{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:06:41Z","timestamp":1792109201143,"version":"4.4.0"},"reference-count":58,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2005,5,1]],"date-time":"2005-05-01T00:00:00Z","timestamp":1114905600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2005,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Chronic hepatitis C virus infection causes B cell lymphoproliferative disorders that include type II mixed cryoglobulinemia and lymphoma. This virus drives the monoclonal expansion and, occasionally, the malignant transformation of B cells producing a polyreactive natural Ab commonly encoded by the VH1\u201369 variable gene. Owing to their property of producing natural Ab, these cells are reminiscent of murine B-1 and marginal zone B cells. We used anti-Id Abs to track the stages of differentiation and clonal expansion of VH1\u201369+ cells in patients with type II mixed cryoglobulinemia. By immunophenotyping and cell size analysis, we could define three discrete stages of differentiation of VH1\u201369+ B cells: naive (small, IgMhighIgDhighCD38+CD27\u2212CD21highCD95\u2212CD5\u2212), \u201cearly memory\u201d (medium-sized, IgMhighIgDlowCD38\u2212CD27+CD21lowCD95+CD5+), and \u201clate memory\u201d (large-sized, IgMlowIgDlow-negCD38\u2212CD27lowCD21low-negCD5\u2212CD95\u2212). The B cells expanded in cryoglobulinemia patients have a \u201cmemory\u201d phenotype; this fact, together with the evidence for intraclonal variation, suggests that antigenic stimulation by hepatitis C virus causes the unconstrained expansion of activated VH1\u201369+ B cells. In some cases, these cells replace the entire pool of circulating B cells, although the absolute B cell number remains within normal limits. Absolute monoclonal VH1\u201369+ B lymphocytosis was seen in three patients with cryoglobulinemia and splenic lymphoma; in two of these patients, expanded cells carried trisomy 3q. The data presented here indicate that the hepatitis C virus-driven clonal expansion of memory B cells producing a VH1\u201369+ natural Ab escapes control mechanisms and subverts B cell homeostasis. Genetic alterations may provide a further growth advantage leading to an overt lymphoproliferative disorder.<\/jats:p>","DOI":"10.4049\/jimmunol.174.10.6532","type":"journal-article","created":{"date-parts":[[2014,4,22]],"date-time":"2014-04-22T04:56:19Z","timestamp":1398142579000},"page":"6532-6539","source":"Crossref","is-referenced-by-count":93,"title":["Hepatitis C Virus Drives the Unconstrained Monoclonal Expansion of VH1\u201369-Expressing Memory B Cells in Type II Cryoglobulinemia: A Model of Infection-Driven Lymphomagenesis"],"prefix":"10.1093","volume":"174","author":[{"given":"Maurizio","family":"Carbonari","sequence":"first","affiliation":[{"name":"Department of Clinical Medicine, Division of Clinical Immunology, University of Rome \u201cLa Sapienza\u201d , Rome ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Caprini","sequence":"additional","affiliation":[{"name":"Istituto Dermopatico dell\u2019Immacolata , Rome ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziana","family":"Tedesco","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Division of Clinical Immunology, University of Rome \u201cLa Sapienza\u201d , Rome ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Mazzetta","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Division of Clinical Immunology, University of Rome \u201cLa Sapienza\u201d , Rome ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Tocco","sequence":"additional","affiliation":[{"name":"Istituto Dermopatico dell\u2019Immacolata , Rome ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milvia","family":"Casato","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Division of Clinical Immunology, University of Rome \u201cLa Sapienza\u201d , Rome ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giandomenico","family":"Russo","sequence":"additional","affiliation":[{"name":"Istituto Dermopatico dell\u2019Immacolata , Rome ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Fiorilli","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Division of Clinical Immunology, University of Rome \u201cLa Sapienza\u201d , Rome ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2005,5,15]]},"reference":[{"key":"2025032616424370400_R1","first-page":"35","volume-title":"J. 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