Reply:

Abstract

We wish to thank Giannini et al. for their interest in our work. They now report new data concerning the role of Bcl-2/IgH rearrangement in HCV-infected patients with mixed cryoglobulinemia (MC). Cells that carry t(14;18) translocation can be detected in normal subjects from 20 to 90 years with an incidence ranging from 8 to 80%, respectively,1, 2 indicating that this recombinational event is age-related.3 T(14;18) translocations found in healthy individuals are typical Bcl-2-MBR/JH rearrangements that cannot be distinguished from those found in neoplastic processes (i.e., in follicular lymphoma) and seem to be modulated by ethnic and environmental factors.4, 5 Technical variations may also account for differences in the detection of Bcl-2/JH rearrangement among different laboratories.3 In addition, t(14;18)-positive cells are not persistently detected in non-neoplastic Bcl-2/JH translocation, especially in peripheral leukocytes.6 Chronic hepatitis C virus (HCV) infection is characterized by a large spectrum of B cell abnormalities. Restriction of humoral immune response, as defined by B-cell clonal expansions, occurs in more than half of infected patients7 in whom lymphoproliferative disorders such as mixed cryoglobulinemia, monoclonal gammopathy of undetermined significance, and B cell non-Hodgkin's lymphoma can be frequently detected. More recently, our group has shown a disproportionate distribution of B cell clonotypes in different biological compartments. We have found that the liver is the major site of B cell clonal expansions which may not appear in the bone marrow or in the circulation, sustaining the notion that IgH VDJ mutational activity may be differentially regulated.8 In this context, t(14;18) chromosomal translocation which results in the rearrangement and upregulation of Bcl-2 protein is believed to be of etiological significance in HCV-infected cryoglobulinemic patients.9 However, we were unable to determine Bcl-2/IgH rearrangements either in the liver-recruited inflammatory cells or in circulating lymphocytes of chronic HCV-infected patients. These results indicate that IgH somatic hypermutation and B cell clonal expansions do not associate with t(14;18) chromosomal translocation in our geographical area. Giannini et al. emphasize the strict relationship between HCV and lymphoid cells, and suggest that occult HCV infection persists at the time of clinical resolution. Indeed, their data show active HCV replication in lymphocytes of patients with mixed cryoglobulinemia and sustained biochemical and virological responses. These data corroborate those of other studies10 and confirm the primary role of lymphoid cells in supporting extrahepatic HCV replication.11 Domenico Sansonno M.D.*, Felicia Anna Tucci B.Sc.*, Valli De Re B.Sc. , Gianfranco Lauletta M.D.*, Michele Montrone M.D.*, Massimo Libra M.D. , Franco Dammacco M.D.*, * Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy, Division of Experimental Oncology I, Centro di Riferimento Oncologico, Aviano (PN), Italy.