Fas‐mediated apoptosis of peripheral blood mononuclear cells in patients with hepatitis C

Taya, Noriyasu; Torimoto, Yoshihiro; Shindo, Motohiro; Hirai, Katsuyuki; Hasebe, Chitomi; Kohgo, Yutaka

doi:10.1046/j.1365-2141.2000.01945.x

Cited by 61 publications

(40 citation statements)

References 35 publications

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“…These observations were consistent with other studies (1,16,24). Upon starvation, monocytes and T lymphocytes from chronic HCV + patients and HCV + patients with liver cirrhosis or hepatocellular carcinoma have been reported to display higher death rates than controls (16).…”

Section: Discussionsupporting

confidence: 82%

Increased Spontaneous Programmed Cell Death Is Associated with Impaired Cytokine Secretion in Peripheral Blood Mononuclear Cells from Hepatitis C Virus-Positive Patients

et al. 2017

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Peripheral blood mononuclear cells (PBMCs) play a critical role in clearing hepatitis C virus (HCV). PBMC defects have been linked with HCV infection; however, the underlying mechanisms remain obscure. We hypothesized that PBMCs of HCV-infected patients are more susceptible to programmed cell death (PCD), and are therefore unable to clear HCV. We compared spontaneous PBMC PCD and cytokine [interleukin (IL)-1, -6, -8, -10, and -12] secretion between untreated (naive) HCV + and treated [sustained responder (SR)] patients with HCV, and HCV -healthy controls. Spontaneous PBMC PCD was assessed by annexin-V fluorescein isothiocyanate/propidium iodide staining, and cytokine levels were measured by cytometric bead array. Differences between groups were analyzed through paired and nonpaired t tests and Mann-Whitney U test. The rate of spontaneous PCD was higher in PBMCs of naive HCV + patients ( p < 0.0001) and SR-HCV patients ( p < 0.002) than in HCV -controls. Significantly low levels of IL-8, -6, and -10 were detected in the supernatant of cell cultures of PBMCs from naive HCV + ( p < 0.05) and SR-HCV ( p < 0.05) patients relative to HCV -controls. There was no difference between the naive HCV + and SR-HCV groups in terms of PBMC PCD rate or cytokine levels. The present findings indicate that HCV infection is associated with increased PBMC susceptibility to PCD and decreased production of IL-8, -6, and -10.

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Section: Discussionsupporting

confidence: 82%

Increased Spontaneous Programmed Cell Death Is Associated with Impaired Cytokine Secretion in Peripheral Blood Mononuclear Cells from Hepatitis C Virus-Positive Patients

et al. 2017

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“…First, Meyer-Olson et al have shown a limitation of the T-cell receptor repertoire that is unable to provide sufficient variability to control the rapidly evolving viral immune evasion (16). In addition, different groups have shown that apoptosis is increased in HCV patients by both activation of apoptotic caspases (17) decreased expression ofNFkappa-B (18) and activation of the Fas-FasL mechanism (19), resulting in a depletion of peripheral lymphocytes. This depletion may be further increased in the lack of an efficient thymic output.…”

