission tomography (PET) or computed tomography (CT) scan, and in the fifth case after tibial fracture during treatment with rituximab (RTX) and polychemotherapy (PCT). PCDLBCL-LT can be asymptomatic and involve bone sites distant from cutaneous lesions. None had other extracutaneous involvement. In our series, all patients received RTX-PCT as first-line chemotherapy and all had early relapses or progression. Second-line treatments had poor efficacy. Our series shows that bone involvement seems to be associated with poor prognosis in PCDLBCL-LT. Bone localization is not diagnosed with initial thoracic-abdominal-pelvic CT when asymptomatic and affecting the limbs only. If there is a suspicion of PCDLBCL-LT, patients should undergo systematic investigation with alternative imaging techniques, including PET, both at baseline and if there is any concern during follow-up.
MeSH term(s)	Humans ; Leg/pathology ; Lymphoma, Large B-Cell, Diffuse/diagnostic imaging ; Lymphoma, Large B-Cell, Diffuse/drug therapy ; Lower Extremity/pathology ; Rituximab/therapeutic use ; Bone Neoplasms/drug therapy ; Skin Neoplasms/pathology
Chemical Substances	Rituximab (4F4X42SYQ6)
Language	English
Publishing date	2023-02-02
Publishing country	England
Document type	Journal Article
ZDB-ID	195504-4
ISSN	1365-2230 ; 0307-6938
ISSN (online)	1365-2230
ISSN	0307-6938
DOI	10.1093/ced/llac044
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Zs.A 1278: Show issues

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Article ; Online: Hypoxia-Inducible Factor 1 Alpha-Mediated RelB/APOBEC3B Down-regulation Allows Hepatitis B Virus Persistence.

Riedl, Tobias / Faure-Dupuy, Suzanne / Rolland, Maude / Schuehle, Svenja / Hizir, Zohier / Calderazzo, Silvia / Zhuang, Xiaodong / Wettengel, Jochen / Lopez, Martin Alexander / Barnault, Romain / Mirakaj, Valbona / Prokosch, Sandra / Heide, Danijela / Leuchtenberger, Corinna / Schneider, Martin / Heßling, Bernd / Stottmeier, Benjamin / Wessbecher, Isabel M / Schirmacher, Peter /

McKeating, Jane A / Protzer, Ulrike / Durantel, David / Lucifora, Julie / Dejardin, Emmanuel / Heikenwalder, Mathias

Hepatology (Baltimore, Md.)

2021 Volume 74, Issue 4, Page(s) 1766–1781

Abstract: ... interferes with immune-mediated induction of the cytidine deaminase, apolipoprotein B mRNA editing enzyme ... decreased the level of v-rel reticuloendotheliosis viral oncogene homolog B protein, but not its mRNA ...

