|
1
|
David P, Santos GDM, Patt YS, Orsi FA, Shoenfeld Y. Immune thrombocytopenia (ITP) - could it be part of autoimmune/inflammatory syndrome induced by adjuvants (ASIA)? Autoimmun Rev 2024; 23:103605. [PMID: 39182594 DOI: 10.1016/j.autrev.2024.103605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Accepted: 05/30/2024] [Indexed: 08/27/2024]
Abstract
Immune thrombocytopenia (ITP) is a complex autoimmune disorder characterized by thrombocytopenia and an increased bleeding risk, arising from autoantibody-mediated platelet destruction and impaired megakaryocyte function. The pathogenesis of ITP involves a multifaceted interplay of genetic predispositions, immune dysregulation, and environmental triggers, though the precise mechanisms remain uncertain. Several infectious agents, mostly viruses, have been implicated in both acute and chronic ITP through mechanisms such as molecular mimicry, direct bone marrow suppression, and immune dysregulation. Vaccinations, particularly those containing adjuvants like aluminum and those capable of inducing molecular mimicry, have also been associated with ITP, either as a new onset or as a relapse in preexisting cases. The role of drugs, particularly quinine, quinidine and certain antibiotics, in inducing ITP through various immunological pathways further illustrates the diverse etiologies of this condition. The multiple triggers of the disease raise the question of whether ITP may be classified as an autoimmune/inflammatory syndrome induced by adjuvants (ASIA). This condition encompasses a range of autoimmune and inflammatory symptoms triggered by adjuvants, such as silicones, polypropylene meshes, metal implants, and mineral oils present in various medical materials and medications. Similar to that observed in some cases of ITP, adjuvants can trigger autoimmune or autoinflammatory responses via molecular mimicry, epitope spreading, and polyclonal activation. This narrative review explores the underlying environmental factors related to ITP and examines ITP triggers that could potentially support an association between ITP and ASIA syndrome.
Collapse
Affiliation(s)
- Paula David
- Internal Medicine B, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel; Leeds Institute of Rheumatic and Musculoskeletal Diseases (LIRMM), University of Leeds, Leeds, UK.
| | - Gabrielle de Mello Santos
- Hospital das Clinicas of University of São Paulo Medical School (HCFMUSP), São Paulo, Brazil; HEMORIO - State Institute of Hematology "Arthur de Siqueira Cavalcanti", Rio de Janeiro, Brazil
| | - Yonatan Shneor Patt
- Internal Medicine B, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel
| | - Fernanda A Orsi
- Hospital das Clinicas of University of São Paulo Medical School (HCFMUSP), São Paulo, Brazil; Department of Pathology, School of Medical Sciences of the University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Yehuda Shoenfeld
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Reichman University, Herzliya, Israel
| |
Collapse
|
|
2
|
Auma AWN, Shive CL, Kostadinova L, Anthony DD. Variable Normalization of Naïve CD4+ Lymphopenia and Markers of Monocyte and T Cell Activation over the Course of Direct-Acting Anti-Viral Treatment of Chronic Hepatitis C Virus Infection. Viruses 2021; 14:50. [PMID: 35062255 PMCID: PMC8780994 DOI: 10.3390/v14010050] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 12/27/2021] [Accepted: 12/28/2021] [Indexed: 12/14/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection is associated with naïve CD4+ T cell lymphopenia and long-standing/persistent elevation of cellular and soluble immune activation parameters, the latter heightened in the setting of HIV co-infection. The underlying mechanisms are not completely understood. However, we recently reported that accelerated peripheral cell death may contribute to naïve CD4+ T cell loss and that mechanistic relationships between monocyte activation, T cell activation, and soluble inflammatory mediators may also contribute. Chronic HCV infection can be cured by direct-acting anti-viral (DAA) therapy, and success is defined as sustained virological response (SVR, undetectable HCV RNA (ribonucleic acid) at 12 weeks after DAA treatment completion). However, there is no general consensus on the short-term and long-term immunological outcomes of DAA therapy. Here, we consolidate previous reports on the partial normalization of naïve CD4+ lymphopenia and T cell immune activation and the apparent irreversibility of monocyte activation following DAA therapy in HCV infected and HCV/HIV co-infected individuals. Further, advanced age and cirrhosis are associated with delayed or abrogation of immune reconstitution after DAA therapy, an indication that non-viral factors also likely contribute to host immune dysregulation in HCV infection.
Collapse
Affiliation(s)
- Ann W. N. Auma
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA; (A.W.N.A.); (C.L.S.)
| | - Carey L. Shive
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA; (A.W.N.A.); (C.L.S.)
- Cleveland VA Medical Center, Cleveland, OH 44106, USA;
| | | | - Donald D. Anthony
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA; (A.W.N.A.); (C.L.S.)
- Cleveland VA Medical Center, Cleveland, OH 44106, USA;
- Metro Health Medical Center, Division of Rheumatology, Cleveland, OH 44106, USA
| |
Collapse
|
|
3
|
Auma AWN, Shive CL, Lange A, Damjanovska S, Kowal C, Zebrowski E, Pandiyan P, Wilson B, Kalayjian RC, Canaday DH, Anthony DD. Naïve CD4+ T Cell Lymphopenia and Apoptosis in Chronic Hepatitis C Virus Infection Is Driven by the CD31+ Subset and Is Partially Normalized in Direct-Acting Antiviral Treated Persons. Front Immunol 2021; 12:641230. [PMID: 33912168 PMCID: PMC8075159 DOI: 10.3389/fimmu.2021.641230] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 03/24/2021] [Indexed: 12/29/2022] Open
Abstract
Background The mechanisms underlying naïve CD4+ lymphopenia during chronic Hepatitis C Virus (HCV) infection are unclear. Whether direct-acting antiviral (DAA) therapy restores peripheral naïve CD4+ T cell numbers and function is unknown. Methods We enumerated frequencies and counts of peripheral naïve CD4+, CD4+CD31+ and CD4+CD31- T cells by flow cytometry in a cross sectional analysis comparing chronic HCV infected (n=34), DAA-treated(n=29), and age-range matched controls (n=25), as well as in a longitudinal cohort of HCV DAA treated persons (n=16). The cross-sectional cohort was stratified by cirrhosis state. Cell apoptosis/survival (AnnexinV+7AAD+/BCL-2 labeling) and cell cycle entry (Ki67 expression) of CD31+ and CD31- naïve CD4+ T cells was analyzed directly ex vivo and following 3 and 5 days of in vitro culture with media, interleukin (IL) -7 or CD3/CD28 activator. Results In the cross-sectional cohort, naïve CD4+ proportions were lower in chronic HCV infected persons compared to controls and DAA-treated persons, an effect in part attributed to cirrhosis. Age was associated with naïve cell counts and proportions in HCV infected and treated persons as well. Naïve CD4+ cell proportions negatively correlated with plasma levels of soluble CD14 following therapy in DAA-treated persons. Naïve CD4+ cells from HCV infected persons exhibited greater direct ex vivo apoptosis and cell-cycling compared to cells from DAA-treated persons and controls, and this was localized to the CD4+CD31+ subset. On the other hand, no remarkable differences in expression of BCL-2 or IL-7 Receptor (CD127) at baseline or following in vitro media or IL7 containing culture were observed. In the longitudinal cohort, naïve CD4+CD31+/CD31- ratio tended to increase 24 weeks after DAA therapy initiation. Conclusions Activation and apoptosis of peripheral naïve CD4+CD31+ T cells appear to contribute to naïve CD4+ lymphopenia in chronic HCV infection, and this defect is partially reversible with HCV DAA therapy. Age and cirrhosis -associated naïve CD4+ lymphopenia is present both before and after HCV DAA therapy. These findings have implications for restoration of host immune function after DAA therapy.
Collapse
Affiliation(s)
- Ann W N Auma
- Department of Pathology, Case Western Reserve University, Cleveland, OH, United States
| | - Carey L Shive
- Department of Pathology, Case Western Reserve University, Cleveland, OH, United States.,GRECC, VA Northeast Ohio Healthcare System, Cleveland, OH, United States
| | - Alyssa Lange
- GRECC, VA Northeast Ohio Healthcare System, Cleveland, OH, United States
| | - Sofi Damjanovska
- GRECC, VA Northeast Ohio Healthcare System, Cleveland, OH, United States
| | - Corinne Kowal
- GRECC, VA Northeast Ohio Healthcare System, Cleveland, OH, United States
| | | | - Pushpa Pandiyan
- Department of Pathology, Case Western Reserve University, Cleveland, OH, United States
| | - Brigid Wilson
- GRECC, VA Northeast Ohio Healthcare System, Cleveland, OH, United States
| | - Robert C Kalayjian
- Department of Medicine, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH, United States
| | - David H Canaday
- GRECC, VA Northeast Ohio Healthcare System, Cleveland, OH, United States
| | - Donald D Anthony
- Department of Pathology, Case Western Reserve University, Cleveland, OH, United States.,GRECC, VA Northeast Ohio Healthcare System, Cleveland, OH, United States.,Department of Medicine, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH, United States
| |
Collapse
|
|
4
|
Shojaie L, Iorga A, Dara L. Cell Death in Liver Diseases: A Review. Int J Mol Sci 2020; 21:ijms21249682. [PMID: 33353156 PMCID: PMC7766597 DOI: 10.3390/ijms21249682] [Citation(s) in RCA: 186] [Impact Index Per Article: 37.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 12/11/2022] Open
Abstract
Regulated cell death (RCD) is pivotal in directing the severity and outcome of liver injury. Hepatocyte cell death is a critical event in the progression of liver disease due to resultant inflammation leading to fibrosis. Apoptosis, necrosis, necroptosis, autophagy, and recently, pyroptosis and ferroptosis, have all been investigated in the pathogenesis of various liver diseases. These cell death subroutines display distinct features, while sharing many similar characteristics with considerable overlap and crosstalk. Multiple types of cell death modes can likely coexist, and the death of different liver cell populations may contribute to liver injury in each type of disease. This review addresses the known signaling cascades in each cell death pathway and its implications in liver disease. In this review, we describe the common findings in each disease model, as well as the controversies and the limitations of current data with a particular focus on cell death-related research in humans and in rodent models of alcoholic liver disease, non-alcoholic fatty liver disease and steatohepatitis (NASH/NAFLD), acetaminophen (APAP)-induced hepatotoxicity, autoimmune hepatitis, cholestatic liver disease, and viral hepatitis.
