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Article ; Online: Association between IL28B polymorphisms and first-phase viral load decrease in chronic hepatitis C virus-infected patients treated with peginterferon alfa-2b/ribavirin.

Arends, Joop E / Fransen, Justin H / Hoepelman, Andy I M / van Baarle, Debbie

International journal of antimicrobial agents

2011 Volume 38, Issue 6, Page(s) 538–539

Abstract: Host polymorphisms in the IL28B region have recently been associated with outcome of treatment for hepatitis C virus (HCV) infection. This study clearly shows an association between first-phase viral load decrease and the IL28B rs12979860 polymorphism in ...

Abstract	Host polymorphisms in the IL28B region have recently been associated with outcome of treatment for hepatitis C virus (HCV) infection. This study clearly shows an association between first-phase viral load decrease and the IL28B rs12979860 polymorphism in chronic HCV-infected patients. Furthermore, a higher treatment efficiency factor (ɛ) was found in those HCV-infected patients with a CC genotype compared with those with a CT and TT genotype. This study highlights the importance of host response mechanisms in relation to favourable clearance of HCV.
MeSH term(s)	Antiviral Agents/therapeutic use ; Hepacivirus/drug effects ; Hepacivirus/physiology ; Hepatitis C, Chronic/drug therapy ; Hepatitis C, Chronic/genetics ; Hepatitis C, Chronic/virology ; Humans ; Interferon alpha-2 ; Interferon-alpha/therapeutic use ; Interferons ; Interleukins/genetics ; Polyethylene Glycols/therapeutic use ; Polymorphism, Single Nucleotide/genetics ; Recombinant Proteins/therapeutic use ; Ribavirin/therapeutic use ; Treatment Outcome ; Viral Load/drug effects
Chemical Substances	Antiviral Agents ; interferon-lambda, human ; Interferon alpha-2 ; Interferon-alpha ; Interleukins ; Recombinant Proteins ; Polyethylene Glycols (3WJQ0SDW1A) ; Ribavirin (49717AWG6K) ; Interferons (9008-11-1) ; peginterferon alfa-2b (G8RGG88B68)
Language	English
Publishing date	2011-10-04
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1093977-5
ISSN	1872-7913 ; 0924-8579
ISSN (online)	1872-7913
ISSN	0924-8579
DOI	10.1016/j.ijantimicag.2011.08.010
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Article ; Online: The effect of HIV coinfection, HAART and TB treatment on cytokine/chemokine responses to Mycobacterium tuberculosis (Mtb) antigens in active TB patients and latently Mtb infected individuals.

Kassa, Desta / de Jager, Wilco / Gebremichael, Gebremedhin / Alemayehu, Yodit / Ran, Leonie / Fransen, Justin / Wolday, Dawit / Messele, Tsehaynesh / Tegbaru, Belete / Ottenhoff, Tom H M / van Baarle, Debbie

Tuberculosis (Edinburgh, Scotland)

2016 Volume 96, Page(s) 131–140

Abstract: Identification of Mtb specific induced cytokine/chemokine host biomarkers could assist in developing novel diagnostic, prognostic and therapeutic tools for TB. Levels of IFN-γ, IL-2, IL-17, IL-10, IP-10 and MIP-1α were measured in supernatants of whole ... ...