Abstract	Background and aims: Therapeutic strategies against HBV focus, among others, on the activation of the immune system to enable the infected host to eliminate HBV. Hypoxia-inducible factor 1 alpha (HIF1α) stabilization has been associated with impaired immune responses. HBV pathogenesis triggers chronic hepatitis-related scaring, leading inter alia to modulation of liver oxygenation and transient immune activation, both factors playing a role in HIF1α stabilization. Approach and results: We addressed whether HIF1α interferes with immune-mediated induction of the cytidine deaminase, apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B; A3B), and subsequent covalently closed circular DNA (cccDNA) decay. Liver biopsies of chronic HBV (CHB) patients were analyzed by immunohistochemistry and in situ hybridization. The effect of HIF1α induction/stabilization on differentiated HepaRG or mice ± HBV ± LTβR-agonist (BS1) was assessed in vitro and in vivo. Induction of A3B and subsequent effects were analyzed by RT-qPCR, immunoblotting, chromatin immunoprecipitation, immunocytochemistry, and mass spectrometry. Analyzing CHB highlighted that areas with high HIF1α levels and low A3B expression correlated with high HBcAg, potentially representing a reservoir for HBV survival in immune-active patients. In vitro, HIF1α stabilization strongly impaired A3B expression and anti-HBV effect. Interestingly, HIF1α knockdown was sufficient to rescue the inhibition of A3B up-regulation and -mediated antiviral effects, whereas HIF2α knockdown had no effect. HIF1α stabilization decreased the level of v-rel reticuloendotheliosis viral oncogene homolog B protein, but not its mRNA, which was confirmed in vivo. Noteworthy, this function of HIF1α was independent of its partner, aryl hydrocarbon receptor nuclear translocator. Conclusions: In conclusion, inhibiting HIF1α expression or stabilization represents an anti-HBV strategy in the context of immune-mediated A3B induction. High HIF1α, mediated by hypoxia or inflammation, offers a reservoir for HBV survival in vivo and should be considered as a restricting factor in the development of immune therapies.
MeSH term(s)	Amino Acids, Dicarboxylic/pharmacology ; Animals ; Cell Line ; Cytidine Deaminase/genetics ; Cytidine Deaminase/metabolism ; DNA, Circular/metabolism ; Down-Regulation ; Gene Knockdown Techniques ; Hepatitis B virus ; Hepatitis B, Chronic/genetics ; Hepatitis B, Chronic/metabolism ; Hepatitis B, Chronic/virology ; Humans ; Hypoxia/genetics ; Hypoxia/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Liver/metabolism ; Lymphotoxin beta Receptor/agonists ; Mice ; Microbial Viability ; Minor Histocompatibility Antigens/genetics ; Minor Histocompatibility Antigens/metabolism ; RNA, Messenger/metabolism ; Transcription Factor RelB/drug effects ; Transcription Factor RelB/genetics ; Transcription Factor RelB/metabolism
Chemical Substances	Amino Acids, Dicarboxylic ; DNA, Circular ; HIF1A protein, human ; Hypoxia-Inducible Factor 1, alpha Subunit ; Lymphotoxin beta Receptor ; Minor Histocompatibility Antigens ; RELB protein, human ; RNA, Messenger ; Relb protein, mouse ; Transcription Factor RelB (147337-75-5) ; APOBEC3B protein, human (EC 3.5.4.5) ; Cytidine Deaminase (EC 3.5.4.5) ; oxalylglycine (VVW38EB8YS)
Language	English
Publishing date	2021-08-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604603-4
ISSN	1527-3350 ; 0270-9139
ISSN (online)	1527-3350
ISSN	0270-9139
DOI	10.1002/hep.31902
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Zs.A 1660: Show issues

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Article ; Online: Receptor binding domain-IgG levels correlate with protection in residents facing SARS-CoV-2 B.1.1.7 outbreaks.

Blain, Hubert / Tuaillon, Edouard / Gamon, Lucie / Pisoni, Amandine / Miot, Stéphanie / Delpui, Valentin / Si-Mohamed, Nejm / Niel, Clémence / Rolland, Yves / Montes, Brigitte / Groc, Soraya / Rafasse, Sophia / Dupuy, Anne-Marie / Gros, Nathalie / Muriaux, Delphine / Picot, Marie-Christine / Bousquet, Jean

Allergy

2021 Volume 77, Issue 6, Page(s) 1885–1894

Abstract: ... response.: Methods: 396 residents from seven NHs suffering a SARS-CoV-2 B.1.1.7 (VOC-α) outbreak ... protection against SARS-CoV-2 B.1.1.7. ...