Collapse
Affiliation(s)
- Layla Shojaie
- Division of Gastrointestinal & Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; (L.S.); (A.I.)
- Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Andrea Iorga
- Division of Gastrointestinal & Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; (L.S.); (A.I.)
- Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Lily Dara
- Division of Gastrointestinal & Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; (L.S.); (A.I.)
- Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Correspondence:
| |
Collapse
|
|
5
|
Goto K, Roca Suarez AA, Wrensch F, Baumert TF, Lupberger J. Hepatitis C Virus and Hepatocellular Carcinoma: When the Host Loses Its Grip. Int J Mol Sci 2020; 21:ijms21093057. [PMID: 32357520 PMCID: PMC7246584 DOI: 10.3390/ijms21093057] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 04/20/2020] [Accepted: 04/24/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic infection with hepatitis C virus (HCV) is a major cause of hepatocellular carcinoma (HCC). Novel treatments with direct-acting antivirals achieve high rates of sustained virologic response; however, the HCC risk remains elevated in cured patients, especially those with advanced liver disease. Long-term HCV infection causes a persistent and accumulating damage of the liver due to a combination of direct and indirect pro-oncogenic mechanisms. This review describes the processes involved in virus-induced disease progression by viral proteins, derailed signaling, immunity, and persistent epigenetic deregulation, which may be instrumental to develop urgently needed prognostic biomarkers and as targets for novel chemopreventive therapies.
Collapse
Affiliation(s)
- Kaku Goto
- Université de Strasbourg, F-67000 Strasbourg, France
- Institut National de la Santé et de la Recherche Médicale, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg (IVH), F-67000 Strasbourg, France
| | - Armando Andres Roca Suarez
- Université de Strasbourg, F-67000 Strasbourg, France
- Institut National de la Santé et de la Recherche Médicale, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg (IVH), F-67000 Strasbourg, France
| | - Florian Wrensch
- Université de Strasbourg, F-67000 Strasbourg, France
- Institut National de la Santé et de la Recherche Médicale, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg (IVH), F-67000 Strasbourg, France
| | - Thomas F. Baumert
- Université de Strasbourg, F-67000 Strasbourg, France
- Institut National de la Santé et de la Recherche Médicale, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg (IVH), F-67000 Strasbourg, France
- Pôle Hépato-digestif, Institut Hopitalo-Universitaire, F-67000 Strasbourg, France
- Institut Universitaire de France, F-75231 Paris, France
- Correspondence: (T.F.B.); (J.L.); Tel.: +33-3-68-85-37-03 (T.F.B. & J.L.); Fax: +33-3-68-85-37-24 (T.F.B. & J.L.)
| | - Joachim Lupberger
- Université de Strasbourg, F-67000 Strasbourg, France
- Institut National de la Santé et de la Recherche Médicale, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg (IVH), F-67000 Strasbourg, France
- Correspondence: (T.F.B.); (J.L.); Tel.: +33-3-68-85-37-03 (T.F.B. & J.L.); Fax: +33-3-68-85-37-24 (T.F.B. & J.L.)
| |
Collapse
|
|
6
|
Eiza N, Zuckerman E, Carlebach M, Rainis T, Goldberg Y, Vadasz Z. Increased killer B cells in chronic HCV infection may lead to autoimmunity and increased viral load. Clin Exp Immunol 2019; 193:183-193. [PMID: 29665000 DOI: 10.1111/cei.13139] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/30/2018] [Indexed: 01/20/2023] Open
Abstract
Regulatory B (Breg ) cells are characterized by various membrane markers and the secretion of different inhibitory cytokines. A new subset of Breg cells was identified as CD5hi Fas-ligand (FasL)hi . Their main reported role is to suppress anti-viral and anti-tumour immune responses, and, hence they have been dubbed 'killer' B cells. In this study, we aim to assess the role of these cells in chronic hepatitis C virus (HCV) infection, and determine if they contribute to the increased viral load and persistence of HCV and its related autoimmunity. (i) FasL expression on CD5hi B cells is increased significantly in HCV-infected patients compared to healthy individuals [28·06 ± 6·71 mean fluorescence intensity (MFI) ± standard error of the mean (s.e.m.), median = 27·9 versus 10·87 ± 3·97 MFI ± s.e.m., median = 10·3, respectively, P < 0·0001]. (ii) Killer B cells from HCV patients increased autologous CD4+ T cell apoptosis compared to the apoptosis in healthy individuals [39·17% ± 7·18% mean ± standard deviation (s.d.), median = 39·6 versus 25·92 ± 8·65%, mean ± s.d., median = 24·1%, P < 0·0001, respectively]. A similar increase was observed in CD8+ T cell apoptosis (54·67 ± 15·49% mean ± s.d., median = 57·3 versus 21·07% ± 7·4%, mean ± s.d., median = 20%, P = 0·0006, respectively). (iii) By neutralizing FasL with monoclonal anti-FasL antibodies, we have shown that the induction of apoptosis by killer B cells is FasL-dependent. (iv) Increased expression of FasL on CD5hi B cells is correlated positively with an increased viral load and the presence of anti-nuclear antibodies and rheumatoid factor in HCV. This is the first study in which killer B cells have been suggested to play a pathogenic role in HCV. They seem to be involved in HCV's ability to escape efficient immune responses.
Collapse
Affiliation(s)
- N Eiza
- Division of Allergy and Clinical Immunology, Bnai Zion Medical Center, Haifa, Israel
| | - E Zuckerman
- Unit of Hepatology, Carmel Medical Center, Haifa, Israel
| | - M Carlebach
- Division of Gastroenterology, Bnai Zion Medical Center, Haifa, Israel.,Faculty of Medicine, Technion, Haifa, Israel
| | - T Rainis
- Division of Gastroenterology, Bnai Zion Medical Center, Haifa, Israel.,Faculty of Medicine, Technion, Haifa, Israel
| | - Y Goldberg
- Department of Statistics, University of Haifa, Haifa, Israel
| | - Z Vadasz
- Division of Allergy and Clinical Immunology, Bnai Zion Medical Center, Haifa, Israel
| |
Collapse
|
|
7
|
Barathan M, Mohamed R, Yong YK, Kannan M, Vadivelu J, Saeidi A, Larsson M, Shankar EM. Viral Persistence and Chronicity in Hepatitis C Virus Infection: Role of T-Cell Apoptosis, Senescence and Exhaustion. Cells 2018; 7:cells7100165. [PMID: 30322028 PMCID: PMC6210370 DOI: 10.3390/cells7100165] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 10/02/2018] [Accepted: 10/09/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) represents a challenging global health threat to ~200 million infected individuals. Clinical data suggest that only ~10–15% of acutely HCV-infected individuals will achieve spontaneous viral clearance despite exuberant virus-specific immune responses, which is largely attributed to difficulties in recognizing the pathognomonic symptoms during the initial stages of exposure to the virus. Given the paucity of a suitable small animal model, it is also equally challenging to study the early phases of viral establishment. Further, the host factors contributing to HCV chronicity in a vast majority of acutely HCV-infected individuals largely remain unexplored. The last few years have witnessed a surge in studies showing that HCV adopts myriad mechanisms to disconcert virus-specific immune responses in the host to establish persistence, which includes, but is not limited to viral escape mutations, viral growth at privileged sites, and antagonism. Here we discuss a few hitherto poorly explained mechanisms employed by HCV that are believed to lead to chronicity in infected individuals. A better understanding of these mechanisms would aid the design of improved therapeutic targets against viral establishment in susceptible individuals.