Abstract	Identification of Mtb specific induced cytokine/chemokine host biomarkers could assist in developing novel diagnostic, prognostic and therapeutic tools for TB. Levels of IFN-γ, IL-2, IL-17, IL-10, IP-10 and MIP-1α were measured in supernatants of whole blood stimulated with Mtb specific fusion protein ESAT-6/CFP-10 using xMAP technology. The study groups were HIV positive TB patients (HIV(+)TB(+)), HIV negative TB patients (HIV(-)TB(+)), HIV positive tuberculin skin test positive (TST+) (HIV(+)TST(+)), HIV negative TST+ (HIV(-)TST(+)), and HIV(-)TST(-) individuals. Compared to HIV(-)TST(-), latent TB infection led to increased levels of IP-10, IFN-γ and IL-17, while levels of IL-2 and IP-10 were increased with active TB. Levels of IFN-γ, IL-17, MIP-1α, and IL-10 were increased in HIV(-)TST(+) individuals compared to HIV(-)TB(+) patients. HIV coinfection decreased the level of IFN-γ, IL-17, IP-10 and IL-2. After six months (M6) of anti-TB treatment (ATT) in HIV(-)TB(+) patients, IFN-γ, IL-10, and MIP-1α levels normalized. After M6 and M18 of ATT plus HAART in HIV(+)TB(+) patients, levels of MIP-1α and IL-10 normalized, while this was not the case for IFN-γ, IL-2, IL-17, and IP-10 levels. In HIV(+)TST(+) patients on HAART, levels of IFN-γ, IL-17, IL-10 and MIP-1α normalized, while no change in the levels of IL-2 and IP-10 were observed. In conclusion, the simultaneous measurement of IFN-γ, IL-17 and IP-10 may assist in diagnosing LTBI; IL-2 and IP-10 may assist in diagnosing active TB; while IFN-γ, IL-17, MIP-1α, and IL-10 levels could help to discriminate LTBI and active TB. In addition, IL-10 and MIP-1α levels could help to monitor responses to TB treatment and HAART.
MeSH term(s)	Adolescent ; Adult ; Aged ; Anti-HIV Agents/therapeutic use ; Antigens, Bacterial/blood ; Antigens, Bacterial/immunology ; Antiretroviral Therapy, Highly Active ; Antitubercular Agents/therapeutic use ; Chemokines/blood ; Chemokines/immunology ; Cytokines/blood ; Cytokines/immunology ; Diagnosis, Differential ; Ethiopia ; Female ; HIV Infections/blood ; HIV Infections/diagnosis ; HIV Infections/drug therapy ; HIV Infections/immunology ; HIV Infections/virology ; Humans ; Latent Tuberculosis/blood ; Latent Tuberculosis/diagnosis ; Latent Tuberculosis/drug therapy ; Latent Tuberculosis/immunology ; Latent Tuberculosis/microbiology ; Male ; Middle Aged ; Mycobacterium tuberculosis/immunology ; Predictive Value of Tests ; Recombinant Fusion Proteins/immunology ; Time Factors ; Treatment Outcome ; Tuberculin Test ; Young Adult
Chemical Substances	Anti-HIV Agents ; Antigens, Bacterial ; Antitubercular Agents ; Chemokines ; Cytokines ; ESAT-6-CFP10 fusion protein ; Recombinant Fusion Proteins
Language	English
Publishing date	2016-01
Publishing country	Scotland
Document type	Journal Article ; Multicenter Study ; Observational Study ; Research Support, Non-U.S. Gov't
ZDB-ID	2046804-0
ISSN	1873-281X ; 1472-9792
ISSN (online)	1873-281X
ISSN	1472-9792
DOI	10.1016/j.tube.2015.05.015
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Article ; Online: Effect of administration of apoptotic blebs on disease development in lupus mice.

Fransen, Justin H / Berden, Jo H / Koeter, Claudia M / Adema, Gosse J / Van Der Vlag, Johan / Hilbrands, Luuk B

Autoimmunity

2012 Volume 45, Issue 4, Page(s) 290–297

Abstract: Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disease characterised by the formation of autoantibodies against nuclear components. Disturbed apoptosis and reduced clearance of apoptotic material have been assigned a role in the ... ...