Abstract	Background: Limited information exists on nursing home (NH) residents regarding BNT162b2 vaccine efficacy in preventing SARS-CoV-2 and severe COVID-19, and its association with post-vaccine humoral response. Methods: 396 residents from seven NHs suffering a SARS-CoV-2 B.1.1.7 (VOC-α) outbreak at least 14 days after a vaccine campaign were repeatedly tested using SARS-CoV-2 real-time reverse-transcriptase polymerase chain reaction on nasopharyngeal swab test (RT-qPCR). SARS-CoV-2 receptor-binding domain (RBD) of the S1 subunit (RBD-IgG) was measured in all residents. Nucleocapsid antigenemia (N-Ag) was measured in RT-qPCR-positive residents and serum neutralizing antibodies in vaccinated residents from one NH. Results: The incidence of positive RT-qPCR was lower in residents vaccinated by two doses (72/317; 22.7%) vs one dose (10/31; 32.3%) or non-vaccinated residents (21/48; 43.7%; p < .01). COVID-19-induced deaths were observed in 5 of the 48 non-vaccinated residents (10.4%), in 2 of the 31 who had received one dose (6.4%), and in 3 of the 317 (0.9%) who had received two doses (p = .0007). Severe symptoms were more common in infected non-vaccinated residents (10/21; 47.6%) than in infected vaccinated residents (15/72; 21.0%; p = .002). Higher levels of RBD-IgG (n = 325) were associated with a lower SARS-CoV-2 incidence. No in vitro serum neutralization activity was found for RBD-IgG levels below 1050 AU/ml. RBD-IgG levels were inversely associated with N-Ag levels, found as a risk factor of severe COVID-19. Conclusions: Two BNT162b2 doses are associated with a 48% reduction of SARS-CoV-2 incidence and a 91.3% reduction of death risk in residents from NHs facing a VOC-α outbreak. Post-vaccine RBD-IgG levels correlate with BNT162b2 protection against SARS-CoV-2 B.1.1.7.
MeSH term(s)	Antibodies, Viral ; BNT162 Vaccine ; COVID-19/epidemiology ; COVID-19/prevention & control ; COVID-19 Vaccines ; Disease Outbreaks/prevention & control ; Humans ; Immunoglobulin G ; SARS-CoV-2 ; Vaccines
Chemical Substances	Antibodies, Viral ; COVID-19 Vaccines ; Immunoglobulin G ; Vaccines ; BNT162 Vaccine (N38TVC63NU)
Language	English
Publishing date	2021-10-29
Publishing country	Denmark
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	391933-x
ISSN	1398-9995 ; 0105-4538
ISSN (online)	1398-9995
ISSN	0105-4538
DOI	10.1111/all.15142
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Uh III Zs.150: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Liver macrophages: Friend or foe during hepatitis B infection?

Faure-Dupuy, Suzanne / Durantel, David / Lucifora, Julie

Liver international : official journal of the International Association for the Study of the Liver

2018 Volume 38, Issue 10, Page(s) 1718–1729

Abstract: The Hepatitis B virus chronically infects the liver of 250 million people worldwide. Over the past ... decades, major advances have been made in the understanding of Hepatitis B virus life cycle in hepatocytes ... in immune responses to pathogens and much less is known about their interplay with Hepatitis B virus. In this review ...

Abstract	The Hepatitis B virus chronically infects the liver of 250 million people worldwide. Over the past decades, major advances have been made in the understanding of Hepatitis B virus life cycle in hepatocytes. Beside these parenchymal cells, the liver also contains resident and infiltrating myeloid cells involved in immune responses to pathogens and much less is known about their interplay with Hepatitis B virus. In this review, we summarized and discussed the current knowledge of the role of liver macrophages (including Kupffer cells and liver monocyte-derived macrophages), in HBV infection. While it is still unclear if liver macrophages play a role in the establishment and persistence of HBV infection, several studies disclosed data suggesting that HBV would favour liver macrophage anti-inflammatory phenotypes and thereby increase liver tolerance. In addition, alternatively activated liver macrophages might also play in the long term a key role in hepatitis B-associated pathogenesis, especially through the activation of hepatic stellate cells. Therapies aiming at a transient activation of pro-inflammatory liver macrophages should therefore be considered for the treatment of chronic HBV infection.
MeSH term(s)	Hepatitis B/immunology ; Hepatitis B/therapy ; Hepatitis B virus ; Host-Pathogen Interactions ; Humans ; Immune Tolerance ; Immunity, Innate ; Kupffer Cells/immunology ; Liver/cytology ; Macrophages/immunology
Language	English
Publishing date	2018-06-09
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2102783-3
ISSN	1478-3231 ; 1478-3223
ISSN (online)	1478-3231
ISSN	1478-3223
DOI	10.1111/liv.13884
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Zs.A 1632: Show issues

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Article ; Online: Early inhibition of hepatocyte innate responses by hepatitis B virus.