Collapse
Affiliation(s)
- Muttiah Barathan
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, LembahPantai, 50603 Kuala Lumpur, Malaysia.
| | - Rosmawati Mohamed
- Department of Medicine, Faculty of Medicine, University of Malaya, 50603 LembahPantai, Kuala Lumpur, Malaysia.
| | - Yean K Yong
- Laboratory Center, Xiamen University Malaysia, 43900 Sepang, Malaysia.
| | - Meganathan Kannan
- Division of Blood and Vascular Biology, Department of Life Sciences, Central University of Tamil Nadu (CUTN), Thiruvarur 610005, India.
| | - Jamuna Vadivelu
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, LembahPantai, 50603 Kuala Lumpur, Malaysia.
| | - Alireza Saeidi
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, LembahPantai, 50603 Kuala Lumpur, Malaysia.
| | - Marie Larsson
- Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linkoping University, 58 183 Linkoping, Sweden.
| | - Esaki Muthu Shankar
- Division of Infection Biology and Medical Microbiology, Department of Life Sciences, Central University of Tamil Nadu (CUTN), Thiruvarur 610005, India.
| |
Collapse
|
|
8
|
Sensitization with vaccinia virus encoding H5N1 hemagglutinin restores immune potential against H5N1 influenza virus. Sci Rep 2016; 6:37915. [PMID: 27892498 PMCID: PMC5124960 DOI: 10.1038/srep37915] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 11/04/2016] [Indexed: 11/08/2022] Open
Abstract
H5N1 highly pathogenic avian influenza (H5N1 HPAI) virus causes elevated mortality compared with seasonal influenza viruses like H1N1 pandemic influenza (H1N1 pdm) virus. We identified a mechanism associated with the severe symptoms seen with H5N1 HPAI virus infection. H5N1 HPAI virus infection induced a decrease of dendritic cell number in the splenic extrafollicular T-cell zone and impaired formation of the outer layers of B-cell follicles, resulting in insufficient levels of antibody production after infection. However, in animals vaccinated with a live recombinant vaccinia virus expressing the H5 hemagglutinin, infection with H5N1 HPAI virus induced parafollicular dendritic cell accumulation and efficient antibody production. These results indicate that a recombinant vaccinia encoding H5 hemagglutinin gene does not impair dendritic cell recruitment and can be a useful vaccine candidate.
Collapse
|
|
9
|
El-Bendary M, Hawas S, El-Hammady D, Al-Hadidy AHM, Eldegla H. Profile of expression of certain markers of apoptosis in chronic hepatitis C and hepatitis B patients in an Egyptian population. Arch Virol 2016; 161:2369-2378. [PMID: 27262945 DOI: 10.1007/s00705-016-2897-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Accepted: 05/16/2016] [Indexed: 10/21/2022]
Abstract
Increased peripheral blood mononuclear cell (PBMC) apoptosis during viral hepatitis has been suggested to cause impaired regulation of the immune response and maintenance of the infection. The purpose of this work was to study the expression of some apoptotic markers in chronic hepatitis B (CHB) and C (CHC) infections in order to understand the underlying mechanisms of immune failure and viral persistence. This study aims to evaluate the level of PBMC apoptosis and the expression of the apoptosis-related proteins Fas and Bcl-2 in CHB and CHC patients. This case control study was carried out on 38 cases (group I: 20 chronic HCV patients; group II: 18 chronic HBV patients) attending the Tropical Medicine Clinic, Mansoura University Hospital, in addition to 10 healthy controls. Morphological assessment of apoptosis of cultured PBMCs was done. The level of Fas and Bcl-2 expression by PBMCs was detected using flow cytometry. An increased level of apoptosis correlated with increased Fas expression, but no increase in Bcl-2 expression was found on the surface of PBMCs in CHC and CHB patients compared to controls. No significant difference in the level of apoptosis, Fas, or Bcl2 expression between CHC and CHB patients was detected. Modulation of apoptosis, particularly by manipulation of Fas receptor activation, may be of therapeutic benefit in chronic CHB and CHC.
Collapse
Affiliation(s)
- Mahmoud El-Bendary
- Tropical Medicine and Hepatology, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt.
| | - Samia Hawas
- Medical Microbiology and Immunology, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Dina El-Hammady
- Tropical Medicine and Hepatology, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | | | - Heba Eldegla
- Medical Microbiology and Immunology, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
| |
Collapse
|
|
10
|
Autoimmune reactions in the course of the hepatitis C virus (HCV) infection. Clin Exp Hepatol 2015; 1:39-43. [PMID: 28856254 PMCID: PMC5497407 DOI: 10.5114/ceh.2015.51804] [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: 05/19/2015] [Accepted: 05/21/2015] [Indexed: 02/08/2023] Open
Abstract
The immune response to the presence of the virus, both specific and non-specific, plays a decisive role in the natural history of the infection, and influences the intensity of lesions in the liver. Despite the great progress which we were able to observe over the last several years, many issues still require clarification. The problem of autoimmune reactions during hepatitis C virus (HCV) infection includes at least two issues. First, the risk of exacerbating reactions against the organism’s own tissues that existed before the treatment. There is also an increased risk of the development of de novo autoimmune reactions, triggered mostly by interferon α. Hepatitis C virus infection predisposes to the development of diseases characterised as being certainly or probably immune-mediated. Currently the situation has changed due to introducing non-interferon therapies for HCV treatment, which eliminate the risk associated with immunotherapy in patients with autoimmune diseases, yet the therapies are not widely available.
Collapse
|
|
11
|
Arain SA, Kazi TG, Afridi HI, Talpur FN, Mughal MA, Shah F, Arain SS, Panhwar AH. Estimation of copper and iron burden in biological samples of various stages of hepatitis C and liver cirrhosis patients. Biol Trace Elem Res 2014; 160:197-205. [PMID: 24973874 DOI: 10.1007/s12011-014-0058-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Accepted: 06/22/2014] [Indexed: 01/19/2023]
Abstract
There is accumulative evidence that the metabolism of iron (Fe) and copper (Cu) is altered in human due to infections, indicating that both elements have roles in pathogenesis and progress of viral diseases. In the present study, the correlation of Cu and Fe was evaluate in biological samples (serum and scalp hair) of hepatitis C (hepatitis C virus (HCV)) patients of both genders at different stages. For comparative study, the scalp hair and serum samples of healthy individuals of same age group (30-50 years) and socioeconomic status were collected. The biological samples were analyzed for Fe and Cu by atomic absorption spectroscopy after microwave-assisted acid digestion. The validity and accuracy of methodology were checked by certified reference materials of same matrixes. The levels of Cu and Fe in biological samples were enhanced in hepatic disorder patients, including acute (after diagnosis test, anti-HCV sero-positive) hepatic fibrosis and liver cirrhosis as compared to healthy referents. The difference was significant (p < 0.01) in the case of liver cirrhotic patients. It was observed that the data of Cu and Fe in referents and patients of both genders had normal distributions. The inter-elemental correlation (r) among Cu vs Fe in serum and scalp hair samples of referents and patients were not significant in both genders (p > 0.1) except in the first stage of HCV (p < 0.1). It was concluded that the increase of Cu and Fe content in human body seems to contribute to the development of cirrhosis in patients with viral hepatitis C.
Collapse
Affiliation(s)
- Salma Aslam Arain
- National Centre of Excellence in Analytical Chemistry, University of Sindh, Jamshoro, Pakistan,
| | | | | | | | | | | | | | | |
Collapse
|
|
12
|
Deghady A, Abdou A, EL-Neanaey WA, Diab I. Association of Genetic Polymorphism −670A>G in the Fas Gene and Serum Markers AST Platelet Ratio Index, AST/ALT with Significant Fibrosis and Cirrhosis in Chronic Hepatitis C. Genet Test Mol Biomarkers 2012; 16:531-5. [DOI: 10.1089/gtmb.2011.0098] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Affiliation(s)
- Akram Deghady
- Department of Clinical Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Alaa Abdou
- Department of Tropical Medicine, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Wafaa Ahmed EL-Neanaey
- Department of Clinical Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Iman Diab
- Department of Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| |
Collapse
|
|
13
|
Piazzolla G, Nuzzaci M, Vitti A, Napoli N, Schiavone M, Piazzolla P, Antonaci S, Tortorella C. Apoptotic effects of a chimeric plant virus carrying a mimotope of the hepatitis C virus hypervariable region 1: role of caspases and endoplasmic reticulum-stress. J Clin Immunol 2012; 32:866-76. [PMID: 22392048 PMCID: PMC3389245 DOI: 10.1007/s10875-012-9676-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2011] [Accepted: 02/20/2012] [Indexed: 12/03/2022]
Abstract
The role of apoptosis in the persistence of hepatitis C virus (HCV) infection is controversial. Moreover, conflicting data on the modulation of this process by HCV proteins have been provided. We evaluated the susceptibility of peripheral lymphocytes from patients with chronic hepatitis C to apoptosis both spontaneous and after incubation with a chimeric Cucumber mosaic virus (CMV) carrying 180 copies of the synthetic R9 mimotope obtained from more than 200 hypervariable region-1 sequences of HCV. Resting T lymphocytes were found to be sensitized to apoptosis as a result of chronic HCV infection. The plant virus-derived vector R9-CMV displayed a strong pro-apoptotic effect associated with activation of both caspase-8 and −9, indicating the involvement of both extrinsic and intrinsic apoptotic pathways. A parallel R9-CMV-mediated activation of endoplasmic reticulum-stress was suggested by the significant induction of BiP/GRP78, GADD153 and caspase-12. These data contribute to define the complex HCV/host interaction, and open new prospects for developing a plant-derived antigen-presenting system to strengthen host defences against persistent pathogens.