Section: Discussionmentioning

confidence: 99%

Impairment of Recent Thymic Emigrants in HCV Infection

Cianci

Pinti

Nasi

et al. 2005

Int J Immunopathol Pharmacol

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Hepatitis C VIrUS (HCV) often has a more favorable course in younger patients. Considering the involution ofthe 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=O.OI). Our study describes a novel immune defect in HCV patients. Additional studies are needed to get further insight in the possible role ofTREC defect in the pathogenesis and prognosis ofthe disease.Hepatitis C virus infection (HCV) is a major issue in world public health, affecting approximately 2% of the world's population (1). The infection has a variable clinical course. The outcome has been related to the evolution of the viral quasispecies (2). Since HCV replicates in lymphatic tissue, several immunological disorders, linked to persistent antigenic stimulation, are associated to patients with chronic active hepatitis. Apart from the viral factors, the immune mechanisms responsible for the highly variable natural history in a given patient are only partially known. Some reports have pointed out a more favorable prognosis in younger patients (3-4). T-lymphocytes are of pivotal importance in host defense against viruses. T-cells are produced in the thymus and this organ undergoes a physiological involution with age.In the last decades, it became possible to evaluate the thymic output, measuring the T-cell receptor excision circles (TREC) present in the so called "recent thymic emigrants" (RTE) (5-6). TREC are DNA fragments representing a byproduct of T-cell receptor rearrangement; there are at least two possible molecules, named coding-joint (cj) and signal-joint (sj) TREC, each of which is produced in a defined moments of the intrathymic maturation of T cells. Since their DNA exists in a circular form, they are not duplicate during mitosis, but progressively diluted in peripheral blood T-cells. TREC are present only in virgin cells, i.e. those newly produced in the thymus, and thus their measurement allows the determination ofRTE. These cells have been proved to be altered in several clinical conditions, with clinical and prognostic implications (7-9).For these reasons, we aimed to verify the hypothesis of thymic impairment in patients with HCV infection by analysis of means of RTE in a prospective case-control study. 0394-6320 (2005) Copyright© by BIOLIFE,s.a.s. This publicationand/orarticleis for individualuse only and may not be further reproducedwithoutwrittenpermi...

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“…Compelling evidence indicates that in chronically HCVinfected patients, liver disease severity is related to peripheral-T-cell Fas-mediated apoptosis (19,60,62) but not to serum ALT levels or virus load (11,19,46). These patients showed a clear association between the increased sensitivity of PBMC to apoptosis, a decrease in their number, and persistence of HCV infection (42,60). Morever, no genotype difference among genotypes 1, 2, and 3 was detected in the increased sensitivity of PBMC to apoptosis, suggesting an intrinsic characteristic of HCV infection.…”

Section: Discussionmentioning

confidence: 99%

“…The interaction between HCV core and TNFR family members has been reported to modulate the apoptosis of core-expressing cells in response to ligands of TNFR family members, depending on the specific cell type. In the case of T cells, the core protein increased the sensitivity of the cells to Fas-mediated apoptosis (22,66), which may explain the increased Fas-mediated apoptosis observed in peripheral blood mononuclear cells (PBMC) from patients chronically infected with HCV (19,60,62). Interestingly, other lymphotropic viruses, such as human immunodeficiency virus, human T-cell leukemia virus, and cytomegalovirus, have been shown to elicit similar effects (28,38,59).…”

mentioning

confidence: 99%

Hepatitis C Virus Core Protein Leads to Immune Suppression and Liver Damage in a Transgenic Murine Model

Soguero

Joo

Chianese‐Bullock

et al. 2002

J Virol

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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.Hepatitis C virus (HCV) is a serious and growing worldwide threat to human health. It is the major etiologic agent of non-A, non-B hepatitis and infects an estimated 400 million people, more than 3% of the world population. One of the remarkable features of HCV infection is the high rate of viral persistence. More than 80% of HCV-infected individuals develop chronic disease, which can progress to liver cirrhosis and hepatocellular carcinoma. In addition to HCV replication in hepatocytes, immune cells, such as monocytes, B cells, and T cells, can also support viral replication (13,33,41), although studies of viral replication in the peripheral lymphocytes of HCV-infected patients have had conflicting results (8). The widespread cellular distribution of CD81 and low-density lipoprotein receptor, putative HCV receptors, is consistent with HCV binding to cells other than hepatocytes (2, 47). However, studies of HCV pathogenesis have been hampered by the lack of a small-animal model.

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Fas‐mediated apoptosis of peripheral blood mononuclear cells in patients with hepatitis C

Cited by 61 publications

References 35 publications

Increased Spontaneous Programmed Cell Death Is Associated with Impaired Cytokine Secretion in Peripheral Blood Mononuclear Cells from Hepatitis C Virus-Positive Patients

Increased Spontaneous Programmed Cell Death Is Associated with Impaired Cytokine Secretion in Peripheral Blood Mononuclear Cells from Hepatitis C Virus-Positive Patients

Impairment of Recent Thymic Emigrants in HCV Infection

Hepatitis C Virus Core Protein Leads to Immune Suppression and Liver Damage in a Transgenic Murine Model

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