Luangsay, Souphalone / Gruffaz, Marion / Isorce, Nathalie / Testoni, Barbara / Michelet, Maud / Faure-Dupuy, Suzanne / Maadadi, Sarah / Ait-Goughoulte, Malika / Parent, Romain / Rivoire, Michel / Javanbakht, Hassan / Lucifora, Julie / Durantel, David / Zoulim, Fabien

Journal of hepatology

2015 Volume 63, Issue 6, Page(s) 1314–1322

Abstract: Background & aims: The outcome of hepatitis B virus (HBV) infection may be influenced by early ...

Abstract	Background & aims: The outcome of hepatitis B virus (HBV) infection may be influenced by early interactions between the virus and hepatocyte innate immune responses. To date, the study of such interactions during the very early step of infection has not been adequately investigated. Methods: We used the HepaRG cell line, as well as primary human hepatocytes to analyze, within 24h of exposure to HBV, either delivered by a physiologic route or baculovirus vector (Bac-HBV), the early modulation of the expression of selected antiviral/pro-inflammatory cytokines and interferon stimulated genes. Experiments were also performed in the presence or absence of innate receptor agonists to investigate early HBV-induced blockade of innate responses. Results: We show that hepatocytes themselves could detect HBV, and express innate genes when exposed to either HBV virions or Bac-HBV. Whereas Bac-HBV triggered a strong antiviral cytokine secretion followed by the clearance of replicative intermediates, a physiologic HBV exposure led to an abortive response. The early inhibition of innate response by HBV was mainly evidenced on Toll-like receptor 3 and RIG-I/MDA5 signaling pathways upon engagement with exogenous agonist, leading to a decreased expression of several pro-inflammatory and antiviral cytokine genes. Finally, we demonstrate that this early inhibition of dsRNA-mediated response is due to factor(s) present in the HBV inoculum, but not being HBsAg or HBeAg themselves, and does not require de novo viral protein synthesis and replication. Conclusions: Our data provide strong evidence that HBV viral particles themselves can readily inhibit host innate immune responses upon virion/cell interactions, and may explain, at least partially, the "stealthy" character of HBV.
MeSH term(s)	Cell Line ; Cells, Cultured ; Gene Expression ; Hepatitis B Surface Antigens/genetics ; Hepatitis B Surface Antigens/immunology ; Hepatitis B e Antigens/genetics ; Hepatitis B e Antigens/immunology ; Hepatitis B virus/genetics ; Hepatitis B virus/immunology ; Hepatitis B virus/pathogenicity ; Hepatocytes/immunology ; Hepatocytes/virology ; Host-Pathogen Interactions/genetics ; Host-Pathogen Interactions/immunology ; Humans ; Immunity, Innate/genetics ; Interleukin-6/biosynthesis ; RNA, Double-Stranded/genetics ; RNA, Double-Stranded/immunology
Chemical Substances	Hepatitis B Surface Antigens ; Hepatitis B e Antigens ; IL6 protein, human ; Interleukin-6 ; RNA, Double-Stranded
Language	English
Publishing date	2015-12
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605953-3
ISSN	1600-0641 ; 0168-8278
ISSN (online)	1600-0641
ISSN	0168-8278
DOI	10.1016/j.jhep.2015.07.014
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Article ; Conference proceedings: Oxygenation and miR138-5 p act as rheostats in APOBEC3B-mediated Hepatitis B Virus control

Riedl, T / Faure-Dupuy, S / Hizir, Z / Neuhaus, K / Farhat, R / Reisinger, F / Zhuang, X / Schönung, M / Stadler, M / Wettengel, J / Barnault, R / Parent, R / Prokosch, S / Schneider, M / Unger, K / Stottmeier, B / Schirmacher, P / Lipka, D / McKeating, J /

Protzer, U / Durantel, D / Lucifora, J / Dejardin, E / Heikenwälder, M

Zeitschrift für Gastroenterologie

2020 Volume 58, Issue 01

Event/congress	36. Jahrestagung der Deutschen Arbeitsgemeinschaft zum Studium der Leber, Mainz, 2020-02-14
Language	English
Publishing date	2020-01-01
Publisher	Georg Thieme Verlag KG
Publishing place	Stuttgart ; New York
Document type	Article ; Conference proceedings
ZDB-ID	201387-3
ISSN	1439-7803 ; 0044-2771 ; 0172-8504
ISSN (online)	1439-7803
ISSN	0044-2771 ; 0172-8504
DOI	10.1055/s-0039-3402258
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Zs.A 111: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Hepatitis B virus-induced modulation of liver macrophage function promotes hepatocyte infection.