Collapse
Affiliation(s)
- G Piazzolla
- Department of Internal Medicine, Immunology and Infectious Diseases, Section of Internal Medicine, University of Bari, 70124, Bari, Italy.
| | | | | | | | | | | | | | | |
Collapse
|
|
14
|
Arends JE, Hoepelman AIM, Nanlohy NM, Höppener FJP, Hirsch KR, Park JG, van Baarle D. Low doses of the novel caspase-inhibitor GS-9450 leads to lower caspase-3 and -8 expression on peripheral CD4+ and CD8+ T-cells. Apoptosis 2011; 16:959-66. [PMID: 21667042 PMCID: PMC3152720 DOI: 10.1007/s10495-011-0620-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Chronic hepatitis C virus (HCV) infection is characterized by increased rates of apoptotic hepatocytes and activated caspases have been shown in HCV-infected patients. GS-9450, a novel caspase-inhibitor has demonstrated hepatoprotective activity in fibrosis/apoptosis animal models. This study evaluated the effects of GS-9450 on peripheral T-cell apoptosis in chronic HCV-infected patients. As sub study of the GS-US-227-0102, a double-blind, placebo-controlled phase 2a trial evaluating the safety and tolerability of GS-9450, apoptosis of peripheral CD4+ and CD8+ T-cells was measured using activated caspase-3, activated caspase-8 and CD95 (Fas). Blood samples were drawn at baseline, day 14 after therapy and at 5 weeks off-treatment follow-up in the first cohort of 10 mg. In contrast to the placebo-treated patients, GS-9450 caused a median of 46% decrease in ALT-values from baseline to day 14 in all treated patients (median of 118-64 U/l) rising again to a median of 140 U/l (19%) at 5 weeks off-treatment follow-up. In GS9450-treated patients, during treatment and follow-up, percentages of activated caspase-3+ and caspase-8 expression tended to decrease, in contrast to placebo-treated patients. Interestingly, compared to healthy controls, higher percentages of caspase-3 and caspase-8 positive CD4+ and CD8+ T-cells were demonstrated in HCV-infected patients at baseline. Decreased ALT-values were observed in all HCV-infected patients during treatment with low dose of the caspase-inhibitor GS-9450 accompanied by a lower expression of caspase-3 and -8 on peripheral T-cells. Furthermore, at baseline percentages of activated caspase-3, activated caspase-8 and CD95+ T-cells were higher in chronic HCV-infected patients compared to healthy controls.
Collapse
Affiliation(s)
- J E Arends
- Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht (UMCU), Heidelberglaan, GA, Utrecht, The Netherlands.
| | | | | | | | | | | | | |
Collapse
|
|
15
|
Panasiuk A, Parfieniuk A, Zak J, Flisiak R. Association among Fas expression in leucocytes, serum Fas and Fas-ligand concentrations and hepatic inflammation and fibrosis in chronic hepatitis C. Liver Int 2010; 30:472-8. [PMID: 19919570 DOI: 10.1111/j.1478-3231.2009.02159.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
BACKGROUND Replication of the hepatitis C virus (HCV) in peripheral blood mononuclear cells (PBMC) may impair immune functions and establish persistent infection. The aim of this study was to assess the influence of HCV on PBMC and their susceptibility to apoptosis in relation to liver inflammation and fibrosis. METHODS Eighty-one patients with chronic hepatitis C (CHC) were enrolled in this study. Flow cytometry was used to determine the amount of T cells (CD4(+), CD8(+)), B cells (CD19(+)), monocytes (CD14(+)) and natural killer cells (CD16(+)) in the peripheral blood and the expression of CD95(+) (CD95/APO-1) in each subset. Serum concentrations of sFas and sFasL were assessed by the enzyme-linked immunosorbent assay method. RESULTS An increased expression of Fas was observed in CD4(+) and CD8(+) cells in CHC. There was a more prominent expression of Fas on CD4(+) cells in HCV genotype 1b in contrast to 3a. Increased Fas expression on CD4(+) cells was seen in advanced stages of liver disease. Fas expression on monocytes was lower in advanced stages of liver inflammation and fibrosis. Serum sFas concentration was higher in CHC compared with the control group. There was an association between sFasL concentration and inflammatory activity in the liver. Serum sFasL concentration correlated positively with the mean intensity of fluorescence of the Fas receptor in CD4(+) and CD8(+) cells, granulocytes and monocytes. CONCLUSION These findings indicate that there is an increased susceptibility of PBMC to apoptosis, which can be attributed to the constant contact of leucocytes with the inflamed liver tissue, or from direct HCV influence.
Collapse
Affiliation(s)
- Anatol Panasiuk
- Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Bialystok, Poland
| | | | | | | |
Collapse
|
|
16
|
Tang L, Yang J, Liu W, Tang X, Chen J, Zhao D, Wang M, Xu F, Lu Y, Liu B, Sun Q, Zhang L, He F. Liver sinusoidal endothelial cell lectin, LSECtin, negatively regulates hepatic T-cell immune response. Gastroenterology 2009; 137:1498-508.e5085. [PMID: 19632227 PMCID: PMC7127102 DOI: 10.1053/j.gastro.2009.07.051] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2008] [Revised: 06/19/2009] [Accepted: 07/09/2009] [Indexed: 01/13/2023]
Abstract
BACKGROUND & AIMS The liver is an organ with paradoxic immunologic properties and is known for its tolerant microenvironment, which holds important implications for hepatic diseases. The molecular basis for this local immune suppression, however, is poorly understood. In this study, we aimed to determine the role of liver sinusoidal endothelial cell lectin (LSECtin), a recently identified member of the dendritic cell-specific ICAM-3 grabbing nonintegrin (DC-SIGN) family, in the regulation of hepatic T-cell immune response. METHODS The regulation of T-cell effector function by LSECtin was determined by co-stimulated T cells with anti-CD3/CD28 monoclonal antibody and LSECtin protein, or co-culture of T-cell receptor transgenic T cells with mouse LSECs in vitro. We generated LSECtin knockout mice and prepared recombinant LSECtin protein and complementary DNA plasmids to analyze the role of LSECtin in hepatic T-cell immune regulation in vivo. RESULTS We showed that LSECtin specifically recognized activated T cells and negatively regulated their immune responses. In mice with T-cell-mediated acute liver injury, the lack of LSECtin accelerated the disease owing to an increased T-cell immune response, whereas the exogenous administration of recombinant LSECtin protein or plasmid ameliorated the disease via down-regulation of T-cell immunity. CONCLUSIONS Our results reveal that LSECtin is a novel regulator of T cells and expose a crucial mechanism for hepatic T-cell immune suppression, perhaps opening up a new approach for treatment of inflammatory diseases in the liver.
Collapse
Key Words
- clr, c-type lectin receptors
- crd, carbohydrate recognition domain
- dc, dendritic cell
- dc-sign, dendritic cell-specific icam-3 grabbing nonintegrin
- egta, ethylene glycol-bis(b-aminoethyl ether)-n,n,n′,n′-tetraacetic acid
- ifn, interferon
- il, interleukin
- l-sign, liver/lymph node specific icam-3 grabbing nonintegrin
- lsec, liver sinusoidal endothelial cell
- mab, monoclonal antibody
- mgl, macrophage galactose-type c-type lectin
- nf-κβ, nuclear factor-κβ
- ova, ovalbumin
- pbl, peripheral blood lymphocyte
- pbmc, peripheral blood mononuclear cell
- pcr, polymerase chain reaction
- pgk, phosphoglycerate kinase
- pma, phorbol-12-myristate-13-acetate
- q-pcr, quantitative pcr
- sars, severe acute respiratory syndrome
- sirna, small interfering
- tcr, t-cell receptor
- tnf, tumor necrosis factor
- wt, wildtype.
Collapse
Affiliation(s)
- Li Tang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
17
|
Abstract
Decreasing hepatocyte injury and death is an attractive therapeutic target in chronic hepatitis C and other liver diseases. Apoptotic cell death is a critical mechanism responsible for liver injury in hepatitis C, and contributes to hepatic fibrogenesis. At the cellular level, apoptosis is executed by a family of cysteine proteases termed caspases. Caspase inhibitors have been developed to inhibit these proteases and attenuate cellular apoptosis in vivo. By reducing hepatocyte apoptosis these agents have the potential to serve as hepatoprotective agents, minimizing liver injury and fibrosis. Studies on a variety of animal models, and time-limited studies in human patients with hepatitis C suggest these are promising therapeutic agents. However, although these agents hold promise, their usefulness requires further studies, especially longer duration studies using hepatic fibrogenesis as the end point before they can be considered further for the treatment of patients infected with the hepatitis C virus.
Collapse
Affiliation(s)
- Howard C. Masuoka
- Division of Gastroenterology and Hepatology, Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
| | - Maria Eugenia Guicciardi
- Division of Gastroenterology and Hepatology, Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
| | - Gregory J. Gores
- Division of Gastroenterology and Hepatology, Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
| |
Collapse
|
|
18
|
Zheng MH, Gu DN, Braddock M, Leishman AJ, Jin C, Wen JS, Gong YW, Chen YP. CD4+ CD25+ regulatory T cells: a therapeutic target for liver diseases. Expert Opin Ther Targets 2008; 12:313-26. [PMID: 18269341 DOI: 10.1517/14728222.12.3.313] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Regulatory T cells (Tregs) have been shown to play an important role in maintaining peripheral immune homeostasis by suppressing autoreactive and allergen-specific T cells and turning off the immune response after the pathogen has been cleared. However, in certain situations Tregs can impair effective immunity to some pathogens and tumour cells. OBJECTIVE To review the role of Tregs in liver pathology and to assess the potential to enhance or inhibit their function as applied to the treatment of liver disease. METHODS The literature was reviewed using standard indexing terms and incorporating publications up to and including those published in 2007. RESULTS/CONCLUSIONS Tregs are therapeutic targets for modulation in autoimmune disease and may provide new opportunities for application to human liver conditions.
