Hepatitis C Virus and Mixed Cryoglobulinaemia

Ferri, Clodoveo; Civita, L. La; Longombardo, G.; Zignego, Anna Linda

doi:10.1093/rheumatology/33.3.301

Cited by 35 publications

(62 citation statements)

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“…E pidemiological, clinical, and experimental data strongly support the idea of a causative role of hepatitis C virus (HCV) in the development of B-cell lymphoproliferative diseases in chronic virus carriers. These diseases include type II mixed cryoglobulinemia (MC), a benign B-cell proliferative disorder with monoclonal B-cell expansions, and a subgroup of B-cell non-Hodgkin lymphomas (B-NHL) (1)(2)(3)(4)(5)(6). The mechanisms by which chronic HCV infection affects B-cell differentiation and predisposes patients to the occurrence of premalignant and malignant B-cell lymphoproliferations are still poorly understood.…”

Section: Hepatitis C Virus (Hcv) Is Considered To Have a Causative Romentioning

confidence: 99%

B Cells in Chronically Hepatitis C Virus-Infected Individuals Lack a Virus-Induced Mutation Signature in theTP53,CTNNB1, andBCL6Genes

Tucci

Broering

Johansson

et al. 2013

J Virol

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E pidemiological, clinical, and experimental data strongly support the idea of a causative role of hepatitis C virus (HCV) in the development of B-cell lymphoproliferative diseases in chronic virus carriers. These diseases include type II mixed cryoglobulinemia (MC), a benign B-cell proliferative disorder with monoclonal B-cell expansions, and a subgroup of B-cell non-Hodgkin lymphomas (B-NHL) (1-6). The mechanisms by which chronic HCV infection affects B-cell differentiation and predisposes patients to the occurrence of premalignant and malignant B-cell lymphoproliferations are still poorly understood. One potential mechanism is the antigen-driven proliferation of HCV-specific B cells. This is supported by the finding of restricted immunoglobulin (Ig) V gene usage in B-cell clones in MC and HCV-associated B-cell lymphomas, and the direct demonstration of B-cell receptor specificity of some HCV-associated lymphomas for HCV antigens (7-10). It is also noteworthy that in livers of chronic HCV carriers, B-cell follicles resembling in several aspects ectopic germinal centers (GC) are found, indicating chronic HCV-driven B-cell proliferation in this organ (11).Another-not mutually exclusive-hypothesis suggests that there is a direct mutagenic effect of HCV on B cells, which might promote B-cell transformation. This idea is mainly based on in vitro studies, in which human B-cell lines were exposed to HCV virions. It was reported that in this setting, HCV activates the enzyme activation-induced cytidine deaminase (AID), which is the key factor for somatic hypermutation of Ig V genes (12). Somatic hypermutation physiologically also targets the BCL6 protooncogene at a low frequency in the GC reaction, so that about 30% of post-GC memory B cells carry one or more mutations in the major mutation cluster in intron 1 of BCL6 (13). In the in vitro studies, enhanced BCL6 mutations were observed in the B-cell lines (12). Besides, HCV can also induce oxidative stress, with accumulation of nitrogen and oxygen reactive species which lead to DNA damage (14-16). TP53 and ␤ catenin (CTNNB1) were identified as target genes of the reactive oxygen species with remarkably high mutation accumulation in the in vitro studies (mutation frequencies of 5 to 11 ϫ 10 Ϫ4 /bp) (12,14). Notably, mutations in TP53, CTNNB1, and BCL6 were also identified in peripheral blood mononuclear cells (PBMC) of HCV-positive patients (12), although only about 10% of PBMC are B cells. As TP53 is a tumor suppressor gene and BCL6 and CTNNB1 are protooncogenes, mutations in these genes might be of pathogenetic relevance.Regarding the reported mutagenic effect of HCV, it should be mentioned that it is still controversially discussed whether HCV indeed infects B cells and induces mutations by a hit-and-run mechanism, or whether the effects seen are due to the binding of HCV to costimulatory receptors expressed on the surface of B cells, such as CD81 (17)(18)(19)(20)(21)(22)(23)(24).In the present work, we aimed to clarify whether the mutagenic effect of HCV on TP53, C...

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Section: Hepatitis C Virus (Hcv) Is Considered To Have a Causative Romentioning

confidence: 99%

B Cells in Chronically Hepatitis C Virus-Infected Individuals Lack a Virus-Induced Mutation Signature in theTP53,CTNNB1, andBCL6Genes

Tucci

Broering

Johansson

et al. 2013

J Virol

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“…A possible consequence is a mono-or polyclonal B-cell expansion with the production of a wide spectrum of autoantibodies and circulating immune complexes [33,34,[39][40][41][42]. Mixed cryoglobulinaemia is the immuno-lymphoproliferative disorder in which a clear-cut association with HCV infection has been largely demonstrated [32,33,42,43]. Clinical manifestations of mixed cryoglobulinaemia, namely purpura, skin ulcers, peripheral neuropathy, membranoproliferative glomerulonephritis, etc., are the effect of the vasculitis secondary to deposition of HCV-containing immune complexes and complement in the smallmedium vessels [41][42][43].…”