Faure-Dupuy, Suzanne / Delphin, Marion / Aillot, Ludovic / Dimier, Laura / Lebossé, Fanny / Fresquet, Judith / Parent, Romain / Matter, Matthias Sebastian / Rivoire, Michel / Bendriss-Vermare, Nathalie / Salvetti, Anna / Heide, Danijela / Flores, Lalo / Klumpp, Klaus / Lam, Angela / Zoulim, Fabien / Heikenwälder, Mathias / Durantel, David / Lucifora, Julie

Journal of hepatology

2019 Volume 71, Issue 6, Page(s) 1086–1098

Abstract: ... pathogenesis. To get further insight on their role during chronic hepatitis B virus (HBV) infections, our aim ... Hepatitis B virus modulates liver macrophage function in order to favour the establishment and likely maintenance ...

Abstract	Background & aims: Liver macrophages can be involved in both pathogen clearance and/or pathogenesis. To get further insight on their role during chronic hepatitis B virus (HBV) infections, our aim was to phenotypically and functionally characterize in vivo and ex vivo the interplay between HBV, primary human liver macrophages (PLMs) and primary blood monocytes differentiated into pro-inflammatory or anti-inflammatory macrophages (M1-MDMs or M2-MDMs, respectively). Methods: PLMs or primary blood monocytes, either ex vivo differentiated into M1-MDMs or M2-MDMs, were exposed to HBV and their activation followed by ELISA or quantitative reverse transcription PCR (RT-qPCR). Liver biopsies from HBV-infected patients were analysed by RT-qPCR or immunohistochemistry. Viral parameters in HBV-infected primary human hepatocytes and differentiated HepaRG cells were followed by ELISA, qPCR and RT-qPCR analyses. Results: HBc protein was present within the macrophages of liver biopsies taken from HBV-infected patients. Macrophages from HBV-infected patients also expressed higher levels of anti-inflammatory macrophage markers than those from non-infected patients. Ex vivo exposure of naive PLMs to HBV led to reduced secretion of pro-inflammatory cytokines. Upon exposure to HBV or HBV-producing cells during differentiation and activation, M1-MDMs secreted less IL-6 and IL-1β, whereas M2-MDMs secreted more IL-10 when exposed to HBV during activation. Finally, cytokines produced by M1-MDMs, but not those produced by HBV-exposed M1-MDMs, decreased HBV infection of hepatocytes. Conclusions: Altogether, our data strongly suggest that HBV modulates liver macrophage functions to favour the establishment of infection. Lay summary: Hepatitis B virus modulates liver macrophage function in order to favour the establishment and likely maintenance of infection. It impairs the production of the antiviral cytokine IL-1β, while promoting that of IL-10 in the microenvironment. This phenotype can be recapitulated in naive liver macrophages or monocyte-derived-macrophages ex vivo by short exposure to the virus or cells replicating the virus, thus suggesting an "easy to implement" mechanism of inhibition.
MeSH term(s)	Cell Differentiation/immunology ; Cells, Cultured ; DNA, Viral/isolation & purification ; Hepatitis B virus/physiology ; Hepatitis B, Chronic/immunology ; Hepatitis B, Chronic/pathology ; Humans ; Immunohistochemistry ; Immunomodulation ; Interleukin-10 ; Interleukin-1beta ; Kupffer Cells/immunology ; Kupffer Cells/pathology ; Macrophage Activation/immunology ; Monocytes/immunology ; Monocytes/pathology ; Mononuclear Phagocyte System/immunology
Chemical Substances	DNA, Viral ; IL10 protein, human ; IL1B protein, human ; Interleukin-1beta ; Interleukin-10 (130068-27-8)
Language	English
Publishing date	2019-07-23
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605953-3
ISSN	1600-0641 ; 0168-8278
ISSN (online)	1600-0641
ISSN	0168-8278
DOI	10.1016/j.jhep.2019.06.032
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