Journal of Hepatology
Volume 35, Issue 6 , Pages 814-815, December 2001

A new route to apoptosis in hepatitis C virus infection

  • Luigi Muratori

      Affiliations

    • Department of Internal Medicine, Cardioangiology and Hepatology, Alma Mater Studiorum, University of Bologna, Policlinico Sant'Orsola-Malpighi, via Massarenti, 9, 40138 Bologna, Italy
    • Corresponding Author InformationCorresponding author. Tel.: +39-51-6363868; fax: +39-51-340877
    • ,
  • Davide Gibellini

      Affiliations

    • Department of Clinical and Experimental Medicine, Microbiology Section, Alma Mater Studiorum, University of Bologna, Policlinico Sant'Orsola-Malpighi, via Massarenti, 9, 40138 Bologna, Italy

Accepted 12 October 2001.

See Article, pages 774–780

Article Outline

 

The interaction between hepatitis C virus (HCV) and the host immune system is the focus of active research. HCV is a quasispecies RNA virus with a high rate of genetic variation, thus the virus may escape the host immune response through the continuous mutation of its relevant epitopes [1], [2]. Another feature associated to HCV infection is a defective humoral and cell-mediated immune response, which not only is inadequate to tackle the virus efficiently, but quite often promotes the development of autoimmune phenomena. Hence, indefinite viral persistence [3] on the one side is accompanied by the development of a spectrum of immunopathological reactions on the other, ranging from the apparently harmless production of non-organ-specific autoantibodies [4], [5] to the association with lymphoproliferative disorders such as type II mixed cryoglobulinaemia and non-Hodgkin's lymphomas [6], [7]. HCV infects and replicates not only in hepatocytes, but also in a significant proportion of peripheral blood mononuclear cells (PBMC) [8], [9], [10] and in bone marrow cells [11], [12]. The lymphotropism of HCV points to a direct interference of the virus or, strictly speaking, of specific viral proteins such as HCV core protein [13], with the regulatory mechanisms and functions of lymphoid cells. The impairment of the fine-tuning of the immune response against HCV antigens and the occurrence of abnormal reactions against ‘self’ proteins could be among the consequences of such interactions. However, the fine molecular mechanisms regulating the interplay between HCV and lymphoid cells are still rather obscure. An initial insight in such a direction comes from the recent paper by Taya and collaborators, suggesting that HCV infection of PBMC induce Fas expression on the cell surface, and that soluble FasL induce accelerated apoptosis of these Fas-expressing cells [14].

In this issue of the Journal, Toubi and collaborators [15] contribute further to the understanding of the possible interactions between HCV and the lymphoid population. They observe that apoptosis of activated peripheral T-cell is enhanced both spontaneously and after dexamethasone treatment in patients with HCV-related chronic liver disease. Nuclear factor-κB (NF-κB), but not bcl-2 expression, is significantly decreased within the nucleus of activated T cells of HCV-infected patients. Interestingly, among patients with HCV-related liver disease, the levels of nuclear NF-κB are significantly lower in those with autoimmune markers such as circulating cryoglobulins and rheumatoid factor.

NF-κB is a transcription factor that plays important roles in cell proliferation and in the government of the immune response, especially in the regulation of T and B lymphocyte activation [16]. NF-κB is mainly a heterodimer consisting of a p65 and a p50 subunits. In unstimulated cells NF-κB is detected in cytoplasm bound to IκB inhibitory proteins, and is inactive. Following a number of different stimuli, specific kinases phosphorylate IκB and cause its rapid degradation. The free NF-κB heterodimer then passes into the nucleus where it binds to κB sites in the promoter regions of genes encoding proinflammatory cytokines, chemokines, inflammatory enzymes, adhesion molecules [17]. The activation of NF-κB leads to a well-coordinated increase in the expression of many genes whose products mediate inflammatory and immune response. Some of the products of the genes regulated by NF-κB also cause the activation of NF-κB, inducing a positive regulatory loop which is capable of amplifying and perpetuating local inflammatory response.

Among the numerous stimuli which activate NF-κB there are also viral trans-activating proteins, and HCV core, a structural protein with regulatory properties, is no exception [18], [19], [20], [21], [22]. However, the effects of HCV core protein on signal transduction cascades may vary significantly depending on the different experimental conditions used in each study [23]. NF-κB expression is enhanced in cell lines transfected with HCV core protein, whereas this is not the case in T-activated lymphocytes separated from PBMC, as reported by Toubi and collaborators [15]. This is not completely surprising given the distinct experimental settings and the diverse cellular ‘milieu’, which probably accounts for the observed opposite results [24].

The logical extension of Toubi's ex vivo findings will be the analysis of the signalling pathway upstream and downstream NF-κB, and the promoter analysis of relevant genes regulated by NF-κB, to better understand the fine details of the molecular mechanisms involved. In addition, it will be attractive to expand these studies to selected lymphoid cell populations, including bone marrow and circulating pluripotent haematopoietic CD34+ stem cells, which appear to sustain productive HCV replication [25]. The paper by Toubi and collaborators represents a preliminary step to understand the complex molecular pathways leading to T-cell apoptosis and a dysregulated immune response in patients with chronic HCV-related liver disease.

Back to Article Outline

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PII: S0168-8278(01)00244-6

Journal of Hepatology
Volume 35, Issue 6 , Pages 814-815, December 2001

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