B-cell frequency in hepatitis C virus-related mixed cryoglobulinemia

Hepatitis C virus (HCV) chronic infection is recognized as the major cause of mixed cryoglobulinemia (MC). Its persistence represents a continuous stimulus for host immune system with production of circulating immune complexes (ICs), one-third of them with cryoprecipitate property. Several factors contribute to the biological activities of ICs, many of which are not completely known. Among them, complement factors play a crucial role in the cold-insoluble ICs-mediated vasculitis, involving primarily small blood vessels in different tissues including skin, kidney, peripheral, and central nervous system. Liver represents the major target of HCV infection with inflammatory infiltrates, resembling secondary lymphoid follicles. Cytokine like CXCL13 contribute to B-cell homing in intraportal lymphoid aggregates, in which B-cell clonal selection may arise. B-cell clonal expansion starts as an antigen-driven event and expands towards indolent and malignant B-cell proliferation. Occurrence of intrahepatic B-cell clonalities correlates with extrahepatic clinical manifestations of HCV infection. In this context, cryoglobulinemic patients should be considered a peculiar HCV-infected population that needs a clinical multidisciplinary approach and more articulated therapeutic measures.

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Prevalence of hepatitis C virus infection in patients with lymphoproliferative disorders

Blood ◽

10.1182/blood.v87.10.4296.bloodjournal87104296 ◽

1996 ◽

Vol 87 (10) ◽

pp. 4296-4301 ◽

Cited By ~ 237

Author(s):

F Silvestri ◽

C Pipan ◽

G Barillari ◽

F Zaja ◽

R Fanin ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

B Cell ◽

Close Association ◽

Mixed Cryoglobulinemia ◽

Lymphoproliferative Disorders ◽

Hcv Infection ◽

Hcv Rna ◽

Hodgkin's Lymphomas ◽

Hcv Genotyping

It has been recently hypothesized that the hepatitis C virus (HCV) might be involved in the pathogenesis of malignant B-cell non-Hodgkin's lymphomas (NHL). On the basis of this observation we sought to determine the prevalence of HCV infection in the patients affected by B- cell NHL and extended our analysis to all the patients affected by lymphoproliferation disorders seen at our institution in the last 30 months. Five hundred and thirty-seven unselected, consecutive patients were studied. HCV infection was investigated through detection of anti- HCV antibodies and HCV-RNA. HCV genotyping was performed on HCV-RNA positive specimens. The risk of being infected by HCV was compared with that of the general population of our area. Among all lymphoproliferative disorders, the prevalence and the relative risk (RR) of being infected by HCV were increased only among B-cell NHL (9%; RR 3.24; p < .0001). Among these, a strong prevalence of HCV was found only in the subgroup of immunocytomas (30%; RR 10.27; P < .0001), while other histotypes were associated with it only occasionally. Because HCV- positive lymphomas clinically behave as essential mixed cryoglobulinemia (EMC), the close association between HCV infection and EMC is confirmed, and evidence is provided that the pathological substrate of EMC corresponds to the immunocytoma. HCV genomic sequences were found in 84% of patients analyzed. Viral genotypes were those more frequent in our area.

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Malignant B-cell lymphoma as possible evolution of mixed cryoglobulinemia associated with hepatitis C virus infection

Biomedicine & Pharmacotherapy ◽

10.1016/0753-3322(93)90199-u ◽

1993 ◽

Vol 47 (6-7) ◽

pp. 274

Author(s):

Luca La Civita ◽

Giovanni Longombardo ◽

Francesco Lombardini ◽

Francesco Greco ◽

Alessandro Mazzoni ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Virus Infection ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Mixed Cryoglobulinemia ◽

Hepatitis C Virus Infection

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Characterization of Antibodies Directed against the Immunoglobulin Light κ Chain Variable Chain Region (VK) of Hepatitis C Virus-Related Type-II Mixed Cryoglobulinemia and B-Cell Proliferations

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.2009.04677.x ◽

2009 ◽

Vol 1173 (1) ◽

pp. 152-160 ◽

Cited By ~ 10

Author(s):

Valli De Re ◽

Maria Paola Simula ◽

Alessandro Pavan ◽

Marica Garziera ◽

Dolores Marin ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

B Cell ◽

Mixed Cryoglobulinemia ◽

Type Ii ◽

Cell Proliferations

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Clonal B cells in patients with hepatitis C virus–associated mixed cryoglobulinemia contain an expanded anergic CD21low B-cell subset

Blood ◽

10.1182/blood-2010-10-312942 ◽

2011 ◽

Vol 117 (20) ◽

pp. 5425-5437 ◽

Cited By ~ 118

Author(s):

