Infection with hepatitis C virus (HCV), a leading cause of chronic liver diseases, can associate with B lymphocyte proliferative disorders, such as mixed cryoglobulinemia and non-Hodgkin lymphoma. The major envelope protein of HCV (HCV-E2) binds, with high affinity CD81, a tetraspanin expressed on several cell types. Here, we show that engagement of CD81 on human B cells by a combination of HCV-E2 and an anti-CD81 mAb triggers the JNK pathway and leads to the preferential proliferation of the naïve (CD27 ؊ ) B cell subset. In parallel, we have found that B lymphocytes from the great majority of chronic hepatitis C patients are activated and that naïve cells display a higher level of activation markers than memory (CD27 ؉ ) B lymphocytes. Moreover, eradication of HCV infection by IFN therapy is associated with normalization of the activation-markers expression. We propose that CD81-mediated activation of B cells in vitro recapitulates the effects of HCV binding to B cell CD81 in vivo and that polyclonal proliferation of naïve B lymphocytes is a key initiating factor for the development of the HCV-associated B lymphocyte disorders.monoclonal antibody ͉ multimeric engagement ͉ B cell antigen receptor ͉ cryoglobulinemia H epatitis C virus (HCV) is a positive-stranded RNA virus of the Flaviviridae family (1). The HCV genome is 9.6 kb in length, with one large translational ORF encoding a single polyprotein, which is processed by host and viral proteases into at least three structural and seven nonstructural proteins with various enzymatic activities (1). Two heavily N-glycosylated proteins E1 and E2 are virion-envelope proteins and form heterodimers in vitro (2). An estimated 170 million individuals are infected with HCV worldwide (3). HCV infection is associated with the development of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (4). B cell abnormalities, including cryoglobulinemia (5) and an increased risk of B cell non-Hodgkin lymphoma (6, 7), have been reported in a minority of HCV infections.Until very recently, it was not possible to grow HCV in cell culture, therefore studies of virus interaction with human cells have been surrogated by the assessment of binding and entry of HCV recombinant glycoproteins (8) or virus pseudotypes (9).We have previously reported that HCV-E2 protein binds with high affinity to the large extracellular loop of human CD81 (CD81-LEL) and that ''bona fide'' HCV particles bind human CD81 (10). Recently, it has been demonstrated that CD81 is required for entry and infection of human cells by in vitro-generated infectious HCV (11). CD81 is a widely distributed cell-surface tetraspanin that participates in different molecular complexes on various cell types, including B, T, and natural killer (NK) cells (12). On human B cells, CD81 is known to form a costimulatory complex with CD19 and CD21 (13,14) and that coligation of the B cell antigen receptor (BCR) with any of the components of this costimulatory complex lowers the threshold required for BCR-mediated B cell proliferat...

Thalidomide was administered to 83 patients with myelodysplastic syndrome (MDS), starting at 100 mg by mouth daily and increasing to 400 mg as tolerated. Thirtytwo patients stopped therapy before 12 weeks (minimum period for response evaluation), and 51 completed 12 weeks of therapy. International Working Group response criteria for MDS were used to evaluate responses. Intent-to-treat (ITT) analysis classified all off-study patients as nonresponders. Off-study patients belonged to a higher risk category (P ‫؍‬ .002) and had a higher percentage of blasts in their pretherapy bone marrow than patients who completed 12 weeks of therapy (P ‫؍‬ .003). No cytogenetic or complete responses were seen, but 16 patients showed hematologic improvement, with 10 previously transfusion-dependent patients becoming transfusion independent. Responders had lower pretherapy blasts (P ‫؍‬ .016), a lower duration of pretherapy platelet transfusions (P ‫؍‬ .013), and higher pretherapy platelets (P ‫؍‬ .003). Among responders, 9 had refractory anemia (RA); 5 had RA with ringed

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