Abstract	Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disease characterised by the formation of autoantibodies against nuclear components. Disturbed apoptosis and reduced clearance of apoptotic material have been assigned a role in the pathogenesis of SLE. During apoptosis, apoptotic blebs are formed, in which SLE autoantigens are clustered. In vitro, apoptotic blebs can induce maturation of dendritic cells (DC), which in turn can stimulate IL-17 production by T cells. Here, we investigated the effects of administration of apoptotic blebs, separate or in combination with dendritic cells, on disease progression and autoantibody production in lupus and normal mice. Methods: A preparation of apoptotic blebs, with or without DC, was intravenously administered to MRL/lpr and CBA mice at weeks 7, 9, and 11 of age. T-cell responses against autoantigens present in blebs were examined by delayed type hypersensitivity reactions. Disease progression of the mice was evaluated by determining proteinuria and the titers of anti-DNA, anti-histone, and anti-nucleosome autoantibodies in plasma. Results: Repeated administration of apoptotic blebs, with or without DC, had no effect on the course of proteinuria or on anti-DNA, anti-histone and anti-nucleosome autoantibody levels in MRL/lpr mice. Intravenous injections of apoptotic blebs resulted in a decrease in the DTH response towards s.c. administered blebs in MRL/lpr mice and in reduced anti-nucleosome antibody titers in CBA mice. These tolerizing effects were lost when apoptotic blebs were administered together with syngeneic DC after 2 hours of co-incubation. Discussion and conclusions: In contrast to previous studies with apoptotic cells, and deviating from our in vitro findings with apoptotic blebs, we observed no stimulating effect of the administration of apoptotic blebs on disease progression in MRL/lpr lupus mice. The tolerogenic effects that were observed may be associated with rapid removal of i.v. administered blebs by phagocytes in an immune-silencing way.
MeSH term(s)	Animals ; Antibodies, Antinuclear/blood ; Antibodies, Antinuclear/immunology ; Apoptosis ; Autoantibodies/blood ; Autoantibodies/immunology ; Autoantigens/administration & dosage ; Autoantigens/immunology ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Disease Progression ; Female ; Histones/immunology ; Hypersensitivity, Delayed/immunology ; Lupus Erythematosus, Systemic/immunology ; Lupus Erythematosus, Systemic/pathology ; Mice ; Mice, Inbred CBA ; Mice, Inbred MRL lpr ; Nucleosomes/immunology ; Proteinuria ; T-Lymphocytes/immunology
Chemical Substances	Antibodies, Antinuclear ; Autoantibodies ; Autoantigens ; Histones ; Nucleosomes
Language	English
Publishing date	2012-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1025450-x
ISSN	1607-842X ; 0891-6934
ISSN (online)	1607-842X
ISSN	0891-6934
DOI	10.3109/08916934.2012.664668
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Article: Association between IL28B polymorphisms and first-phase viral load decrease in chronic hepatitis C virus-infected patients treated with peginterferon alfa-2b/ribavirin

Arends, Joop E / Fransen, Justin H / Hoepelman, Andy I.M / van Baarle, Debbie

International journal of antimicrobial agents. 2011 Dec., v. 38, no. 6

2011

Abstract	Host polymorphisms in the IL28B region have recently been associated with outcome of treatment for hepatitis C virus (HCV) infection. This study clearly shows an association between first-phase viral load decrease and the IL28B rs12979860 polymorphism in chronic HCV-infected patients. Furthermore, a higher treatment efficiency factor (ɛ) was found in those HCV-infected patients with a CC genotype compared with those with a CT and TT genotype. This study highlights the importance of host response mechanisms in relation to favourable clearance of HCV.
Keywords	Hepatitis C virus ; anti-infective agents ; chronic hepatitis C ; genotype ; patients ; viral load
Language	English
Dates of publication	2011-12
Size	p. 538-539.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	1093977-5
ISSN	0924-8579
ISSN	0924-8579
DOI	10.1016/j.ijantimicag.2011.08.010
Database	NAL-Catalogue (AGRICOLA)

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Zs.A 3368: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: The role of dendritic cells in the pathogenesis of systemic lupus erythematosus.

Fransen, Justin H / van der Vlag, Johan / Ruben, Jurjen / Adema, Gosse J / Berden, Jo H / Hilbrands, Luuk B

Arthritis research & therapy

2010 Volume 12, Issue 2, Page(s) 207

Abstract: The etiology of the autoimmune disease systemic lupus erythematosus is not known, but aberrant apoptosis and/or insufficient clearance of apoptotic material have been assigned a pivotal role. During apoptosis, nucleosomes and several endogenous danger- ... ...

Abstract	The etiology of the autoimmune disease systemic lupus erythematosus is not known, but aberrant apoptosis and/or insufficient clearance of apoptotic material have been assigned a pivotal role. During apoptosis, nucleosomes and several endogenous danger-associated molecular patterns are incorporated in blebs. Recent data indicate that apoptotic blebs induce maturation of myeloid dendritic cells, resulting in IL-17 production by T cells. In this review we summarize current knowledge on the role of dendritic cells in the pathogenesis of systemic lupus erythematosus with special emphasis on the uptake of apoptotic blebs by dendritic cells, and the subsequent induction of Th17 cells.
MeSH term(s)	Animals ; Apoptosis/immunology ; Autoantigens/immunology ; Autoantigens/metabolism ; Dendritic Cells/pathology ; Dendritic Cells/physiology ; Disease Models, Animal ; Humans ; Interleukin-17/metabolism ; Lupus Erythematosus, Systemic/etiology ; Lupus Erythematosus, Systemic/metabolism ; Lupus Erythematosus, Systemic/pathology ; Models, Biological
Chemical Substances	Autoantigens ; Interleukin-17
Language	English
Publishing date	2010-04-26
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2107602-9
ISSN	1478-6362 ; 1478-6354
ISSN (online)	1478-6362
ISSN	1478-6354
DOI	10.1186/ar2966
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Article: Mouse dendritic cells matured by ingestion of apoptotic blebs induce T cells to produce interleukin-17.