Section: Chronic Hcv Infectionmentioning

confidence: 99%

“…Mixed cryoglobulinaemia is the immuno-lymphoproliferative disorder in which a clear-cut association with HCV infection has been largely demonstrated [32,33,42,43]. Clinical manifestations of mixed cryoglobulinaemia, namely purpura, skin ulcers, peripheral neuropathy, membranoproliferative glomerulonephritis, etc., are the effect of the vasculitis secondary to deposition of HCV-containing immune complexes and complement in the smallmedium vessels [41][42][43]. Mixed cryoglobulinaemia is relatively more frequent in Italy and Southern Europe than in other Western countries; this geographical heterogeneity suggests the contribution of other unknown infectious, genetic and environmental factors, together with a variable role of different HCV genotypes [33,44].…”

Section: Chronic Hcv Infectionmentioning

confidence: 99%

Viruses and cancers: possible role of hepatitis C virus

Ferri

Civita

Zignego

et al. 1997

Eur J Clin Investigation

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Abstract. Oncogenesis is a multifactorial process in which environmental, genetic and infectious factors are variably involved. A possible role of specific viruses has been suggested in at least 15% of human cancers. Hepatitis C virus (HCV), which is both hepato-and lymphotropic, is responsible for various liver disorders, i.e. chronic hepatitis, cirrhosis and hepatocellular carcinoma, as well as for a constellation of extrahepatic immune-mediated manifestations, among which is mixed cryoglobulinaemia. This is a systemic disorder secondary to a chronic, benign B-lymphocyte proliferation, which in some subjects may evolve to a malignant non-Hodgkin's lymphoma (NHL). Interestingly, recent studies reported the appearance of malignant B-cell neoplasias in patients with type C chronic hepatitis; moreover, in a significant number (from 22% to 50%) of 'idiopathic' NHLs, the presence of HCV infection has been demonstrated. The presence of a geographical etherogeneity in the prevalence of HCV-positive NHL suggests that other co-factors, i.e. genetic and environmental, could be involved in the lymphomagenesis. HCV may exert its oncogenic potential in two different directions, leading to liver cancer or B-cell lymphoma.

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“…More recently, HCV has been implicated as the causative agent of mixed cryoglobulinemia and in the pathogenesis of B-cell non-Hodgkin's lymphoma (1,27,28,34). The high frequency of chronic infection suggests that an effective antiviral immune response is not initiated or maintained and that virus-mediated immune evasion strategies may be operating.…”

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confidence: 99%

Hepatitis C Virus Glycoproteins Interact with DC-SIGN and DC-SIGNR

Pöhlmann

Zhang²,

Baribaud

et al. 2003

J Virol

344

263

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Hepatitis C virus (HCV) is an enveloped, positive-stranded RNA virus classified in the family Flaviviridae. Infection is often associated with chronic disease, sometimes resulting in hepatitis, cirrhosis, and hepatocellular carcinoma. Although chronic infection occurs in up to 70% of individuals, the mechanisms leading to viral persistence have not been defined. The principal site of replication is thought to be the liver, although several laboratories have suggested that HCV may infect a wider range of cell types, including monocytes/macrophages and B cells (28,33,44).HCV encodes two putative envelope glycoproteins, E1 and E2, which are believed to be type I integral transmembrane proteins with C-terminal hydrophobic anchor domains. In vitro expression studies have shown that both glycoproteins associate to form heterodimers, which accumulate in the endoplasmic reticulum, the proposed site for HCV assembly and budding (reviewed in reference 53). Being an enveloped virus, HCV likely interacts with specific cell surface receptors that either induce conformational changes in the E1 and E2 glycoproteins, resulting in fusion between the viral and cellular membranes, or mediate internalization of virus particles to endosomes, where the acidic environment triggers membrane fusion-inducing conformational changes. The E2 glycoprotein is thought to be responsible for initiating virus attachment (29,54,67,71), and we have hypothesized that the E1 glycoprotein contains the fusion peptide responsible for mediating fusion of the virus and cell membranes (31).The lack of in vitro systems for HCV propagation has hampered biological and physiochemical studies of the virion and its mechanism of cell entry, so that the cellular receptors remain unknown. Difficulties encountered in purifying sufficient quantities of HCV from plasma have limited studies with native virus. In addition, HCV purified from plasma has been reported to exist in association with immune complexes and plasma lipoproteins (2, 6, 57). The association of the virus with lipoproteins has led to the suggestion that HCV may use the low-density lipoprotein receptor to gain entry into cells (3,71).In the absence of native HCV particles, virus-like particles expressed in insect cell systems (11,15,63,67) and truncated versions of the E2 glycoprotein have been used as mimics to study virus-cell interactions (29,54,58). Truncated E2 binds specifically to human cells and was used to identify CD81 as a putative receptor for some HCV strains (54). Recent reports suggest antigenic differences between the truncated form of E2 and that present on virus-like particles for reactivity with E2-specific monoclonal antibodies and CD81 (15,63,67). Since CD81 is expressed on the majority of cell types, it is unlikely to be the sole determinant of viral tropism, and additional cell surface molecules may be required for HCV entry into a target cell (45).While virus receptors typically play important roles in defining virus tropism, other cell surface molecules can significantly enhanc...

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Hepatitis C Virus and Mixed Cryoglobulinaemia

Cited by 35 publications

References 0 publications

B Cells in Chronically Hepatitis C Virus-Infected Individuals Lack a Virus-Induced Mutation Signature in theTP53,CTNNB1, andBCL6Genes

B Cells in Chronically Hepatitis C Virus-Infected Individuals Lack a Virus-Induced Mutation Signature in theTP53,CTNNB1, andBCL6Genes

Viruses and cancers: possible role of hepatitis C virus

Hepatitis C Virus Glycoproteins Interact with DC-SIGN and DC-SIGNR

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