High levels of soluble tumor necrosis factor superfamily receptors in patients with hepatitis C virus infection and lymphoproliferative 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.
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2007, Autoimmunity ReviewsCitation Excerpt :This may provide B-cells with a pro-inflammatory environment and a myriad of co-stimulatory signals promoting clonal expansion. Fas, an important regulatory B-cell receptor, and soluble TNF receptors I and II, have been shown to be elevated in patients infected with HCV and more so in HCV infected patient with MC type II and NHL [36]. Another regulatory element implicated is the B-lymphocyte stimulator (BLyS), an important survival signal that may also serve as a co-stimulatory proliferation signal.
Chapter 12 Renal Disease in Cryoglobulinemic Vasculitis
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2003, Journal of HepatologyCitation Excerpt :Interestingly, it was recently reported that serum levels of soluble tumor necrosis factor receptor (sTNFR) type I and II were similar in patients with lymphoplasmacytoid lymphoma, cryoglobulinemia and HCV infection when compared to those with cryoglobulinemia and HCV. The authors also state that other HCV-positive low-grade B-cell NHL showed lower sTNFR concentrations, thus rendering unlikely the possibility that the significantly higher levels detected in type II cryoglobulinemia or lymphoplasmacytoid lymphoma could merely reflect a cumulative effect due to viral infection and a lymphoproliferative disorder [49]. The high levels of soluble TNF-α receptors found in HCV-infected individuals with type II cryoglobulinemia, in the study mentioned above, may reflect an activation of the TNF system [50].