Collapse
Affiliation(s)
- Ming-Hua Zheng
- First Affiliated Hospital of Wenzhou Medical College, Department of Infection and Liver Diseases, Wenzhou 325000, Zhejiang Province, China
| | | | | | | | | | | | | | | |
Collapse
|
|
19
|
Kessel A, Elias G, Pavlotzky E, Zuckerman E, Rosner I, Toubi E. Anti-C-reactive protein antibodies in chronic hepatitis C infection: Correlation with severity and autoimmunity. Hum Immunol 2007; 68:844-8. [DOI: 10.1016/j.humimm.2007.06.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2007] [Revised: 06/10/2007] [Accepted: 06/10/2007] [Indexed: 01/21/2023]
|
|
20
|
Osman HG, Gabr OM, Lotfy S, Gabr S. SERUM LEVELS OF BCL-2 AND CELLULAR OXIDATIVE STRESS IN PATIENTS WITH VIRAL HEPATITIS. Indian J Med Microbiol 2007. [DOI: 10.1016/s0255-0857(21)02045-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
|
|
21
|
Hassan MI, Kassim SK, Ahmad MI, Fawzy S. Antiproliferative effect of hepatitis C virus on mitogen-stimulated peripheral blood mononuclear cells: potential role in viral persistence in Egyptian patients. Clin Biochem 2007; 40:1173-9. [PMID: 17888896 DOI: 10.1016/j.clinbiochem.2007.07.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2006] [Revised: 07/15/2007] [Accepted: 07/29/2007] [Indexed: 11/23/2022]
Abstract
OBJECTIVES We aimed to study the effect of hepatitis C virus (HCV) and sera of chronic HCV patients on phytohemagglutinin (PHA)-stimulated normal donor PBMCs and to study the effect of chronic HCV infection on some cytokine profile. SUBJECTS AND METHODS (3)H-Thymidine uptake was utilized to study effect of pelleted virus and patients sera on PBMCs proliferation in vitro. The study included 337 Egyptian chronic liver patients from Ain Shams University Hospitals and 90 healthy control subjects. The patients' group included chronic hepatitis C (250 subjects), and other chronic liver diseases (87 subjects). All subjects' sera were subjected to RT-PCR for HCV RNA detection, IL-4, IL-1beta, and TNF-alpha measurement by EIA, and biochemical measurement of ALT and albumin. RESULTS Treatment of PHA-stimulated normal donor PBMCs with pelleted virus led to decrease (dose response) in their rate of proliferation. This was partially reversed after addition of HCV RNA positive patients' sera. HCV RNA positive patients were significantly higher in IL-4 and ALT, and lower in IL-1beta and albumin than HCV RNA negative patients. CONCLUSION HCV infection suppresses early immune response. This leads to increased IL-4 Th2 cytokine.
Collapse
Affiliation(s)
- Mahmoud I Hassan
- Oncology Dignostic Unit, Medical Biochemistry Department, Faculty of Medicine, Ain Shams University, Abbassia, Cairo, Egypt
| | | | | | | |
Collapse
|
|
22
|
Alatrakchi N, Graham CS, van der Vliet HJJ, Sherman KE, Exley MA, Koziel MJ. Hepatitis C virus (HCV)-specific CD8+ cells produce transforming growth factor beta that can suppress HCV-specific T-cell responses. J Virol 2007; 81:5882-92. [PMID: 17376924 PMCID: PMC1900307 DOI: 10.1128/jvi.02202-06] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Hepatitis C virus (HCV)-specific T-cell responses are rarely detected in peripheral blood, especially in the presence of human immunodeficiency virus (HIV) coinfection. Based on recent evidence that T-regulatory cells may be increased in chronic HCV, we hypothesized that functional blockade of regulatory cells could raise HCV-specific responses and might be differentially regulated in the setting of HIV coinfection. Three groups of subjects were studied: HCV monoinfected, HCV-HIV coinfected, and healthy controls. Frequencies of peripheral T cells specific for peptides derived from HCV core, HIV type 1 p24, and recall antigens were analyzed by gamma interferon (IFN-gamma) enzyme-linked immuno-spot assay. HCV-specific T-cell responses were very weak in groups with HCV and HCV-HIV infections. Addition of blocking antibodies against transforming growth factor beta1 (TGF-beta1), -2, and -3 and interleukin-10 specifically increased the HCV-specific T-cell responses in both infected groups; however, this increase was attenuated in the group with HCV-HIV coinfection compared to HCV infection alone. No increase in recall antigen- or HIV-specific responses was observed. Flow cytometric sorter analysis demonstrated that regulatory-associated cytokines were produced by HCV-specific CD3(+)CD8(+)CD25(-) cells. Enhancement of the IFN-gamma effect was observed for both CD4 and CD8 T cells and was mediated primarily by TGF-beta1, -2, and -3 neutralization. In conclusion, blockade of TGF-beta secretion could enhance peripheral HCV-specific T-cell responses even in the presence of HIV coinfection.
Collapse
Affiliation(s)
- Nadia Alatrakchi
- Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, MA 02115, USA.
| | | | | | | | | | | |
Collapse
|
|
23
|
El-Sayed HH, Amin Husse N, Yousef Gha L, Megeed Lot AA, Raouf Raaf MA. Clinical Spectrum of Hepatitis-Associated Cryoglobulinemia: Cross-Link between Hematological and Immunological Phenomena. JOURNAL OF MEDICAL SCIENCES 2006. [DOI: 10.3923/jms.2007.31.41] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
|
|
24
|
Núñez M, Soriano V, López M, Ballesteros C, Cascajero A, González-Lahoz J, Benito JM. Coinfection with hepatitis C virus increases lymphocyte apoptosis in HIV-infected patients. Clin Infect Dis 2006; 43:1209-12. [PMID: 17029144 DOI: 10.1086/508355] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2006] [Accepted: 07/13/2006] [Indexed: 12/21/2022] Open
Abstract
To test the role of hepatitis C virus (HCV) in CD4 cell depletion in human immunodeficiency virus (HIV)-coinfected patients, T cell apoptosis was measured by annexin V labeling in 31 HIV-infected and 30 HIV-HCV-coinfected patients who were not receiving antiretroviral therapy. Apoptosis in naive CD4(+) T cells and in naive and memory CD8(+) T cells was significantly higher in HIV-HCV-coinfected than in monoinfected patients.
Collapse
Affiliation(s)
- Marina Núñez
- Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain.
| | | | | | | | | | | | | |
Collapse
|
|
25
|
Chiou HL, Hsieh YS, Hsieh MR, Chen TY. HCV E2 may induce apoptosis of Huh-7 cells via a mitochondrial-related caspase pathway. Biochem Biophys Res Commun 2006; 345:453-8. [PMID: 16681997 DOI: 10.1016/j.bbrc.2006.04.118] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2006] [Accepted: 04/20/2006] [Indexed: 01/29/2023]
Abstract
INTRODUCTION One unusual characteristic of HCV is to establish chronic infection and the precise mechanisms remain unclear. MATERIALS AND METHODS Huh-7 cells were transiently transfected with E2 and subjected to MTT assay, DNA fragmentation assay, and Western blotting to see the impact of E2 protein on apoptosis. RESULTS AND DISCUSSION E2 may inhibit cell proliferation by inducing apoptosis and pro-caspases 3, 8, and 9 were cleaved and activated to result in the presence of active forms in a time-dependent fashion, which suggest that E2-induced apoptosis is caspase-dependent. Furthermore, the cytosolic level of cytochrome c was increased together with a gradually down-regulated Bcl-2 and up-regulated Bax protein expression. The continuing reduction of Bid protein and the gradual increase of tBid protein also indicated that a time-dependent increased turn-over of Bid protein into tBid. Taken together, our data suggested that HCV E2 may induce apoptosis through a mitochondrial damage-mediated caspase pathway.
Collapse
Affiliation(s)
- Hui-Ling Chiou
- School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan, ROC.
| | | | | | | |
Collapse
|
|
26
|
Iken K, Huang L, Bekele H, Schmidt EV, Koziel MJ. Apoptosis of activated CD4+ and CD8+ T cells is enhanced by co-culture with hepatocytes expressing hepatitis C virus (HCV) structural proteins through FasL induction. Virology 2006; 346:363-72. [PMID: 16336987 PMCID: PMC2865190 DOI: 10.1016/j.virol.2005.11.017] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2005] [Revised: 08/23/2005] [Accepted: 11/12/2005] [Indexed: 01/01/2023]
Abstract
A central unresolved issue in hepatitis C virus (HCV) infection is how the virus establishes chronic infection. Recent studies suggest that the liver microenvironment leads to apoptosis of activated T cells, which may be involved in the tolerance to liver allograft. Here, We report that murine hepatocytes expressing a transgene encoding the HCV structural proteins core, envelope 1 (E1) and envelope 2 (E2) enhance apoptosis of activated T cells. Unlike normal liver, which appears to selectively remove only activated CD8+ T cells, enhanced apoptosis was seen for both CD4+ and CD8+ T cells. Enhanced apoptosis of activated T lymphocytes was associated with upregulation of FasL by HCV transgenic hepatocytes and was specifically inhibited by anti-FasL blocking antibody. Increased apoptosis of activated T cells induced by HCV structural proteins could amplify the ability of the liver to down-modulate T cell responses, leading to attenuation of anti-viral responses and facilitating viral persistence.