Fransen, Justin H / Hilbrands, Luuk B / Ruben, Jurjen / Stoffels, Monique / Adema, Gosse J / van der Vlag, Johan / Berden, Jo H

Arthritis and rheumatism

2009 Volume 60, Issue 8, Page(s) 2304–2313

Abstract: Objective: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the formation of antinuclear autoantibodies. Increased apoptosis and reduced clearance of apoptotic material have been assigned a role in the pathogenesis of SLE, ... ...

Abstract	Objective: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the formation of antinuclear autoantibodies. Increased apoptosis and reduced clearance of apoptotic material have been assigned a role in the pathogenesis of SLE, but the underlying mechanisms remain elusive. During apoptosis apoptotic blebs are formed in which autoantigens are clustered. The cellular remnants after blebbing are referred to as apoptotic cell bodies. We undertook this study to compare the effects of apoptotic blebs and apoptotic cell bodies on maturation of dendritic cells (DCs) and their T cell stimulatory capacity in a murine setting. Methods: The uptake by DCs of apoptotic blebs and apoptotic cell bodies was analyzed by flow cytometry and confocal microscopy. DC maturation and DC-induced T cell activation were determined by measuring expression of costimulatory molecules using flow cytometry and by measuring production of cytokines using enzyme-linked immunosorbent assay. Results: DCs internalized apoptotic blebs more efficiently than apoptotic cell bodies. Incubation of DCs with apoptotic blebs resulted in increased CD40 and CD86 expression and increased interleukin-6 (IL-6) and tumor necrosis factor alpha production, while apoptotic cell bodies had no stimulatory effects. Using chloroquine, apoptotic bleb-induced DC maturation was shown to be independent of Toll-like receptors 3, 7, and 9. Interestingly, in cocultures with allogeneic T cells, bleb-matured DCs induced production of IL-2, interferon-gamma, and, in particular, IL-17, suggesting a Th1/Th17 response. Conclusion: Apoptotic blebs, in contrast to apoptotic cell bodies, induce DC maturation, thereby providing DCs with increased Th17 cell stimulatory capacity. These data imply that apoptotic bleb-induced DC maturation represents an important driving force in the autoimmune response in SLE.
MeSH term(s)	4-Nitroquinoline-1-oxide/toxicity ; Animals ; Apoptosis/drug effects ; Apoptosis/immunology ; Autoantigens/metabolism ; Bone Marrow Cells/immunology ; Bone Marrow Cells/metabolism ; Bone Marrow Cells/pathology ; Cell Differentiation/immunology ; Cell Surface Extensions/immunology ; Cell Surface Extensions/metabolism ; Cells, Cultured ; Dendritic Cells/drug effects ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Dendritic Cells/pathology ; Disease Models, Animal ; Flow Cytometry ; Humans ; Interleukin-17/immunology ; Interleukin-17/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Inbred CBA ; Microscopy, Confocal ; Phagocytosis ; Quinolones/toxicity ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; T-Lymphocytes/pathology
Chemical Substances	4-nitroquinolone-1-oxide ; Autoantigens ; Interleukin-17 ; Quinolones ; 4-Nitroquinoline-1-oxide (56-57-5)
Language	English
Publishing date	2009-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	127294-9
ISSN	1529-0131 ; 0004-3591 ; 2326-5191
ISSN (online)	1529-0131
ISSN	0004-3591 ; 2326-5191
DOI	10.1002/art.24719
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Zs.A 24: 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: Complementary role of HCV and HIV in T-cell activation and exhaustion in HIV/HCV coinfection.

