High levels of soluble tumor necrosis factor superfamily receptors in patients with hepatitis C virus infection and lymphoproliferative disorders

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Abstract

Background: Chronic hepatitis C virus (HCV) infection is associated with a variety of extrahepatic disorders that may relate to direct or indirect effects of virus infection. Increased levels of soluble forms of tumor necrosis factor (TNF) receptors I and II, found in lymphoproliferative and infectious diseases, can interfere with TNF induced apoptotic cell death. The aim of the present study was to evaluate soluble TNF family receptors levels in lymphoproliferative disorders associated with HCV infection.

Methods: One hundred and forty-nine subjects were studied, including 120 anti-HCV positive patients (60 without lymphoproliferative manifestations, 47 with type II cryoglobulinemia and 13 with low-grade B-cell non-Hodgkin's lymphoma (B-NHL)) and 29 anti-HCV negative subjects (19 with low-grade B-NHLs and ten normal controls).

Results: Soluble forms of TNF receptor I, TNF receptor II and Fas were significantly higher in HCV positive patients compared with normal controls. The highest levels were found in patients affected by type II cryoglobulinemia or HCV positive lymphoplasmacytoid lymphomas (LP-NHLs), while HCV positive patients without type II cryoglobulinemia or with other B-NHLs had lower values (P<0.01).

Conclusions: Among HCV infected individuals, very high levels of soluble TNF receptors are significantly associated with type II cryoglobulinemia and LP-NHLs, suggesting that they may be involved in these proliferative disorders.

Introduction

In chronic hepatitis C virus (HCV) infection, a wide spectrum of hepatic and extrahepatic manifestations is observed. Liver involvement is very heterogeneous, and ranges from minimal necroinflammatory activity to chronic hepatitis of variable severity, cirrhosis and hepatocellular carcinoma [1]. Apart from these hepatic manifestations, chronic HCV infection has also been associated with a variety of extrahepatic disorders, including type II mixed cryoglobulinemia, autoimmune disorders and low-grade B-cell non-Hodgkin's lymphomas (B-NHLs), mainly the lymphoplasmacytoid lymphoma (LP-NHL), characterized by clonal expansion of IgM secreting lymphoplasmacytoid lymphocytes [2], [3], [4], [5], [6].

The mechanisms triggering these extrahepatic manifestations are not yet fully understood. A common link between the development of mixed cryoglobulinemia and lymphoproliferative disorders to chronic HCV infection may either relate to direct infection of B lymphocytes or to chronic stimulation of B-cells, leading to their proliferation and clonal expansion [7], [8], [9], [10]. It has recently been reported that the envelope protein, E2, of HCV binds to CD81 on B-cells, forming a complex in association with CD21 and CD19, which may lower the B-cell activation and proliferation threshold [11]. Other HCV components, namely the core NS3 and NS5 proteins, have been shown to interfere with apoptotic cell death, and this effect may have a role in the expansion of the proliferating B-cell clones [12], [13], [14], [15], [16].

Fas is the most important member of a family of receptors that transduce the apoptotic signal leading to programmed cell death. It belongs to the tumor necrosis factor (TNF) receptor superfamily where TNF receptor I and TNF receptor II were first discovered and characterized [17], [18]. These receptors are expressed on the surface of different cell types, and their soluble forms can be released and detected in serum due to the cleavage of extra-cytoplasmic domains or alternative splicing [19]. Increased circulating levels of these soluble forms have been reported in both lymphoproliferative and infectious diseases, including lymphomas [20], leukemias [21], autoimmune disorders [22], [23], sepsis [24], HIV [25], [26] and HCV [27], [28] infection. While it has been proposed that the presence of sTNF receptors may reflect activation of the TNF system [29], a direct involvement in clinical manifestations can occur, interfering with apoptotic cell death by competitive interaction with the corresponding ligand [30]. A similar inhibitory effect has been described for soluble forms of Fas [19], [22].