Collapse
Affiliation(s)
- Khadija Iken
- Division of Infectious Disease, Beth Israel Deaconess Hospital, HIM 223a, 330 Brookline Ave., Boston, MA 02215, USA
- Harvard Medical School, Boston, MA 02215, USA
| | - Lin Huang
- Division of Infectious Disease, Beth Israel Deaconess Hospital, HIM 223a, 330 Brookline Ave., Boston, MA 02215, USA
- Harvard Medical School, Boston, MA 02215, USA
- Division of Gastroenterology, Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Hewan Bekele
- Division of Infectious Disease, Beth Israel Deaconess Hospital, HIM 223a, 330 Brookline Ave., Boston, MA 02215, USA
- Harvard Medical School, Boston, MA 02215, USA
| | - Emmett V. Schmidt
- Tumor Biology Program, Massachusetts General Hospital, Charlestown, MA 02129, USA
| | - Margaret James Koziel
- Division of Infectious Disease, Beth Israel Deaconess Hospital, HIM 223a, 330 Brookline Ave., Boston, MA 02215, USA
- Harvard Medical School, Boston, MA 02215, USA
| |
Collapse
|
|
27
|
Cianci R, Pinti M, Nasi M, Starnino S, Cammarota G, Miele L, De Luca A, Cauda R, Raducci F, Grieco A, Rapaccini G, Gasbarrini G, Cossarizza A, Pandolfi F. Impairment of recent thymic emigrants in HCV infection. Int J Immunopathol Pharmacol 2005; 18:723-728. [PMID: 16388721 DOI: 10.1177/039463200501800415] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Hepatitis C Virus (HCV) often has a more favorable course in younger patients. Considering the involution of the thymic function with age, we investigated the output of recent thymic emigrants (RTE) in HCV patients. To evaluate RTE, we used a competitive quantitative PCR in order to determine the percentages of cells with cj-T cell receptor excision circles (TREC). This study was performed in 14 HCV patients at diagnosis and before any anti-HCV treatment. The results obtained in this group were compared to those obtained in a group of age-matched controls. We found that in the 14 HCV patients naive for anti-HCV treatment the mean percentage of cj-TREC was 3%. We could not detect a correlation between the percentages of cj-TREC and age or patients' viremia. In contrast, in the 26 age-matched controls mean percentage of cj-TREC was 5.6% (P=0.01). Our study describes a novel immune defect in HCV patients. Additional studies are needed to get further insight in the possible role of TREC defect in the pathogenesis and prognosis of the disease.
Collapse
Affiliation(s)
- R Cianci
- Institute of Internal Medicine, Catholic University of Rome, Italy
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
28
|
Ko WS, Guo CH, Yeh MS, Lin LY, Hsu GSW, Chen PC, Luo MC, Lin CY. Blood micronutrient, oxidative stress, and viral load in patients with chronic hepatitis C. World J Gastroenterol 2005; 11:4697-702. [PMID: 16094713 PMCID: PMC4615414 DOI: 10.3748/wjg.v11.i30.4697] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the extent of micronutrient and oxidative stress in blood and to examine their linkages with viral loads in chronic hepatitis C patients.
METHODS: Hepatitis C virus (HCV)-RNA levels were quantified in the serum from 37 previously untreated patients with chronic hepatitis C. The plasma and erythrocyte micronutrients (zinc, selenium, copper, and iron) were estimated, and malondialdehyde (MDA) contents were determined as a marker to detect oxidative stress. Antioxidant enzymes, superoxide dismutase (SOD), glutathione peroxidase (GPX) and glutathione reductase (GR) activities in blood were also measured. The control group contained 31 healthy volunteers.
RESULTS: The contents of zinc (Zn), and selenium (Se) in plasma and erythrocytes were significantly lower in hepatitis C patients than in the controls. On the contrary, copper (Cu) levels were significantly higher. Furthermore, plasma and erythrocyte MDA levels, and the SOD and GR activities in erythrocytes significantly increased in hepatitis C patients compared to the controls. However, the plasma GPX activity in patients was markedly lower. Plasma Se (r = -0.730, P < 0.05), Cu (r = 0.635), and GPX (r = -0.675) demonstrated correlations with HCV-RNA loads. Significant correlation coefficients were also observed between HCV-RNA levels and erythrocyte Zn (r = -0.403), Se (r = -0.544), Cu (r = 0.701) and MDA (r = 0.629) and GR (r = 0.441).
CONCLUSION: The levels of Zn, Se, Cu, and oxidative stress (MDA), as well as related anti-oxidative enzymes (GR and GPX) in blood have important impact on the viral factors in chronic hepatitis C. The distribution of these parameters might be significant biomarkers for HCV.
Collapse
Affiliation(s)
- Wang-Sheng Ko
- Department of Food and Nutrition, Hung Kuang University, Taichung, Taiwan, China
| | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Anatol P, Danuta P, Janusz D, Bozena P. Expression of bcl-2 protein in chronic hepatitis C: Effect of interferon alpha 2b with ribavirin therapy. World J Gastroenterol 2005; 11:2949-52. [PMID: 15902734 PMCID: PMC4305665 DOI: 10.3748/wjg.v11.i19.2949] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Mechanisms responsible for persistence of HCV infection and liver damage in chronic hepatitis C are not clear. Apoptosis is an important form of host immune response against viral infections. Anti-apoptotic protein bcl-2 expression on liver tissue as well as the influence of interferon alpha 2b (IFNα2b) and ribavirin (RBV) were analyzed in patients with chronic hepatitis C.
METHODS: In 30 patients with chronic hepatitis C (responders - R and non-responders - NR) treated with IFNα2b+RBV, protein bcl-2 was determined in hepatocytes and in liver associated lymphocytes before and after the treatment.
RESULTS: The treatment diminished bcl-2 protein accumulation in liver cells in patients with hepatitis C (P<0.05). Before and after the therapy, we detected bcl-2 protein in R in 87±15% and 83±20% of hepatocytes and in 28±18% and 26±10% of liver-associated lymphocytes, respectively. In NR, the values before treatment decreased from 94±32% to 88±21% of hepatocytes and 39±29% to 28±12% of lymphocytes with bcl-2 expression. There was no statistical correlation between bcl-2 expression on liver tissue with inflammatory activity, fibrosis and biochemical parameters before and after the treatment.
CONCLUSION: IFNα2b+RBV treatment, by bcl-2 protein expression decrease, enables apoptosis of hepatocytes and associated liver lymphocytes, which in turn eliminate hepatitis C viruses.
Collapse
Affiliation(s)
- Panasiuk Anatol
- Department of Infectious Diseases, Medical University of Bialystok, Zurawia Str, 14, 15-540 Bialystok, Poland.
| | | | | | | |
Collapse
|
|
30
|
Cruise MW, Melief HM, Lukens J, Soguero C, Hahn YS. Increased Fas ligand expression of CD4+ T cells by HCV core induces T cell-dependent hepatic inflammation. J Leukoc Biol 2005; 78:412-25. [PMID: 15894587 DOI: 10.1189/jlb.0105005] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Hepatitis C virus (HCV) infection is associated with a high rate of viral persistence and the development of chronic liver disease. The expression of HCV core protein in T cells has previously been reported to alter T cell activation and has been linked to the development of liver inflammation. However, the molecular and cellular basis for the role of HCV core-expressing T cells in liver inflammation is not understood. Here, using double-transgenic mice of CD2/HCV-core transgenic mice and ovalbumin (OVA)-specific T cell receptor transgenic mice, we demonstrated that in vivo antigenic stimulation (OVA peptide administration) triggers a marked influx of core-expressing, antigen-specific, transgenic CD4+ T cells into the liver of these mice. Phenotypic analysis of the liver-infiltrating T cells revealed high expression levels of CD44 and Fas ligand (FasL). Adoptive transfer of liver-infiltrating, core-expressing CD4+ T cells into severe combined immunodeficiency mice directly demonstrated the capacity of these activated T cells to induce liver inflammation. It is important that anti-FasL antibody treatment of the mice at the time of cell transfer abrogated the liver inflammation induced by core-expressing CD4+ T cells. These findings suggest that activated T lymphocytes expressing elevated levels of FasL may be involved in the bystander killing of hepatocyte, as well as the induction of chronic liver inflammation, by promoting recruitment of proinflammatory cells to the liver.
Collapse
Affiliation(s)
- Michael W Cruise
- Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA
| | | | | | | | | |
Collapse
|
|
31
|
Kessel A, Rosner I, Rozenbaum M, Zisman D, Sagiv A, Shmuel Z, Sabo E, Toubi E. Increased CD8+ T cell apoptosis in scleroderma is associated with low levels of NF-kappa B. J Clin Immunol 2004; 24:30-6. [PMID: 14997031 DOI: 10.1023/b:joci.0000018060.36183.bb] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Our objectives were (1) to compare lymphocyte subpopulation apoptosis rates in SSc patients versus healthy controls and (2) to compare Bcl-2 and NF-kappa B expression in cultured CD8 lymphocytes of SSc patients versus controls. Peripheral blood samples were obtained from 27 SSc patients meeting the American College of Rheumatology criteria for SSc and 28 healthy individuals. Mononuclear cells were isolated by Ficoll-Hypaque density gradient separation and cultured for 48 hr. For determination of apoptosis within specific cell populations, samples were labeled with PE-conjugated monoclonal antibody to CD8, CD4, and a FITC-conjugated monoclonal antibody to Annexin V. Flow cytometry was carried out with a FACS operating with Cellquest software. CD8+ lymphocytes were positively selected with magnetic microbeads conjugated to antihuman CD8. CD8 T cells were separated, then incubated with activation for 48 hr, and NF-kappa B and Bcl-2 analysis was carried out using Western immunoblotting. The CD4:CD8 ratio was increased in SSc compared to controls (2.6 +/- 1.13 vs.1.87 +/- 0.76; P = 0.018). The spontaneous apoptosis rate of SSc CD8 lymphocytes was increased compared to that of controls of (21.9 +/- 13.7 vs. 13.3 +/- 9.9; P = 0.019). No difference was found in the rate of CD4 apoptosis of SSc patients versus controls (9.8 +/- 5.2 vs. 7.18 +/- 4.89%; P = ns). The expression of NF-kappa B in SSc CD8 lymphocytes was decreased compared with that of CD8 lymphocytes from healthy controls (144 +/- 13 vs. 188 +/- 11; P = 0.018). Whereas expression of Bcl-2 was similar in activated CD8+ T cells of SSc patients and healthy controls, CD8+ T cell apoptosis rate was found to be in reverse correlation with expression of NF-kappa B in these cells ( r = - 0.53, P = 0.029). The increased CD4:CD8 ratio in SSC may result from increased CD8+ T cell apoptosis. Increased SSc CD8 T cell apoptosis is associated with low levels of NF-kappa B.