Feuth, Thijs / Arends, Joop E / Fransen, Justin H / Nanlohy, Nening M / van Erpecum, Karel J / Siersema, Peter D / Hoepelman, Andy I M / van Baarle, Debbie

PloS one

2013 Volume 8, Issue 3, Page(s) e59302

Abstract: Objectives: To investigate whether T-cell activation and exhaustion is linked to HCV- and HIV disease parameters in HIV/HCV infected individuals, we studied T-cell characteristics in HIV/HCV coinfected patients and controls.: Methods: 14 HIV/HCV ... ...

Abstract	Objectives: To investigate whether T-cell activation and exhaustion is linked to HCV- and HIV disease parameters in HIV/HCV infected individuals, we studied T-cell characteristics in HIV/HCV coinfected patients and controls. Methods: 14 HIV/HCV coinfected, 19 HCV monoinfected, 10 HIV monoinfected patients and 15 healthy controls were included in this cross-sectional study. Differences in expression of activation and exhaustion markers (HLA-DR, CD38, PD-1, Tim-3 and Fas) and phenotypic markers on CD4(+) and CD8(+) T-cells were analysed by flow cytometry and were related to HCV disease parameters (HCV-viremia, ALT and liver fibrosis). Results: Frequencies of activated CD4(+) and CD8(+) T-cells were higher in HIV/HCV-coinfected compared to healthy controls and HCV or HIV mono-infected individuals. Coinfected patients also showed high expression of the exhaustion marker PD-1 and death receptor Fas. In contrast, the exhaustion marker Tim-3 was only elevated in HIV-monoinfected patients. T-cell activation and exhaustion were correlated with HCV-RNA, suggesting that viral antigen influences T-cell activation and exhaustion. Interestingly, increased percentages of effector CD8(+) T-cells were found in patients with severe (F3-F4) liver fibrosis compared to those with no to minimal fibrosis (F0-F2). Conclusions: HIV/HCV coinfected patients display a high level of T-cell activation and exhaustion in the peripheral blood. Our data suggest that T-cell activation and exhaustion are influenced by the level of HCV viremia. Furthermore, high percentages of cytotoxic/effector CD8(+) T-cells are associated with liver fibrosis in both HCV monoinfected and HIV/HCV coinfected patients.
MeSH term(s)	Adult ; Antigens, CD/genetics ; Antigens, CD/immunology ; Biomarkers/metabolism ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/pathology ; CD4-Positive T-Lymphocytes/virology ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/pathology ; CD8-Positive T-Lymphocytes/virology ; Case-Control Studies ; Coinfection ; Cross-Sectional Studies ; Female ; Fibrosis ; Gene Expression ; HIV Infections/immunology ; HIV Infections/pathology ; HIV Infections/virology ; HIV-1/immunology ; HLA-DR Antigens/genetics ; HLA-DR Antigens/immunology ; Hepacivirus/immunology ; Hepatitis C/immunology ; Hepatitis C/pathology ; Hepatitis C/virology ; Humans ; Liver/pathology ; Liver/virology ; Lymphocyte Activation ; Male ; Middle Aged
Chemical Substances	Antigens, CD ; Biomarkers ; HLA-DR Antigens
Language	English
Publishing date	2013-03-15
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0059302
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Article ; Online: Complementary role of HCV and HIV in T-cell activation and exhaustion in HIV/HCV coinfection.

Thijs Feuth / Joop E Arends / Justin H Fransen / Nening M Nanlohy / Karel J van Erpecum / Peter D Siersema / Andy I M Hoepelman / Debbie van Baarle

PLoS ONE, Vol 8, Iss 3, p e

2013 Volume 59302

Abstract: OBJECTIVES: To investigate whether T-cell activation and exhaustion is linked to HCV- and HIV disease parameters in HIV/HCV infected individuals, we studied T-cell characteristics in HIV/HCV coinfected patients and controls. METHODS: 14 HIV/HCV ... ...

