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: 10.43). 03/2008; 111(3):1344-56. DOI: 10.1182/blood-2007-07-101717
Source: PubMed

ABSTRACT 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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Available from: Svetlana Marukian, Aug 10, 2015
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    • "AID is induced by nuclear factor kappa B activation via both HCV and HP, causing gene mutations in Ig and non-Ig genes, consistent with the notion that HCV and HP drive B-cell proliferation and directly modulate cellular function, thus giving cell growth advantages and resistance to apoptosis [4]. In fact, HCV infection is associated with proliferation of B-cells expressing CD5 and/or IgM [8], and lymphoid aggregates or less frequent plasmacytosis in the bone marrow is found in over 30% of HCV-infected patients [5]. Thus, it is possible that in our case, CD5-positive B-cells had differentiated to IgM plasma cells under the influence of HCV infection. "
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    ABSTRACT: A 71-year-old Japanese male patient infected with HCV was diagnosed with thrombocytopenia. Histological examination of the bone marrow aspirate showed numerous lymphoid aggregates with Russell bodies. Immunohistochemistry and flow cytometric analysis demonstrated clonal expansion of CD5+ CD23+ B cells. Russell bodies were positive for IgM and lambda immunoglobulin light chain. The patient also underwent gastric biopsy, which revealed Helicobacter pylori (HP) infection. Subsequent eradication of the bacteria resulted in improvement of his thrombocytopenia. The clinical course remained uneventful at 15-month follow-up, consistent with monoclonal B-cell lymphocytosis. The observed clonal expansion with plasmacytic differentiation may have occurred under the influence of HCV with HP infection.
    03/2011; 2011:814372. DOI:10.1155/2011/814372
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    • "ever, despite the fact that a wealth of information on T-cell immunity has been generated over the past several years, only limited data are available on the phenotypic and functional status of B cells in these conditions, with most studies predominantly focusing on HCV-induced cryoglobulinemia [8] [9] [10] [11] [12] [13] [14] [15]. In consideration of the limited information on B-cell phenotype and the virtual absence of correlative functional data on differentiation and proliferative capacity in viral hepatitis, we have performed a phenotypic and functional analysis in a substantial number of patients with chronic HBV and HCV infections with the intent of gaining important insights into B-cell pathobiology in these conditions. "
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    ABSTRACT: Chronic microbial infections are frequently associated with B-cell activation and polyclonal proliferation, potentially leading to autoimmunity and lymphoproliferative disorders. We assessed B-cell phenotype and function in chronic hepatitis B (HBV) and chronic hepatitis C (HCV) virus infection. We studied 70 patients with chronic HCV infection, 34 with chronic HBV infection and 54 healthy controls. B-cell phenotype was assessed by flow cytometry using monoclonal antibodies specific for CD27, the CD69, CD71, and CD86 activation markers and the chemokine receptor CXCR3. Differentiation into immunoglobulin-producing cells (IPC) was analysed by ELISpot upon stimulation and with CD40 ligand±IL-10 as surrogate bystander T-cell help or CpG oligodeoxynucleotide±IL-2, as innate immunity signal. Proliferation was examined by flow cytometry using carboxyfluorescein diacetate succinimidyl ester (CFSE) after stimulation with CpG. A significantly higher proportion of B cells from both HCV- and HBV-infected patients expressed activation markers compared with controls and a positive correlation was found between CXCR3(+) B cells and HCV RNA values. Memory B cells from patients with chronic HCV and HBV infections showed enhanced differentiation into IPC compared with controls, although this was restricted to IgG and at a lower level in HCV-compared with HBV-infected patients. Moreover, patients' activated B cells displayed significantly lower proliferative ability compared to healthy donors despite low expression of the FcRL4 exhaustion marker. B-cell activation, but not exhaustion, is common in chronic viral hepatitis. However, enhanced B-cell differentiation and deficient proliferative capacity were not associated with commitment to terminal differentiation.
    Journal of Hepatology 11/2010; 55(1):53-60. DOI:10.1016/j.jhep.2010.10.016 · 10.40 Impact Factor
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