Collapse
Affiliation(s)
- Aharon Kessel
- Division of Clinical Immunology, Bnai-Zion Medical Center, Haifa, Israel.
| | | | | | | | | | | | | | | |
Collapse
|
|
32
|
Toubi E, Kessel A, Peri R, Shmuel Z, Bamberger E, Sabo E, Zuckerman E. Enhanced apoptosis of peripheral CD5-negative B lymphocytes from chronically hepatitis C virus-infected patients: reversal after antiviral treatment. J Virol 2004; 78:11379-84. [PMID: 15452259 PMCID: PMC521799 DOI: 10.1128/jvi.78.20.11379-11384.2004] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Whereas enhanced peripheral T-cell apoptosis and its association with autoimmunity have recently been reported, the apoptotic status of peripheral B cells in chronic hepatitis C virus (HCV) infection remains ambiguous. We therefore sought to investigate the sensitivity of peripheral B cells to apoptosis and to assess the possible benefits of antiviral treatment in mitigating these effects. Spontaneous apoptosis, the extent of apoptosis rescue, and NF-kappaB expression in peripheral B cells were studied in patients with chronic HCV infections (group 1), in sustained responders after antiviral treatment (group 2), and in healthy controls (group 3). For group 1, spontaneous B-cell apoptosis was increased (26% +/- 4.6%) and apoptosis rescue was altered (39%) compared to group 3 (18% +/- 5% and 50%, respectively; P = 0.001). In contrast, apoptosis and apoptosis rescue were similar for groups 2 and 3. Enhanced B-cell apoptosis was associated with decreased NF-kappaB expression and was found only in CD5-negative (CD5(neg)) B cells, whereas CD5(pos) cells were apoptosis resistant. Chronic HCV infection is associated with enhanced peripheral B-cell apoptosis and decreased apoptosis rescue. Successful antiviral treatment reverses these abnormalities to the levels seen in healthy individuals. The relative resistance of the CD5(pos) B-cell subpopulation to apoptosis may play a role in HCV-related autoimmunity and lymphoproliferation.
Collapse
Affiliation(s)
- Elias Toubi
- Division of Clinical Immunology and Allergy, Bnai Zion Medical Center, Golomb St. 47, P.O.B. 4940, Haifa 31048, Israel.
| | | | | | | | | | | | | |
Collapse
|
|
33
|
Zhu LX, Liu J, Xie YH, Kong YY, Ye Y, Wang CL, Li GD, Wang Y. Expression of hepatitis C virus envelope protein 2 induces apoptosis in cultured mammalian cells. World J Gastroenterol 2004; 10:2972-8. [PMID: 15378776 PMCID: PMC4576255 DOI: 10.3748/wjg.v10.i20.2972] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To explore the role of hepatitis C virus (HCV) envelope protein 2 (E2) in the induction of apoptosis.
METHODS: A carboxyterminal truncated E2 (E2-661) was transiently expressed in several cultured mammalian cell lines or stably expressed in Chinese hamster ovary (CHO) cell line. Cell proliferation was assessed by 3H thymidine uptake. Apoptosis was examined by Hoechst 33258 staining, flow cytometry and DNA fragmentation analysis.
RESULTS: Reduced proliferation was readily observed in the E2-661 expressing cells. These cells manifested the typical features of apoptosis, including cell shrinkage, chromatin condensation and hypodiploid genomic DNA content. Similar apoptotic cell death was observed in an E2-661 stably expressing cell line.
CONCLUSION: HCV E2 can induce apoptosis in cultured mammalian cells.
Collapse
Affiliation(s)
- Li-Xin Zhu
- State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | | | | | | | | | | | | | | |
Collapse
|
|
34
|
Thorén F, Romero A, Lindh M, Dahlgren C, Hellstrand K. A hepatitis C virus-encoded, nonstructural protein (NS3) triggers dysfunction and apoptosis in lymphocytes: role of NADPH oxidase-derived oxygen radicals. J Leukoc Biol 2004; 76:1180-6. [PMID: 15371490 DOI: 10.1189/jlb.0704387] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The persistent infection caused by hepatitis C virus (HCV) is presumably explained by a deficient immune response to the infection, but the basis for the inefficiency of immune-mediated virus eradication is not known in detail. This study addresses mechanisms of relevance to dysfunction of cytotoxic lymphocytes in HCV infection, with a focus on the role of phagocyte-derived oxygen radicals. We show that NS3, a nonstructural, HCV-encoded protein, induces a prolonged release of oxygen radicals from mononuclear and polymorphnuclear phagocytes by activating a key enzyme in radical formation, the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The NS3-activated phagocytes, in turn, induced dysfunction and/or apoptosis in three major subsets of lymphocytes of relevance to defense against HCV infection: CD3+/56- T cells, CD3-/56+ natural killer (NK) cells, and CD3+/56+ NKT cells. Two inhibitors of the NADPH oxidase, histamine and diphenylene iodonium, suppressed the NS3-induced oxygen radical production and efficiently protected lymphocytes against NS3-induced apoptosis and dysfunction. In conclusion, we propose that NS3, by triggering oxygen radical formation in phagocytes, may contribute to the dysfunction of antiviral lymphocytes in HCV-infected liver tissue and that strategies to circumvent oxidative stress may be useful in preventing HCV-associated carcinogenesis and facilitating lymphocyte-mediated clearance of infected cells.
Collapse
Affiliation(s)
- Fredrik Thorén
- Department of Clinical Virology, Göteborg University, Guldhedsgatan 10b, S-413 46 Göteborg, Sweden.
| | | | | | | | | |
Collapse
|
|
35
|
Abstract
The apoptotic process appears to be a host defence mechanism against viral infections and tumourigenesis. However, many viral genomes encode proteins, which repress apoptosis so as to escape from immune attack by the host. Therefore, virus-host interactions may determine viral persistence, extent and severity of liver inflammation and possibly viral hepatocarcinogenesis. Apoptosis of liver cells may play a significant role in the pathogenesis of hepatitis C. Pathomorphologic features of increased apoptosis include shrinkage and fragmentation of nuclei/cytoplasm in piecemeal necrosis areas, acidophilic bodies, and focal cell dropout in the liver lobule. The hepatitis C virus (HCV) core protein exhibits both proapoptotic or antiapoptotic actions. Modulation of apoptosis may involve binding of HCV core protein to the intracellular signal transducing portion of death receptors and displacement of signalling molecules. Apoptosis may occur in the absence of significant transaminase elevation, thereby explaining the lack of correlation between biochemical activity and liver cell histological injury. Monitoring caspase activation might provide a reliable tool to estimate the efficacy of HCV therapy, and might open challenging therapeutic strategies in HCV infection. The antiviral effect of interferon may be mediated through induction of apoptosis. Lastly, administration of the antiapoptotic ursodeoxycholic acid in HCV infection is compatible with the notion that apoptosis may represent a mechanism for viral shedding rather than for viral elimination, thereby raising the concept that inhibition of apoptosis could ameliorate hepatitis C.
Collapse
Affiliation(s)
- J Kountouras
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Greece.
| | | | | |
Collapse
|
|
36
|
Moorman JP, Prayther D, McVay D, Hahn YS, Hahn CS. The C-terminal region of hepatitis C core protein is required for Fas-ligand independent apoptosis in Jurkat cells by facilitating Fas oligomerization. Virology 2003; 312:320-9. [PMID: 12919737 DOI: 10.1016/s0042-6822(03)00208-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Hepatitis C virus (HCV) is remarkable for its ability to establish persistent infection. Studies suggest that HCV core protein modulates immune responses to viral infection and can bind Fas receptor in vitro. To further examine the role of HCV core protein in Fas signaling, full-length (aa 1-192) and truncated (aa 1-152) HCV core proteins were expressed in Jurkat lymphocytes and cells were assayed for apoptotic response, caspase activation, and Fas activation. Jurkat expressing full-length but not truncated core protein exhibited ligand-independent apoptosis. Cytoplasmic targeting of truncated core protein recapitulated its ability to induce apoptosis. Activation of caspases 8 and 3 was necessary and sufficient for full-length core to induce apoptosis. Jurkat cells expressing full-length but not truncated core protein induced Fas receptor aggregation. HCV core activates apoptotic pathways in Jurkat via Fas and requires cytoplasmic localization of core. Infection of host lymphocytes by HCV may alter apoptotic signaling and skew host responses to acute infection.
