Charles, E. D. et al. Clonal expansion of immunoglobulin M+CD27+ B cells in HCV-associated mixed cryoglobulinemia. Blood 111, 1344-1356

Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, Rockefeller University, New York, NY 10021, USA.
Blood (Impact Factor: 10.45). 03/2008; 111(3):1344-56. DOI: 10.1182/blood-2007-07-101717
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Hepatitis C virus (HCV) is associated with B-cell lymphoproliferative disorders such as mixed cryoglobulinemia (MC) and B-cell non-Hodgkin lymphoma (B-NHL). The pathogenesis of these disorders remains unclear, and it has been proposed that HCV drives the pro-liferation of B cells. Here we demonstrate that certain HCV(+)MC(+) subjects have clonal expansions of immunoglobulin M (IgM)(+)kappa(+)IgD(low/-)CD21(low)CD27(+) B cells. Using RT-PCR to amplify Ig from these singly sorted cells, we show that these predominantly rheumatoid factor-encoding V(H)1-69/J(H)4 and V(kappa)3-20 gene segment-restricted cells have low to moderate levels of somatic hypermutations. Ig sequence analysis suggests that antigen selection drives the generation of mutated clones. These findings lend further support to the notion that specific antigenic stimulation leads to B-cell proliferation in HCV MC and that chronic B-cell stimulation may set the stage for malignant transformation and the development of B-NHL. The finding that these hypermutated, marginal zone-like IgM(+)CD27(+) B cells are clonally expanded in certain subjects with MC offers insight into mechanisms of HCV-associated MC and B-cell malignancy. This study was registered at as NCT00219999.

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    • "In this respect, clonal B cells involved in HCV-associated type II MC as well as in NHL from different patients carry closely homologous (“stereotyped”) complementarity-determining region 3 (CDR3) sequences. In particular, the IGHV1–69, IGHV3–7, IGHV4–59 variable heavy (VH)- and IGKV3–20 and IGKV3–15 variable light (VL)-chain genes are the most represented [20], [22], [23], suggesting a model of antigen-driven origin for such lymphoproliferative disorders with the recognition of a limited subset of HCV antigens [24], [23]. "
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    ABSTRACT: Hepatitis C virus (HCV) has been identified as one of the major risk factors for type II mixed cryoglobulinemia (MC), during the clinical evolution of chronic hepatitis, which may lead to development of B cell non-Hodgkin's lymphoma (NHL). We have previously shown that the candidate idiotype vaccine, based on the IGKV3-20 light chain protein, is able to induce activation and maturation of circulating antigen presenting cells (APCs) in both HCV-positive and HCV-negative healthy control subjects, with production of Th2-type cytokines. Here, the effect of the recombinant IGKV3-20 protein on human peripheral blood mononuclear cells (PBMCs) from HCV-positive subjects, with known blood levels of cryoglobulins, is shown via gene expression profiling analysis combined to multiparameter flow cytometry and multiplex analyses of cytokines.
    PLoS ONE 09/2012; 7(9):e44870. DOI:10.1371/journal.pone.0044870 · 3.23 Impact Factor
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    • "Therefore, it has been postulated that an initial activation of these cells may be followed by the emergence of a dominant clone that synthesize a monoclonal RF supporting the development of type II MC after a transition phase in which an IgM clonal heterogeneity may define a type II-type III variant [17]. In a subset of HCV-positive patients with MC, a clonal expansion of IgM+CD27+ B cells expressing hyper-mutated RF-like Ig has been demonstrated in peripheral blood in association to VH1–69/JH4 and VH3–20 gene segment restriction [51]. These findings have been interpreted as a B-cell proliferation induced by specific antigen stimulation, thus sustaining the notion that persistent B-cell stimulation may represent a first step to malignant evolution. "
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    ABSTRACT: 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.
    Clinical and Developmental Immunology 07/2012; 2012(2):502156. DOI:10.1155/2012/502156 · 2.93 Impact Factor
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    • "Furthermore, it has been observed that the majority of VH1-69-expressing B cells in HCV positive patients had a memory phenotype and express modestly somatically mutated IgM, indicating that a clonal population of memory VH1-69 expressing B cells progressively invades the circulating B-cell compartment of patients with HCV-associated MCII [99]. It has also been reported that the peripheral B-cell repertoire of HCV patients may be represented almost completely by VH1-69 monoclonal B cells [78, 106]. "
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    ABSTRACT: The association between hepatitis C virus (HCV) infection and type II mixed cryoglobulinemia (MCII) is well established, but the role played by distinct HCV proteins and by specific components of the anti-HCV humoral immune response remains to be clearly defined. It is widely accepted that HCV drives the expansion of few B-cell clones expressing a restricted pool of selected immunoglobulin variable (IgV) gene subfamilies frequently endowed with rheumatoid factor (RF) activity. Moreover, the same IgV subfamilies are frequently observed in HCV-transformed malignant B-cell clones occasionally complicating MCII. In this paper, we analyze both the humoral and viral counterparts at the basis of cryoglobulins production in HCV-induced MCII, with particular attention reserved to the single IgV subfamilies most frequently involved.
    Clinical and Developmental Immunology 05/2012; 2012(1):705013. DOI:10.1155/2012/705013 · 2.93 Impact Factor
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