In the present study, the serum levels of soluble TNF receptors were measured in a large series of HCV chronic carriers with and without lymphoproliferative disease, where type II cryoglobulinemia and HCV positive and negative B-NHLs were included.

Section snippets

Patients with HCV infection

One hundred and twenty patients with chronic HCV infection were studied. The following different subgroups have been included: (A), 12 untreated asymptomatic HCV carriers with persistently normal transaminases (testing every 3–6 months for more than 3 years) and liver biopsy (available in seven of them) with features of minimal inflammation and no fibrosis (HAI<3); (B), 40 untreated patients with persistently elevated transaminases and liver histological findings consistent with the diagnosis

Serum levels of soluble TNF receptors

As shown in Fig. 1, the mean serum levels of sTNF-R I and sTNF-R II were significantly higher in patients with chronic hepatitis C compared with healthy HCV negative controls (means±SD: sTNF-RI, 1274±315 vs. 903±353 pg/ml, P<0.05; sTNF-RII, 3583±745 vs. 2176±340 pg/ml, P<0.005). In asymptomatic HCV carriers, the levels of sTNF-RI were elevated as in chronic hepatitis C (mean±SD, 1436±548 pg/ml), while those of sTNF-RII were higher than those of healthy controls (mean±SD, 2692±411; P<0.05), but

Discussion

The association of HCV infection with lymphoproliferative disorders, in particular with type II cryoglobulinemia and LP-NHLs, has been repeatedly described in the literature [2], [3], [4], [5], [6]. A possible causative role of the virus has been speculated, although no definitive mechanisms have been yet identified [35], [36]. In this study, a large group of HCV positive patients with and without lymphoproliferative disorders has been evaluated. Consistent data have been provided indicating

Acknowledgements

This work was supported in part by grant number 775/01/97 from Regione Veneto, Italy.

References (47)

  • P Pontisso et al.

    Clinical and virological profiles in patients with multiple hepatitis virus infection

    Gastroenterology

    (1993)
  • G Pozzato et al.

    Low-grade malignant lymphoma, hepatitis C virus infection, and mixed cryoglobulinemia

    Blood

    (1994)
  • L Muratori et al.

    Quantification of hepatitis C virus-infected peripheral blood mononuclear cells by in situ reverse transcriptase–polymerase chain reaction

    Blood

    (1996)
  • C.A Smith et al.

    T2 open reading frame from the shope fibroma virus encodes a soluble form of the TNF receptor

    Biochem Biophys Res Commun

    (1991)
  • C Upton et al.

    Myxoma virus expresses a secreted protein with homology to the tumor necrosis factor receptor gene family that contributes to viral virulence

    Virology

    (1991)
  • F-Q Hu et al.

    Cowpox virus contains two copies of an early gene encoding a soluble secreted form of the type II TNF receptor

    Virology

    (1994)
  • H Tilg et al.

    Serum levels of cytokines in chronic liver diseases

    Gastroenterology

    (1992)
  • E Larrea et al.

    Tumor necrosis factor α gene expression and the response to interferon in chronic hepatitis C

    Hepatology

    (1996)
  • M.J Alter et al.

    The natural history of community-acquired hepatitis C in the United States

    N Engl J Med

    (1992)
  • V Agnello et al.

    A role for hepatitis C virus infection in type II cryoglobulinemia

    N Engl J Med

    (1992)
  • I Rasul et al.

    Detection of occult low-grade B-cell non-Hodgkin's lymphoma in patients with chronic hepatitis C infection and mixed cryoglobulinemia

    Hepatology

    (1999)
  • A Gabrielli et al.

    Active hepatitis C virus infection in bone marrow and peripheral blood mononuclear cells from patients with mixed cryoglobulinemia

    Clin Exp Immunol

    (1994)
  • A.L Zignego et al.

    Hepatitis C virus infection in mixed cryoglobulinemia and B-cell non-Hodgkin's lymphoma: evidence for a pathogenetic role

    Arch Virol

    (1997)
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