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-chain sequences on 17 hepatitis C virus (HCV)-associated non-Hodgkin lymphomas (NHLs) (9 patients also had type II mixed cryoglobulinemia [MC] syndrome and 8 had NHL unrelated to MC) and analysis of intraclonal diversity on 8 of them suggest that such malignant lymphoproliferations derive from an antigen-driven pathologic process, with a selective pressure for the maintenance of a functional IgR and a negative pressure for additional amino acid mutations in the framework regions (FRs). For almost all NHLs, both heavy- and light-chain complementarity-determining regions (CDR3) showed the highest similarity 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 acid sequences of some HCV-associated NHLs also present a high homology for antibody specific for the E2 protein of HCV, it may be reasonable to speculate that HCV E2 protein is one of the chronic antigenic stimuli involved in the lymphomagenetic process. Finally, the use of specific segments, in particular the D segment, in assembling the IgH chain of IgR seems to confer B-cell disorders with the property to produce antibody with RF activity, which may contribute to the manifestation of an overt MC syndrome.
De Re
V
V
Divisions of Experimental Oncology 1, Medical Oncology, and Pathology, Centro di Riferimento Oncologico, Aviano, Italy.
De Vita
S
S
Marzotto
A
A
Rupolo
M
M
Gloghini
A
A
Pivetta
B
B
Gasparotto
D
D
Carbone
A
A
Boiocchi
M
M
D000368:Aged; D001483:Base Sequence; D019070:Cell Lineage / Q000276:immunology; D002999:Clone Cells; D022801:Complementarity Determining Regions / Q000737:chemistry / Q000235:genetics; D003449:Cryoglobulinemia / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015321:Gene Rearrangement; D016174:Hepacivirus / Q000276:immunology*; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry / Q000235:genetics; D007147:Immunoglobulin Light Chains / Q000737:chemistry / Q000235:genetics; D007145:Immunoglobulin kappa-Chains / Q000737:chemistry / Q000235:genetics; D008228:Lymphoma, Non-Hodgkin / Q000209:etiology* / Q000276:immunology* / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000737:chemistry / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000737:chemistry / Q000235:genetics; D011961:Receptors, Fc / Q000737:chemistry / Q000235:genetics; D012217:Rheumatoid Factor / Q000378:metabolism; D020539:Sequence Analysis, Protein
D022801:Complementarity Determining Regions; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D007145:Immunoglobulin kappa-Chains; D009363:Neoplasm Proteins; D011947:Receptors, Antigen, B-Cell; D011961:Receptors, Fc; D012217:Rheumatoid Factor