Collapse
Affiliation(s)
- Jonathan P Moorman
- Department of Internal Medicine, East Tennessee State University, James H. Quillen College of Medicine, Johnson City, TN 37614, USA.
| | | | | | | | | |
Collapse
|
|
37
|
Ben-Ari Z, Schmilovotz-Weiss H, Belinki A, Pappo O, Sulkes J, Neuman MG, Kaganovsky E, Kfir B, Tur-Kaspa R, Klein T. Circulating soluble cytochrome c in liver disease as a marker of apoptosis. J Intern Med 2003; 254:168-75. [PMID: 12859698 DOI: 10.1046/j.1365-2796.2003.01171.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVES To measure levels of soluble cytochrome c, a clinical marker of apoptosis in patients with liver disease; determine whether soluble cytochrome c is derived from the liver; and correlate soluble cytochrome c level with histology and disease activity. DESIGN Laboratory research study with comparison group. SETTING Liver Institute, at the Rabin Medical Center, Israel, and In Vitro Toxicology Laboratory, Canada. SUBJECTS A total of 108 patients with liver disease and 30 healthy controls. INTERVENTIONS Paired hepatic and portal vein samples were taken via the transjugular vein in patients after liver biopsy and transjugular intrahepatic portacaval shunt, and bile from patients with external biliary drainage. Soluble cytochrome c was measured with an enzyme-linked immunosorbent assay in peripheral blood. Apoptotic cells in liver tissue were identified by morphological criteria and quantitated with the dUTP nick-end-labelling (TUNEL) assay. MAIN OUTCOME MEASURES Soluble cytochrome c level by type of liver disease by clinical and histological findings. RESULTS Soluble cytochrome c concentration (mean 187.1 +/- 219.5 ng x mL(-1)) was significantly higher in patients with liver disease than in controls (39.8 +/- 35.1 ng x mL(-1); P = 0.0001), with highest levels in the primary sclerosing cholangitis group (mean 1041.0 +/- 2844.8 ng x mL(-1); P = 0.001). Cytochrome c levels were correlated with serum bilirubin, alkaline phosphatase, creatinine levels, necroinflammatory score and apoptotic index, but not with serum alanine aminotransferase and synthetic liver function tests. In the 16 paired samples, soluble cytochrome c level was higher in the hepatic (mean 267.9 +/- 297.0 ng x mL(-1)) than the portal vein (mean 169.2 +/- 143.3 ng x mL(-1)), and it was highly detectable in bile (mean 2288.0 +/-4596.0 ng x mL(-1)) (P = 0.001). Untreated patients with chronic viral hepatitis (B and C) had significantly higher levels (mean 282.8 +/-304.3 ng x mL(-1)) than treated patients (77.9 +/- 35.8 ng x mL(-1); P = 0.001). CONCLUSIONS Soluble cytochrome c levels are increased in different types of liver disease. Soluble cytochrome c is probably derived from the liver and secreted into the bile. Levels correlate with the apoptotic index and are affected by antiviral treatment. Soluble cytochrome c may serve as a serum marker of apoptosis.
Collapse
Affiliation(s)
- Z Ben-Ari
- Liver Institute and Department of Medicine D, Beilinson Campus, Rabin Medical Center, Petah Tiqva, Israel.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
38
|
Tempestini A, Schiavone N, Papucci L, Witort E, Lapucci A, Cutrì M, Donnini M, Capaccioli S. The mechanisms of apoptosis in biology and medicine: a new focus for ophthalmology. Eur J Ophthalmol 2003; 13 Suppl 3:S11-8. [PMID: 12749672 DOI: 10.1177/112067210301303s03] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Defects in apoptosis (programmed cell death) have recently emerged as being closely involved in the pathogenesis of most ocular diseases and, therefore, apoptosis is now a topic of exponential interest in ophthalmology. This review summarizes recent works on mechanisms of apoptosis, from its initiation and modulation to the switching-on of its execution machinery. Interactions of cell death with cell division programs to orchestrate ontogenesis, aging, and adult life and their alterations in human diseases are pointed out. Two main apoptotic signaling pathways are identified: a death receptor-dependent (extrinsic) pathway and a mitochondrion-dependent (intrinsic) pathway. Mitochondrion harbors both antiapoptotic (Bcl-2, Bcl-XL) and apoptotic factors (Smac/Diablo, Apaf-1, cytochrome c). Its permeability transition pore (mPTP) is the main trigger of cell suicide. The process of mPTP opening, in association with extrusion to cytoplasm of a variety of apoptotic factors, is shown. Cytochrome c is one of these apoptotic factors. When expelled to cytoplasm, this double-faced respiratory chain component assembles with two other modules, Apaf-1 and procaspase 9, to form a protein complex--the apoptosome--that starts apoptosis execution. Another respiratory chain component, the CoQ10, is believed to counteract mPTP opening. What makes apoptosis particularly exciting for medicine is that its dysfunctions play a central role in the pathogenesis of several human diseases. For instance, excesses of apoptosis lead to cell loss that accompanies neurodegenerative diseases, whereas genetically determined defects of apoptosis lead to the deregulated cell proliferation typical of cancer. A variety of ophthalmologic diseases, such as post-keratectomy haze, corneal lesions, cataract, glaucoma, senile maculopathies, and genetic ocular pathologies, that underlie apoptosis dysfunctions are treated in detail in the other reviews of this issue.
Collapse
Affiliation(s)
- A Tempestini
- Research Group on Apoptosis applied to Ophthalmology (Firenze Division), Department of Experimental Pathology and Oncology, University of Firenze, Italy
| | | | | | | | | | | | | | | |
Collapse
|
|
39
|
Abstract
Alcohol is the most commonly abused substance in the United States, and alcohol abuse leads to alcoholic liver disease, a long recognized major public health concern. The high prevalence of chronic hepatitis C virus (HCV) infection, along with the clinical observation that HCV infection is common in alcoholic patients presenting with liver disease, has directed attention to the interaction between alcohol and HCV infection. Clinical studies have identified alcohol use as an independent risk factor for progression of fibrosis in chronic HCV infection. Experimental evidence suggests additive inhibitory effects between HCV and alcohol on antiviral immune responses. In addition, specific pathways have been identified by which HCV core protein and alcohol interact to activate hepatocytes. Nonspecific inflammatory cell recruitment and proinflammatory cytokine activation have also been implicated in both alcohol- and HCV-induced liver diseases. Further investigation of these and other pathways by which alcohol and HCV interact should unravel the mechanisms that accelerate the progression of liver disease.
Collapse
Affiliation(s)
- Gyongyi Szabo
- Hepatology and Liver Center, Division of Gastroenterology, Department of Medicine, University of Massachusetts Medical School, 365 Plantation Street, Worcester, MA 01605, USA.
| |
Collapse
|
|
40
|
Bantel H, Schulze-Osthoff K. Apoptosis in hepatitis C virus infection. Cell Death Differ 2003; 10 Suppl 1:S48-58. [PMID: 12655346 DOI: 10.1038/sj.cdd.4401119] [Citation(s) in RCA: 121] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2002] [Revised: 06/03/2002] [Accepted: 06/11/2002] [Indexed: 12/11/2022] Open
Abstract
Infection with hepatitis C virus (HCV) is characterized by inflammatory liver damage and a long viral persistence associated with an increased risk of developing hepatocellular carcinoma. Both in liver damage and in oncogenesis a disturbance of apoptosis has been implicated, although the underlying mechanisms in these apparently opposite processes are incompletely understood. HCV-triggered liver injury is mediated mainly by host immune mechanisms and eventually by direct cytopathic effects of HCV. Recent data shows that caspase activation, either triggered by death ligands, other cytokines, granzyme B or HCV proteins, is considerably upregulated in HCV-infected liver. Interestingly, caspase activation appears to correlate closely with the inflammatory response. Data about the role of single HCV proteins, either in cultured cells or transgenic animals models, however, are contradictory, as both pro- and anti-apoptotic effects have been observed. Nevertheless, apoptosis induction upon HCV infection may critically contribute to liver damage, while inhibition of apoptosis may result in HCV persistence and development of hepatocellular carcinoma.
Collapse
Affiliation(s)
- H Bantel
- Institute of Molecular Medicine, University of Düsseldorf, Germany
| | | |
Collapse
|
|
41
|
Soguero C, Joo M, Chianese-Bullock KA, Nguyen DT, Tung K, Hahn YS. Hepatitis C virus core protein leads to immune suppression and liver damage in a transgenic murine model. J Virol 2002; 76:9345-54. [PMID: 12186917 PMCID: PMC136450 DOI: 10.1128/jvi.76.18.9345-9354.2002] [Citation(s) in RCA: 66] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Hepatitis C virus (HCV) is remarkably efficient in establishing persistent infection, possibly mediated by an impaired immune response to HCV infection. There is compelling evidence that HCV can infect immune cells, such as macrophages, B cells, and T cells. It has been previously reported that HCV core, the first protein expressed during the early phase of viral infection, contains the immunomodulatory function of suppressing host immune responses. This altered function of immune cells caused by HCV infection may explain the ineffective immune response to HCV. To further characterize the immunomodulatory role of HCV core in vivo, we generated transgenic (TG) mice by directing the expression of core protein to T lymphocytes by using the CD2 promoter. T-lymphocyte responses, including the production of gamma interferon and interleukin-2, were significantly diminished in these mice compared to their non-TG littermates. The inhibition of T-lymphocyte responsiveness may be due to the increased susceptibility of peripheral T lymphocytes to Fas-mediated apoptosis. Surprisingly, significant lymphocyte infiltration was observed in the portal tracts of livers isolated from core TG mice, associated with increasing serum alanine aminotransferase levels. Moreover, no intrahepatic lymphocytes or liver damage was found in non-TG littermates and core TG mice bred to Fas-deficient lpr mice. These results suggest that HCV core drives liver injury by increasing Fas-mediated apoptosis and liver infiltration of peripheral T cells.
Collapse
Affiliation(s)
- Carolina Soguero
- Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22908, USA
| | | | | | | | | | | |
Collapse
|
|
42
|
|