Edgar D. Charles ◽

Claudia Brunetti ◽

Svetlana Marukian ◽

Kimberly D. Ritola ◽

Andrew H. Talal ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

B Cells ◽

B Cell ◽

Rheumatoid Factor ◽

Transcriptional Profiling ◽

Cell Subset ◽

Mixed Cryoglobulinemia ◽

Memory B Cell ◽

Peripheral B Cells

Abstract Hepatitis C virus (HCV) is associated with the B-cell lymphoproliferative disorders mixed cryoglobulinemia (MC) and non-Hodgkin lymphoma. We have previously reported that HCV+MC+ patients have clonal expansions of hypermutated, rheumatoid factor–bearing marginal zone-like IgM+CD27+ peripheral B cells using the VH1-69 gene. Here we coupled transcriptional profiling with immunophenotypic and functional studies to ascertain these cells' role in MC pathogenesis. Despite their fundamental role in MC disease, these B cells have overall transcriptional features of anergy and apoptosis instead of neoplastic transformation. Highly up-regulated genes include SOX5, CD11C, galectin-1, and FGR, similar to a previously described FCRL4+ memory B-cell subset and to an “exhausted,” anergic CD21low memory B-cell subset in HIV+ patients. Moreover, HCV+MC+ patients' clonal peripheral B cells are enriched with CD21low, CD11c+, FCRL4high, IL-4Rlow memory B cells. In contrast to the functional, rheumatoid factor–secreting CD27+CD21high subset, the CD27+CD21low subpopulation exhibits decreased calcium mobilization and does not efficiently differentiate into rheumatoid factor–secreting plasmablasts, suggesting that a large proportion of HCV+MC+ patients' clonally expanded peripheral B cells is prone to anergy and/or apoptosis. Down-regulation of multiple activation pathways may represent a homeostatic mechanism attenuating otherwise uncontrolled stimulation of circulating HCV-containing immune complexes. This study was registered at www.clinicaltrials.gov as #NCT00435201.

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A 385 insertion in the hypervariable region 1 of hepatitis C virus E2 envelope protein is found in some patients with mixed cryoglobulinemia type 2

Blood ◽

10.1182/blood.v98.9.2657 ◽

2001 ◽

Vol 98 (9) ◽

pp. 2657-2663 ◽

Cited By ~ 20

Author(s):

Martina Gerotto ◽

Francesca Dal Pero ◽

Stefano Loffreda ◽

Francesco B. Bianchi ◽

Alfredo Alberti ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

B Cell ◽

Hypervariable Region ◽

Mixed Cryoglobulinemia ◽

Immunoglobulin M ◽

Host Cells ◽

Control Group ◽

Hypervariable Region 1

AbstractChronic hepatitis C virus (HCV) infection has been associated with development of mixed cryoglobulinemia type 2 (MC2), a lymphoproliferative disorder characterized by B cell monoclonal expansion and immunoglobulin M/k cryoprecipitable immunoglobulin production. A short sequence (codons 384-410) of the HCV E2 protein, which has the potential to promote B cell proliferation, was investigated in 21 patients with HCV-related MC2 and in a control group of 20 HCV carriers without MC2. In 6 of the 21 (29%) patients with MC2, all the clones isolated from plasma, peripheral blood mononuclear cells, and liver showed sequence length variation compared with the hypervariable region 1 (HVR1) consensus sequence; 5 patients had an insertion at codon 385, and 1 patient had a deletion at codon 384. Inserted residues at position 385 were different within and between patients. No such mutations were observed in any of the HVR1 clones from control patients without MC2, and the difference between the 2 groups was statistically significant (P = .02). Analysis of 1345 HVR1 sequences obtained from GenBank strongly supported the conclusion that the observed insertions and deletion represent a rare event in HCV-infected patients, suggesting that they are significantly associated with MC2. The physical and chemical profiles of the 385 inserted residues detected in the MC2 patients were consistent with the possibility that these mutations, which occurred in a region containing immunodominant epitopes for neutralizing antibodies and binding sites for B lymphocytes, may be selected by functional constraints for interaction with host cells.

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Hepatitis C virus within a malignant lymphoma lesion in the course of type II mixed cryoglobulinemia

Blood ◽

10.1182/blood.v86.5.1887.bloodjournal8651887 ◽

1995 ◽

Vol 86 (5) ◽

pp. 1887-1892 ◽

Cited By ~ 122

Author(s):

S De Vita ◽

D Sansonno ◽

R Dolcetti ◽

G Ferraccioli ◽

A Carbone ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

B Cell ◽

Human Herpesvirus ◽

Mixed Cryoglobulinemia ◽

Hcv Infection ◽

Etiologic Factor ◽

Type Ii ◽

B Cell Malignancies

Hepatitis C virus (HCV) has been implicated as the major etiologic factor sustaining B-cell clonal expansion in type II mixed cryoglobulinemia (MC). A putative pathogenetic role of HCV in the development of MC-associated B-cell malignancies has also been speculated. We report for the first time the localization of HCV within a parotid non-Hodgkin's lymphoma (NHL) lesion in the course of HCV- related type II essential MC, an important step to implicate any infectious agent in the lymphomagenesis. Plus and minus strand HCV RNA was first demonstrated by polymerase chain reaction on the whole RNA from the lesion. Further immunohistochemical studies localized HCV c22 proteins in the residual ductal or acinar parotid structures, which also abnormally expressed HLA-DR antigens. Weak c22 signals were inconstantly detected in cells strictly confined around the residual epithelium, while all the remaining infiltrating cells in the parotid lesion stained c-22-negative. Staining for c33 and c100 HCV antigens was negative. In situ hybridization (ISH) studies again identified the residual parotid epithelial cells as the site of HCV infection and replication in the NHL lesion. Sialotropic viruses previously involved in lymphoproliferation, ie, Epstein-Barr virus and human herpesvirus-6, were absent in the same tissue lesion. According to the current models of B-cell lymphomagenesis, a role of HCV as an exogenous antigenic stimulus should be considered for NHL development in the present case, whereas malignant B cells do not appear permissive of active HCV replication. Further efforts would be worthwhile to clarify a role of HCV infection in the development of some B-cell malignancies.

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