Abstract	OBJECTIVES: To investigate whether T-cell activation and exhaustion is linked to HCV- and HIV disease parameters in HIV/HCV infected individuals, we studied T-cell characteristics in HIV/HCV coinfected patients and controls. METHODS: 14 HIV/HCV coinfected, 19 HCV monoinfected, 10 HIV monoinfected patients and 15 healthy controls were included in this cross-sectional study. Differences in expression of activation and exhaustion markers (HLA-DR, CD38, PD-1, Tim-3 and Fas) and phenotypic markers on CD4(+) and CD8(+) T-cells were analysed by flow cytometry and were related to HCV disease parameters (HCV-viremia, ALT and liver fibrosis). RESULTS: Frequencies of activated CD4(+) and CD8(+) T-cells were higher in HIV/HCV-coinfected compared to healthy controls and HCV or HIV mono-infected individuals. Coinfected patients also showed high expression of the exhaustion marker PD-1 and death receptor Fas. In contrast, the exhaustion marker Tim-3 was only elevated in HIV-monoinfected patients. T-cell activation and exhaustion were correlated with HCV-RNA, suggesting that viral antigen influences T-cell activation and exhaustion. Interestingly, increased percentages of effector CD8(+) T-cells were found in patients with severe (F3-F4) liver fibrosis compared to those with no to minimal fibrosis (F0-F2). CONCLUSIONS: HIV/HCV coinfected patients display a high level of T-cell activation and exhaustion in the peripheral blood. Our data suggest that T-cell activation and exhaustion are influenced by the level of HCV viremia. Furthermore, high percentages of cytotoxic/effector CD8(+) T-cells are associated with liver fibrosis in both HCV monoinfected and HIV/HCV coinfected patients.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2013-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: Pegylated interferon-α monotherapy leads to low response rates in HIV-infected patients with acute hepatitis C.

Arends, Joop E / van Assen, Sander / Stek, Cari J / Wensing, Annemarie Mj / Fransen, Justin H / Schellens, Ingrid M / Spijkers, Sanne Nm / Mudrikova, Tania / van Baarle, Debbie / Sprenger, Herman G / Hoepelman, Andy Im

Antiviral therapy

2011 Volume 16, Issue 7, Page(s) 979–988

Abstract: Background: Despite a rising incidence of acute HCV in patients infected with HIV, the optimal therapeutic strategy (pegylated interferon-α [PEG-IFN-α] monotherapy or in combination with ribavirin) is still under debate.: Methods: A total of 23 HIV- ... ...

Abstract	Background: Despite a rising incidence of acute HCV in patients infected with HIV, the optimal therapeutic strategy (pegylated interferon-α [PEG-IFN-α] monotherapy or in combination with ribavirin) is still under debate. Methods: A total of 23 HIV-infected patients were prospectively diagnosed with acute HCV and treated with PEG-IFN-α2a monotherapy (180 μg/week) for 24 or 48 weeks. Add-on ribavirin was allowed from week 4 of therapy onwards. There were three patients who were not included for different reasons. Blood samples were routinely drawn for viral load measurement and IL28B polymorphism analysis. Results: Spontaneous viral clearance occurred in 1 (4%) patient. Nineteen patients (13 genotype 1 and 6 genotype 4) received treatment with PEG-IFN-α monotherapy (3 with add-on ribavirin) resulting in a rapid virological response (HCV RNA<50 IU/ml at week 4) in 7 (37%) patients. A sustained virological response (SVR) was reached in 7 (37%) patients, whereas 9 (47%) patients were null-responders to treatment (that is, <2 log₁₀ drop in HCV RNA at week 12 of therapy). The unfavourable G allele of the IL28B polymorphism rs8099917 was detected in 66% of the non-responders. In case of re-emergence of HCV viraemia after treatment discontinuation, sequence analysis of quasispecies confirmed an HCV relapse in 3 patients while 2 patients were re-infected by their previously non-responding partner. Conclusions: PEG-IFN-α monotherapy resulted in a low SVR rate and a high percentage of null-response, whereas non-SVR was associated with a polymorphism in the IL28B gene (rs8099917).
MeSH term(s)	Adult ; Alleles ; Antiviral Agents/administration & dosage ; Antiviral Agents/therapeutic use ; Cohort Studies ; Female ; Genotype ; HIV Infections/complications ; HIV Infections/drug therapy ; Hepacivirus/drug effects ; Hepatitis C/complications ; Hepatitis C/drug therapy ; Hepatitis C/genetics ; Humans ; Interferon-alpha/administration & dosage ; Interferon-alpha/therapeutic use ; Interferons ; Interleukins/genetics ; Male ; Middle Aged ; Polyethylene Glycols/administration & dosage ; Polyethylene Glycols/therapeutic use ; Polymorphism, Single Nucleotide ; Prospective Studies ; RNA, Viral/blood ; RNA, Viral/genetics ; Recombinant Proteins/administration & dosage ; Recombinant Proteins/therapeutic use ; Recurrence ; Ribavirin/administration & dosage ; Ribavirin/therapeutic use ; Treatment Outcome ; Viral Load
Chemical Substances	Antiviral Agents ; interferon-lambda, human ; Interferon-alpha ; Interleukins ; RNA, Viral ; Recombinant Proteins ; Polyethylene Glycols (3WJQ0SDW1A) ; Ribavirin (49717AWG6K) ; Interferons (9008-11-1) ; peginterferon alfa-2a (Q46947FE7K)
Language	English
Publishing date	2011-10-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1339842-8
ISSN	2040-2058 ; 1359-6535
ISSN (online)	2040-2058
ISSN	1359-6535
DOI	10.3851/IMP1843
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Zs.A 4877: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Apoptosis-induced acetylation of histones is pathogenic in systemic lupus erythematosus.

