Sequence analysis of the immunoglobulin antigen receptor of hepatitis C virus-associated non-Hodgkin lymphomas suggests that the malignant cells are derived from the rheumatoid factor-producing cells that occur mainly in type II cryoglobulinemia

Analysis of the immunoglobulin receptor (IGR) variable heavy- and light-cha in sequences on 17 hepatitis C virus (HCV)associated non-Hodgkin lymphomas (NHLs) (9 patients also had type II mixed cryoglobulinemia [MC] syndrome an d 8 had NHL unrelated to MC) and analysis of intraclonal diversity on 8 of them suggest that such malignant lymphoproliferations derive from an antige n-driven pathologic process, with a selective pressure for the maintenance of a functional IgR and a negative pressure for additional amino acid mutat ions in the frame-work regions (FRs). For almost all NHLs, both heavy- and light-chain complementarity-determining regions (CDR3) showed the highest s imilarity to antibodies with rheumatoid factor (RF) activity that have been found in the MC syndrome, thus suggesting that a common antigenic stimulus is Involved in MC syndrome and in HCV-associated lymphomagenesis. Moreover , because HCV is the recognized pathologic agent of MC and the CDR3 amino a cid sequences of some HCV-associated NHLs also present a high homology for antibody specific for the E2 protein of HCV; it may be reasonably to specul ate that HCV E2 protein is one of the chronic antigenic stimuli involved in the lymphomagenetic process. Finally, the use of specific segments, in par ticular the a segment, in assembling the IgH chain of IgR seems to confer B -cell disorders with the property to produce antibody with RF activity, whi ch may contribute to the manifestation of an overt WIC syndrome. (C) 2000 b y The American Society of Hematology.