Dieker, Jürgen W / Fransen, Justin H / van Bavel, Casandra C / Briand, Jean-Paul / Jacobs, Cor W / Muller, Sylviane / Berden, Jo H / van der Vlag, Johan

Arthritis and rheumatism

2007 Volume 56, Issue 6, Page(s) 1921–1933

Abstract: Objective: In systemic lupus erythematosus (SLE), inadequate removal of apoptotic cells may lead to challenge of the immune system with immunogenic self antigens that have been modified during apoptosis. We undertook this study to evaluate whether ... ...

Abstract	Objective: In systemic lupus erythematosus (SLE), inadequate removal of apoptotic cells may lead to challenge of the immune system with immunogenic self antigens that have been modified during apoptosis. We undertook this study to evaluate whether apoptosis-induced histone modifications are targets for the immune system in SLE. Methods: The epitope of KM-2, a monoclonal antihistone autoantibody derived from a lupus mouse, was mapped by random peptide phage display. The reactivity of KM-2 and plasma with (acetylated) histone H4 (H4) peptides and with nonapoptotic, apoptotic, and hyperacetylated histones was determined by immunofluorescence staining, enzyme-linked immunosorbent assay, and Western blotting. Results: KM-2 recognized apoptosis-induced acetylation of H4 at lysines 8, 12, and 16. The majority of plasma samples from SLE patients and lupus mice showed higher reactivity with triacetylated H4 peptide (residues 1-22) and with hyperacetylated and apoptotic histones than with nonacetylated H4 peptide and normal histones. Importantly, administration of triacetylated H4 peptide to lupus-prone mice before disease onset accelerated the disease by enhancing mortality and aggravating proteinuria, skin lesions, and glomerular IgG deposition, while the nonacetylated H4 peptide had no pathogenic effect. The delayed-type hypersensitivity response in lupus mice against the triacetylated H4 peptide was higher than that against the nonacetylated H4 peptide. Bone marrow-derived dendritic cells (DCs) cultured in the presence of hyperacetylated nucleosomes showed increased expression/production of CD40, CD86, interleukin-6 (IL-6), and tumor necrosis factor alpha compared with DCs cultured in the presence of normal nucleosomes. Finally, DCs cultured in the presence of hyperacetylated nucleosomes were able to activate syngeneic T cells, because IL-2 production increased. Conclusion: Apoptosis-induced acetylation of nucleosomes may represent an important driving force in the development of lupus.
MeSH term(s)	Acetylation ; Animals ; Antibodies, Monoclonal/immunology ; Apoptosis/physiology ; Autoantibodies/immunology ; Chromatin/immunology ; Dendritic Cells/cytology ; Dendritic Cells/physiology ; Epitopes/immunology ; Histones/immunology ; Histones/metabolism ; Humans ; Immune System/immunology ; Jurkat Cells ; Lupus Erythematosus, Systemic/metabolism ; Lupus Erythematosus, Systemic/physiopathology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred MRL lpr ; Nucleosomes/physiology ; T-Lymphocytes/physiology ; U937 Cells
Chemical Substances	Antibodies, Monoclonal ; Autoantibodies ; Chromatin ; Epitopes ; Histones ; Nucleosomes
Language	English
Publishing date	2007-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	127294-9
ISSN	1529-0131 ; 0004-3591 ; 2326-5191
ISSN (online)	1529-0131
ISSN	0004-3591 ; 2326-5191
DOI	10.1002/art.22646
Database	MEDical Literature Analysis and Retrieval System OnLINE

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